研究者データベース

久下 裕司(クゲ ユウジ)
アイソトープ総合センター
教授

基本情報

所属

  • アイソトープ総合センター

職名

  • 教授

学位

  • 博士(京都大学)

科研費研究者番号

  • 70321958

J-Global ID

研究キーワード

  • 分子イメージング   放射線   動脈硬化   腫瘍   癌   ポジトロンCT(PET)   シングルフォトンCT(SPECT)   治療   インビボイメージング   inflammation   鑑別診断   移植・再生医療   炎症   マイクロ・ナノデバイス   脳虚血病態   薬学   医療・福祉   放射性薬品化学・核医学・脳循環代謝学・病態分析学   Pathofunctional Bioanalysis   Nuclear Medicine   Molecular Imaging   Radiopharmaceutical   

研究分野

  • ライフサイエンス / 放射線科学
  • ライフサイエンス / 薬系分析、物理化学
  • ライフサイエンス / 放射線科学
  • ライフサイエンス / 薬系分析、物理化学

職歴

  • 2009年 - 現在 北海道大学アイソトープ総合センター 教授
  • 2007年 - 2009年 北海道大学大学医学研究科 教授
  • 2002年 - 2007年 京都大学大学院薬学研究科 助教授
  • 1999年04月 - 2002年 北海道大学大学院医学研究科 教員(客員助教授)

学歴

  •         - 1987年   京都大学   薬学系研究科   放射性薬品化学
  •         - 1987年   京都大学
  •         - 1985年   京都大学   薬学部   製薬化学科放射性薬品化学専攻
  •         - 1985年   京都大学

所属学協会

  • 国際放射性薬品科学会   日本分子イメージング学会   日本放射線安全管理学会   米国核医学会   日本脳循環代謝学会   日本薬理学会   日本薬学会   日本核医学会   

研究活動情報

論文

  • A novel PET probe “[18F]DiFA” accumulates in hypoxic region via glutathione conjugation following reductive metabolism.
    Shimizu Y, Zhao S, Yasui H, Nishijima K, Matsumoto H, Shiga T, Tamaki N, Ogawa M, Kuge Y
    Mol Imaging Biol 21 1 122 - 129 2019年 [査読有り][通常論文]
  • Glutathione and cysteines suppress cytotoxicity of gas phase of cigarette smoke by direct reacting with unsaturated carbonyl compounds in the gas phase.
    Higashi T, Elmeligy E, Mai Y, Noya Y, Terada K, Mazaki Y, Kuge Y, Miwa S
    Biochem Biophys Res Commun. 509 4 988 - 993 2019年 [査読有り][通常論文]
  • Comparative evaluation of [18F]DiFA and its analogs as novel hypoxia positron emission tomography and [18F]FMISO as the standard.
    Nakata N, Kiriu M, Okumura Y, Zhao S, Nishijima KI, Shiga T, Tamaki N, Kuge Y, Matsumoto H
    Nucl Med Biol. 70 39 - 45 2019年 [査読有り][通常論文]
  • Voxel based comparison and texture analysis of 18F-FDG and 18F-FMISO PET of patients with head-and-neck cancer.
    Kroenke M, Hirata K, Gafita A, Watanabe S, Okamoto S, Magota K, Shiga T, Kuge Y, Tamaki N
    PLoS One 14 2 e0213111  2019年 [査読有り][通常論文]
  • Accumulation of hypoxia imaging probe "18F-FMISO" in macrophages depends on macrophage polarization in addition to hypoxic state.
    Shimizu Y, Motomura A, Takakura H, Tamaki N, Kuge Y, Ogawa M
    Ann Nucl Med. 33 5 362 - 367 2019年 [査読有り][通常論文]
  • Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models
    Zhao S, Yu W, Ukon N, Tan C, Nishijima KI, Shimizu Y, Higashikawa K, Shiga T, Yamashita H, Tamaki N, Kuge Y
    EJNMMI Res. 9 1 51  2019年 [査読有り][通常論文]
  • Biodistribution and radiation dosimetry of the novel hypoxia PET probe [18F]DiFA and comparison with [18F]FMISO
    Watanabe S, Shiga T, Hirata K, Magota K, Okamoto S, Toyonaga T, Higashikawa K, Yasui H, Kobayashi J, Nishijima KI, Iseki K, Matsumoto H, Kuge Y, Tamaki N
    EJNMMI Res. 9 1 60  2019年 [査読有り][通常論文]
  • Yamasaki K, Yamashita A, Zhao Y, Shimizu Y, Nishii R, Kawai K, Tamaki N, Zhao S, Asada Y, Kuge Y
    Nucl Med Biol 56 21 - 25 2018年 [査読有り][通常論文]
  • Komatsu Y, Nishijima K, Oomagari S, Kanai Y, Naka S, Higashikawa K, Ebita Y, Shiga T, Hatazawa J, Tamaki N, Kuge Y
    RADIOISOTOPES 67 75 - 83 2018年 [査読有り][通常論文]
  • [18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia.
    Tan C, Zhao S, Higashikawa K, Wang Z, Kawabori M, Abumiya T, Nakayama N, Kazumata K, Ukon N, Yasui H, Tamaki N, Kuge Y, Shichinohe H, Houkin K
    EJNMMI Res 8 1 35  2018年 [査読有り][通常論文]
  • Anti PD-1 treatment increases [18F]FDG uptake by cancer cells in a mouse B16F10 melanoma model.
    Tomita M, Yasui H, Higashikawa K, Nakajima K, Takakura H, Shiga T, Kuge Y, Ogawa M
    EJNMMI Res 8 1 82  2018年 [査読有り][通常論文]
  • Relationship between intelligence quotient (IQ) and cerebral metabolic rate of oxygen in patients with neurobehavioural disability after traumatic brain injury.
    Abiko K, Shiga T, Katoh C, Hirata K, Kuge Y, Kobayashi K, Ikeda S, Ikoma K
    Brain Inj 32 11 1367 - 1372 2018年 [査読有り][通常論文]
  • Nobuhiro Oshima, Hiromichi Akizawa, Hirotake Kitaura, Hidekazu Kawashima, Songji Zhao, Yan Zhao, Ken-ichi Nishijima, Yoji Kitamura, Yasushi Arano, Yuji Kuge, Kazue Ohkura
    NUCLEAR MEDICINE AND BIOLOGY 54 18 - 26 2017年11月 [査読有り][通常論文]
     
    Introduction: In-111-DTPA-D-Phe(1)-octreotide scintigraphy is an important method of detecting neuroendocrine tumors. We previously reported that a new derivative of In-111-DTPA-D-Phe(1)-octreotide, In-111-DTPA-D-Phe(-1)-Asp(0)-D-Phe(1)-octreotide, accomplished the reduction of prolonged renal accumulation of radioactivity. The aim of this study was to evaluate the tumor accumulation of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide in vitro and in vivo by comparing it with In-111-DTPA-D-Phe(1)-octreotide. Methods: The tumor accumulation of this octreotide derivative was determined by measuring its uptake using cultured AR42J cells in vitro and biodistribution studies in vivo. The distribution of the radiotracer and the extent of somatostatin receptor-specific uptake in the tumor were estimated by a counting method using AR42J tumor-bearing mice. The radioactive metabolite species in the tumor and kidney were identified by HPLC analyses at 3 and 24 h post-injection of the In-111-DTPA-conjugated peptide. Results: In both cases, in vitro and in vivo, the tumor radioactivity levels of In-111-DTPA-D-Phe(-1)-Asp-D-Phe-loctreotide were approximately 2-4 times higher than those of In-111-DTPA-D-Phe(1)-octreotide. On in vitro cellular uptake inhibition and radioreceptor assay, In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide exhibited a binding affinity to somatostatin receptor highly similar to that of In-111-DTPA-D-Phe(1)-octreotide. As the additional cellular uptake of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide was significantly lower at low temperature than at 37 degrees C, it was considered that a cellular uptake pathway is involved in energy-dependent endocytotic processes. In the radiometabolite analysis of In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide, In-111-DTPA-D-Phe-Asp-OH was a major metabolite in the tumor at 24 h post-injection. Conclusion: In-111-DTPA-D-Phe(-1)-Asp-D-Phe(1)-octreotide exhibited higher tumor accumulation and persistence of tumor radioactivity than In-111-DTPA-D-Phe(1)-octreotide. We reasoned that this higher tumor accumulation would not be based on the receptor affinity but on a receptor-mediated endocytotic process involved in temperature-dependent cellular uptake. The present study demonstrated the great potential of the pharmaceutical development of a new radiolabeled peptide with high tumor accumulation and low renal radioactivity by the chemical modification of In-111-DTPA-D-Phe(1)-octreotide. (C) 2017 Elsevier Inc. All rights reserved.
  • Yukiko Masaki, Yoichi Shimizu, Takeshi Yoshioka, Ken-ichi Nishijima, Songji Zhao, Kenichi Higashino, Yoshito Numata, Nagara Tamaki, Yuji Kuge
    ANNALS OF NUCLEAR MEDICINE 31 8 596 - 604 2017年10月 [査読有り][通常論文]
     
    Objective F-18-fluoromisonidazole (FMISO), a well-known PET imaging probe for diagnosis of hypoxia, is believed to accumulate in hypoxic cells via covalent binding with macromolecules after reduction of the nitro group. Previously, we showed the majority of F-18-FMISO was incorporated into low-molecular-weight metabolites in hypoxic tumors, and the glutathione conjugate of reduced FMISO (amino-FMISO-GS) distributed in the tumor hypoxic regions as revealed by imaging mass spectrometry (IMS). The present study was conducted to clarify whether FMISO is metabolized to amino-FMISO-GS within tumor cells and how amino-FMISO-GS contributes to FMISO accumulation in hypoxic cells. We also evaluated the relationship between FMISO accumulation and the glutathione conjugation-related factors in the cells. Methods Tumor cells (FaDu, LOVO, and T24) were treated with F-18-FMISO and incubated under normoxic or hypoxic conditions for 4 h. The FMISO metabolites were analyzed with LC-ESI-MS. Several glutathione conjugation-related factors of tumor cells were evaluated in vitro. FaDu tumor-bearing mice were intravenously injected with F-18-FMISO and the tumors were excised at 4 h post-injection. Autoradiography, IMS and histologic studies were performed. Results Amino-FMISO-GS was the main contributor to FMISO incorporated in hypoxic FaDu cells in vitro and in vivo. Total FMISO uptake levels and amino-FMISO-GS levels were highest in FaDu, followed by LOVO, and then T24 (total uptake: 0.851 +/- 0.009 (FaDu), 0.617 +/- 0.021 (LOVO) and 0.167 +/- 0.006 (T24) % dose/mg protein; amino-FMISO-GS: 0.502 +/- 0.035 (FaDu), 0.158 +/- 0.013 (LOVO), and 0.007 +/- 0.001 (T24) % dose/mg protein). The glutathione level of FaDu was significantly higher than those of LOVO and T24. The enzyme activity of glutathione-S-transferase catalyzing the glutathione conjugation reaction in FaDu was similar levels to that in LOVO, and was higher than that in T24. Quantitative RT-PCR analysis revealed that the expression levels of efflux transporters of the glutathione conjugate (multidrug resistance-associated protein 1) were lowest in FaDu, followed by LOVO, and then T24. Conclusions FMISO accumulates in hypoxic cells through reductive metabolism followed by glutathione conjugation. We illustrated the possibility that increased production and decreased excretion of amino-FMISO-GS contribute to FMISO accumulation in tumor cells under hypoxic conditions.
  • Jun Sato, Yoshimasa Kitagawa, Shiro Watanabe, Takuya Asaka, Noritaka Ohga, Kenji Hirata, Shozo Okamoto, Tohru Shiga, Masanobu Shindoh, Yuji Kuge, Nagara Tamaki
    ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY 124 3 261 - 270 2017年09月 [査読有り][通常論文]
     
    Objective. Hypoxia is a common feature and prognostic factor in cancer. F-18-fluoromisonidazole (FMISO) positron emission tomography (PET) can detect tumor hypoxia noninvasively. The aim of this study was to assess the correlations between FMISO-PET and F-18-fluorodexyglucose (FDG)-PET parameters with cell proliferation and hypoxia in patients with oral squamous cell carcinoma (OSCC). Study Design. Twenty-three preoperative patients with OSCC were included. The tumor/muscle ratio (TMR) of FMISO-PET, the maximum standardized uptake values (SUVmax) of FDG-PET, metabolic tumor volume, and total lesion glycolysis were measured. Ki-67 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression was immunohistochemically evaluated. Results. FMISO TMR (P = .003) and FDG SUVmax (P = .04) were significantly higher in patients with high expression of Ki-67 compared with those with low expression of Ki-67. FMISO TMR (P = .006) and FDG SUVmax (P = .01) were also significantly higher in patients with HIF-1 alpha expression than in those without HIF-1 alpha expression. Metabolic tumor volume was not significantly related to either Ki-67 or HIF-1 alpha expression. Multivariate analysis showed that FMISO TMR was independently predictive of Ki-67 (P = .002; odds ratio 31.1) and HIF-1 alpha (P = .049; odds ratio 10.5) expression. Conclusions. FMISO-PET showed significant relationships with Ki-67 and HIF-1 alpha expression, which are key features of cell proliferation and hypoxia in OSCC.
  • Wenwen Yu, Songji Zhao, Yan Zhao, Chowdhury Nusrat Fatema, Masahiro Murakami, Ken-Ichi Nishijima, Yoshimasa Kitagawa, Nagara Tamaki, Yuji Kuge
    ONCOLOGY LETTERS 14 2 2341 - 2346 2017年08月 [査読有り][通常論文]
     
    A mechanistic dissociation exists between tumor starvation and vascular normalization after antiangiogenic therapy. Thus, improved understanding of tumor responses (tumor starvation or vascular normalization) is important for optimizing treatment strategies. F-18-fluoromisonidazole (F-18-FMISO) is widely used for imaging tumor hypoxia. To clarify the tumor response to the antiangiogenic drug sorafenib, the present study evaluated the changes in the tumor oxygen state using F-18-FMISO in mice bearing a renal cell carcinoma xenograft (A498). Mice bearing A498 xenografts were assigned to the control and three sorafenib-treatment groups and administered sorafenib (0, 10, 20 or 40 mg/kg/day, per os) once daily for 3 days. Following one day after the final administration, the mice were injected with F-18-FMISO and pimonidazole (a hypoxia marker). F-18-FMISO accumulation in the tumor was determined by autoradiography. Immunohistochemistry of pimonidazole and cluster of differentiation (CD) 31 (a vascular marker) was also performed. F-18-FMISO accumulation levels in the tumor significantly increased by 4.3-, 8.4- and 8.6-fold compared with in the control group following 10, 20 and 40 mg/kg sorafenib treatments, respectively [0.07 +/- 0.04, 0.32 +/- 0.11, 0.62 +/- 0.15 and 0.63 +/- 0.23 (% ID/m(2)) x kg for the control, and 10, 20 and 40 mg treatments, respectively; all P<0.0083 vs. the control]. The number of pimonidazole-positive cells also significantly increased by 6.8-, 12.3-and 20.2-fold compared with in the control group following 10, 20 and 40 mg/kg sorafenib treatments, respectively (0.78 +/- 0.79, 5.36 +/- 2.29, 9.66 +/- 1.58 and 15.85 +/- 4.59% pimonidazole-positive cells; all P<0.0083 vs. the control). The number of microvessels in tumors markedly decreased to 33.5, 17.6, and 14.0% of the control following 10, 20 and 40 mg/kg sorafenib treatments, respectively (17.1 +/- 2.5, 5.7 +/- 1.0, 3.0 +/- 1.0 and 2.4 +/- 0.3 vessels/mm(2); P<0.0083 vs. the control). The F-18-FMISO expression level in the tumor increased sorafenib-dose-dependently, which is consistent with the increase in the number of pimonidazole-positive cells and decrease in the number of microvessels. These findings indicated that the present sorafenib treatment protocol induces 'tumor hypoxia/starvation' in the renal cell carcinoma xenograft (A498) due to its antiangiogenic properties.
  • Yoichi Shimizu, Hiroko Hanzawa, Yan Zhao, Sagiri Fukura, Ken-ichi Nishijima, Takeshi Sakamoto, Songji Zhao, Nagara Tamaki, Mikako Ogawa, Yuji Kuge
    MOLECULAR IMAGING AND BIOLOGY 19 4 531 - 539 2017年08月 [査読有り][通常論文]
     
    Vulnerable plaques are key factors for ischemic diseases. Thus, their precise detection is necessary for the diagnosis of such diseases. Immunoglobulin G (IgG)-based imaging probes have been developed for imaging biomolecules related to plaque formation for the diagnosis of atherosclerosis. However, IgG accumulates nonspecifically in atherosclerotic regions, and its accumulation mechanisms have not yet been clarified in detail. Therefore, we explored IgG accumulation mechanisms in atherosclerotic lesions and examined images of radiolabeled IgG for the diagnosis of atherosclerosis. Mouse IgG without specificity to biomolecules was labeled with technetium-99m via 6-hydrazinonicotinate to yield [Tc-99m]IgG. ApoE(-/-) or C57BL/6J mice were injected intravenously with [Tc-99m]IgG, and their aortas were excised 24 h after injection. After radioactivity measurement, serial aortic sections were autoradiographically and histopathologically examined. RAW264.7 macrophages were polarized into M1 or M2 and then treated with [Tc-99m]IgG. The radioactivities in the cells were measured after 1 h of incubation. [Tc-99m]IgG uptake in M1 macrophages was also evaluated after the pretreatment with an anti-Fc gamma receptor (Fc gamma R) antibody. The expression levels of Fc gamma Rs in the cells were measured by western blot analysis. [Tc-99m]IgG accumulation levels in the aortas were significantly higher in apoE(-/-) mice than in C57BL/6J mice (5.1 +/- A 1.4 vs 2.8 +/- A 0.5 %ID/g, p < 0.05). Autoradiographic images showed that the accumulation areas highly correlated with the macrophage-infiltrated areas. M1 macrophages showed significantly higher levels of [Tc-99m]IgG than M2 or M0 (nonpolarized) macrophages [2.2 +/- A 0.3 (M1) vs 0.5 +/- A 0.1 (M2), 0.4 +/- A 0.1 (M0) %dose/mg protein, p < 0.01] and higher expression levels of Fc gamma RI and Fc gamma RII. [Tc-99m]IgG accumulation in M1 macrophages was suppressed by pretreatment with the anti-Fc gamma R antibody [2.2 +/- A 0.3 (nonpretreatment) vs 1.2 +/- A 0.2 (pretreatment) %ID/mg protein, p < 0.01]. IgG accumulated in pro-inflammatory M1 macrophages via Fc gamma Rs in atherosclerotic lesions. Thus, the target biomolecule-independent imaging of active inflammation should be taken into account in the diagnosis of atherosclerosis using IgG-based probes.
  • Nobuhiro Oshima, Hiromichi Akizawa, Hidekazu Kawashima, Songji Zhao, Yan Zhao, Ken-ichi Nishijima, Yoji Kitamura, Yasushi Arano, Yuji Kuge, Kazue Ohkura
    NUCLEAR MEDICINE AND BIOLOGY 48 16 - 25 2017年05月 [査読有り][通常論文]
     
    Introduction: Radiolabeled octreotide derivatives have been studied as diagnostic and therapeutic agents for somatostatin receptor-positive tumors. To prevent unnecessary radiation exposure during their clinical application, the present study aimed to develop radiolabeled peptides which could reduce radioactivity levels in the kidney at both early and late post-injection time points by introducing a negative charge with an acidic amino acid such as L-aspartic acid (Asp) at a suitable position in In-111-DTPA-conjugated octreotide derivatives. Methods: Biodistribution of the radioactivity was evaluated in normal mice after administration of a novel radiolabeled peptide by a counting method. The radiolabeled species remaining in the kidney were identified by comparing their HPLC data with those obtained by alternative synthesis. Results: The designed and synthesized radiolabeled peptide In-111-DTPA-D-Phe(-1)-Aspo(o)-D-phe(1)-octreotide exhibited significantly lower renal radioactivity levels than those of the known In-111-DTPA-D-Phe(-1)-octreotide at 3 and 24 h post-injection. The radiolabeled species in the kidney at 24 h after the injection of new octreotide derivative represented In-111-DTPA-D-Phe-OH and In-111-DTPA-D-Phe-Asp-OH as the metabolites. Their radiometabolites and intact In-111-DTPA-conjugated octreotide derivative were observed in urine within 24 h post-injection. Conclusion: The present study provided a new example of an In-111-DTPA-conjugated octreotide derivative having the characteristics of both reduced renal uptake and shortened residence time of radioactivity in the kidney. It is considered that this kinetic control was achieved by introducing a negative charge on the octreotide derivative thereby suppressing the reabsorption in the renal tubules and affording the radiometabolites with appropriate lipophilicity. (C) 2017 Elsevier Inc. All rights reserved.
  • Takuya Toyonaga, Shigeru Yamaguchi, Kenji Hirata, Kentaro Kobayashi, Osamu Manabe, Shiro Watanabe, Shunsuke Terasaka, Hiroyuki Kobayashi, Naoya Hattori, Tohru Shiga, Yuji Kuge, Shinya Tanaka, Yoichi M Ito, Nagara Tamaki
    European journal of nuclear medicine and molecular imaging 44 4 611 - 619 2017年04月 [査読有り][通常論文]
     
    PURPOSE: Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients. EXPERIMENTAL DESIGN: Glioblastoma patients (n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV × FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis. RESULTS: All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS (p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS (p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV, patients' age, or Karnofsky performance scale (KPS) was significantly correlated with PSF or OS. The hMTV and hTLG were found to be independent factors affecting PFS and OS on multivariate analysis. CONCLUSIONS: We introduced hMTV and hTLG using FDG and FMISO PET to define metabolically active hypoxic volume. Univariate and multivariate analyses demonstrated that both hMTV and hTLG are significant predictors for PFS and OS in glioblastoma patients.
  • 阿保憲史, 野矢洋一, 東川桂, 安井博宣, 久下裕司
    日本放射線安全管理学会誌 16 2 85 - 90 2017年 [査読有り][通常論文]
  • I-123 iomazenil single photon emission computed tomography for detecting loss of neuronal integrity in patients with traumatic brain injury
    Abiko K, Ikoma K, Shiga T, Katoh C, Hirata K, Kuge Y, Kobayashi K, Tamaki N
    EJNMMI Res 7 1 28  2017年 [査読有り][通常論文]
  • Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits
    Matsuura Y, Yamashita A, Zhao Y, Iwakiri T, Yamasaki K, Sugita C, Koshimoto C, Kitamura K, Kawai K, Tamaki N, Zhao S, Kuge Y, Asada Y
    PLoS One 12 4 e0175976  2017年 [査読有り][通常論文]
  • Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors
    Nishikawa Y, Yasuda K, Okamoto S, Ito YM, Onimaru R, Shiga T, Tsuchiya K, Watanabe S, Takeuchi W, Kuge Y, Peng H, Tamaki N, Shirato H
    Radiation Oncology 12 148  2017年 [査読有り][通常論文]
  • Naoyuki Ukon, Songji Zhao, Wenwen Yu, Yoichi Shimizu, Ken-ichi Nishijima, Naoki Kubo, Yoshimasa Kitagawa, Nagara Tamaki, Kei Higashikawa, Hironobu Yasui, Yuji Kuge
    EJNMMI RESEARCH 6 1 90  2016年12月 [査読有り][通常論文]
     
    Background: Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl-H-3(N)]-3'-fluoro-3'-deoxythythymidine ([H-3]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[F-18]fluoro-3'-deoxythymidine ([F-18] FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [F-18] FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [F-18] FLT. Results: The dynamic pattern of [F-18] FLT levels in the tumor significantly changed after the treatment. The rate constant of [F-18] FLT phosphorylation (k(3)) was significantly higher in the treatment group (0.111 +/- 0.027 [1/min]) than in the control group (0.082 +/- 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [F-18] FLT forward transport (K-1) to reverse transport (k(2)), between the two groups (0.556 +/- 0.073 and 0. 641 +/- 0.052 [mL/g] in the control group). Conclusions: Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic modeling could provide improved understanding of the biochemical processes involved in tumor responses to therapy.
  • Shozo Okamoto, Tohru Shiga, Koichi Yasuda, Shiro Watanabe, Kenji Hirata, Ken-ichi Nishijima, Keiichi Magota, Katsuhiko Kasai, Rikiya Onimaru, Kazuhiko Tuchiya, Yuji Kuge, Hiroki Shirato, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 43 12 2147 - 2154 2016年11月 [査読有り][通常論文]
     
    The purpose of this study was to prospectively investigate reoxygenation in the early phase of fractionated radiotherapy and serial changes of tumoricidal effects associated with intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer (HNC) using F-18 fluoromisonidazole (FMISO) PET and F-18 fluorodeoxyglucose (FDG) PET. Patients with untreated HNC underwent FMISO-PET and FDG-PET studies prospectively. A PET evaluation was conducted before each IMRT (Pre-IMRT), during IMRT (at 30 Gy/15 fr) (Inter-IMRT), and after completion of IMRT (70 Gy/35 fr) (Post-IMRT). FMISO-PET images were scanned by a PET/CT scanner at 4 h after the FMISO injection. We quantitatively analyzed the FMISO-PET images of the primary lesion using the maximum standardized uptake (SUVmax) and tumor-to-muscle ratio (TMR). The hypoxic volume (HV) was calculated as an index of tumor hypoxia, and was defined as the volume when the TMR was aeyen 1.25. Each FDG-PET scan was started 1 h after injection. The SUVmax and metabolic tumor volume (MTV) values obtained by FDG-PET were analyzed. Twenty patients finished the complete PET study protocol. At Pre-IMRT, 19 patients had tumor hypoxia in the primary tumor. In ten patients, the tumor hypoxia disappeared at Inter-IMRT. Another seven patients showed the disappearance of tumor hypoxia at Post-IMRT. Two patients showed tumor hypoxia at Post-IMRT. The FMISO-PET results showed that the reduction rates of both SUVmax and TMR from Pre-IMRT to Inter-IMRT were significantly higher than the corresponding reductions from Inter-IMRT to Post-IMRT (SUVmax: 27 % vs. 10 %, p = 0.025; TMR: 26 % vs. 12 %, p = 0.048). The reduction rate of SUVmax in FDG-PET from Pre-IMRT to Inter-IMRT was similar to that from Inter-IMRT to Post-IMRT (47 % vs. 48 %, p = 0.778). The reduction rate of the HV in FMISO-PET from Pre-IMRT to Inter-IMRT tended to be larger than that from Inter-IMRT to Post-IMRT (63 % vs. 40 %, p = 0.490). Conversely, the reduction rate of the MTV in FDG-PET from Pre-IMRT to Inter-IMRT was lower than that from Inter-IMRT to Post-IMRT (47 % vs. 74 %, p = 0.003). Both the intensity and the volume of tumor hypoxia rapidly decreased in the early phase of radiotherapy, indicating reoxygenation of the tumor hypoxia. In contrast, the FDG uptake declined gradually with the course of radiotherapy, indicating that the tumoricidal effect continues over the entire course of radiation treatment.
  • Yukiko Masaki, Yoichi Shimizu, Takeshi Yoshioka, Fei Feng, Songji Zhao, Kenichi Higashino, Yoshito Numata, Yuji Kuge
    PLOS ONE 11 8 e0161639  2016年08月 [査読有り][通常論文]
     
    Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole- based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group. However, the detailed mechanism of its accumulation remains unknown. In this study, we investigated the accumulation mechanism of pimonidazole in hypoxic tumor tissues in a mouse model by mass spectrometric analyses including imaging mass spectrometry (IMS). Pimonidazole and its reductive metabolites were observed in the tumor tissues. However, their locations in the tumor sections were not similar to the positively stained areas in pimonidazole-immunohistochemistry, an area considered hypoxic. The glutathione conjugate of reduced pimonidazole, a low-molecular-weight metabolite of pimonidazole, was found in tumor tissues by LC-MS analysis, and our IMS study determined that the intratumor localization of the glutathione conjugate was consistent with the area positively immunostained for pimonidazole. We also found complementary localization of the glutathione conjugate and reduced glutathione (GSH), implying that formation of the glutathione conjugate occurred in the tumor tissue. These results suggest that in hypoxic tumor cells, pimonidazole is reduced at its nitro group, followed by conjugation with GSH.
  • Nobuya Kobashi, Hiroki Matsumoto, Songji Zhao, Shunsuke Meike, Yuki Okumura, Tsutomu Abe, Hiromichi Akizawa, Kazue Ohkura, Ken-ichi Nishijima, Nagara Tamaki, Yuji Kuge
    JOURNAL OF NUCLEAR MEDICINE 57 8 1276 - 1281 2016年08月 [査読有り][通常論文]
     
    Recently, companion diagnostics with nuclear medicine techniques have been anticipated as more suitable means than biopsy for predicting treatment efficacy. The anticancer effect of capecitabine, an orally administered chemotherapeutic agent activated by thymidine phosphorylase (TP), is positively associated with tumor TP expression levels. This study aimed to assess whether TP imaging using a radiolabeled uracil derivative, I-123-5-iodo-6-[(2-iminoimidazolidinyl) methyl] uracil (I-123-IIMU), could predict the efficacy of capecitabine treatment. Methods: Sensitivity to doxifluridine, a metabolite of capecitabine and direct substrate for TP, was assessed by water-soluble tetrazolium salt assays in vitro for 3 human colon cancer cell lines with different TP expression profiles. The intracellular uptake and retention of I-123-IIMU were evaluated. Mice inoculated with each cell line were treated with capecitabine for 2 wk, and tumor growth was compared. In vivo distribution studies and SPECT/CT imaging of I-123-IIMU were performed in inoculated mice. Results: In vitro experiments showed a positive relation between TP expression levels and doxifluridine sensitivity. In vitro studies revealed that intracellular uptake and retention of I-123-IIMU were dependent on TP expression levels. In vivo experiments in inoculated mice showed that I-123-IIMU accumulation in tumor tissue was in line with TP expression levels and susceptibility to capecitabine treatment. Moreover, SPECT/CT imaging of I-123-IIMU in tumor-inoculated mice showed that I-123-IIMU reflects TP expression levels in tumor tissues. Conclusion: I-123-IIMU could be used as an in vivo companion diagnostic for predicting the efficacy of capecitabine treatment.
  • Masayuki Sugimoto, Yoichi Shimizu, Songji Zhao, Naoyuki Ukon, Ken-ichi Nishijima, Masato Wakabayashi, Takeshi Yoshioka, Kenichi Higashino, Yoshito Numata, Tomohiko Okuda, Nagara Tamaki, Hisatoshi Hanamatsu, Yasuyuki Igarashi, Yuji Kuge
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS 1861 8 688 - 702 2016年08月 [査読有り][通常論文]
     
    Sphingomyelin synthase 2 (SMS2) is a proposed potential therapeutic target for obesity and insulin resistance. However, the contributions of SMS2 to glucose metabolism in tissues and its possible therapeutic mechanisms remain unclear. Thus, to determine whole-body glucose utilization and the contributions of each insulin-targeted tissue to glucose uptake, we performed a glucose kinetics study, using the radiolabeled glucose analog F-18-2-fluoro-2-deoxy-D-glucose (F-18-FDG), in wild-type (WT) and SMS2 knockout (KO) mice. Insulin signaling was enhanced in the liver, white adipose tissue and skeletal muscle of SMS2 KO mice compared with those of WT mice. In addition, compared with in WT mice, blood clearance of F-18-FDG was accelerated in SMS2 KO mice when they were fed either a normal or a high fat diet. F-18-FDG uptake was also increased in insulin-targeted tissues such as skeletal muscle in the SMS2 KO mice. Whereas skeletal muscle sphingolipid content was not clearly affected, plasma levels of very long-chain fatty acid (VLCFA)-containing ceramides were markedly increased in SMS2 KO mice, compared with in WT mice. We also generated liver-conditional SMS2 KO mice and performed glucose and insulin tolerance tests on mice with a high fat diet. However, no significant effect was observed. Thus, our study provided evidence that genetic inhibition of SMS2 elevated glucose clearance through activation of glucose uptake into insulin-targeted tissues such as skeletal muscle by a mechanism independent of hepatic SMS2. Our findings further indicate that this occurs, at least in part, via indirect mechanisms such as elevation of VLCFA-containing ceramides. (C) 2016 Elsevier B.V. All rights reserved.
  • Hiroyuki Kimura, Kenji Tomatsu, Hidekazu Saiki, Kenji Arimitsu, Masahiro Ono, Hidekazu Kawashima, Ren Iwata, Hiroaki Nakanishi, Eiichi Ozeki, Yuji Kuge, Hideo Saji
    PLOS ONE 11 7 e0159303  2016年07月 [査読有り][通常論文]
     
    In the field of positron emission tomography ( PET) radiochemistry, compact microreactors provide reliable and reproducible synthesis methods that reduce the use of expensive precursors for radiolabeling and make effective use of the limited space in a hot cell. To develop more compact microreactors for radiosynthesis of F-18-labeled compounds required for the multistep procedure, we attempted radiosynthesis of N-succinimidyl 4-[F-18]fluorobenzoate ([F-18]SFB) via a three-step procedure using a microreactor. We examined individual steps for [F-18]SFB using a batch reactor and microreactor and developed a new continuous-flow synthetic method with a single microfluidic chip to achieve rapid and efficient radiosynthesis of [F-18]SFB. In the synthesis of [F-18]SFB using this continuous-flow method, the three-step reaction was successfully completed within 6.5 min and the radiochemical yield was 64 +/- 2% (n = 5). In addition, it was shown that the quality of [F-18]SFB synthesized on this method was equal to that synthesized by conventional methods using a batch reactor in the radiolabeling of bovine serum albumin with [F-18]SFB.
  • Takuya Toyonaga, Kenji Hirata, Shigeru Yamaguchi, Kanako C Hatanaka, Sayaka Yuzawa, Osamu Manabe, Kentaro Kobayashi, Shiro Watanabe, Tohru Shiga, Shunsuke Terasaka, Hiroyuki Kobayashi, Yuji Kuge, Nagara Tamaki
    European journal of nuclear medicine and molecular imaging 43 8 1469 - 76 2016年07月 [査読有り][通常論文]
     
    PURPOSE: Tumor necrosis is one of the indicators of tumor aggressiveness. (18)F-fluoromisonidazole (FMISO) is the most widely used positron emission tomography (PET) tracer to evaluate severe hypoxia in vivo. Because severe hypoxia causes necrosis, we hypothesized that intratumoral necrosis can be detected by FMISO PET in brain tumors regardless of their histopathology. We applied FMISO PET to various types of brain tumors before tumor resection and evaluated the correlation between histopathological necrosis and FMISO uptake. METHODS: This study included 59 brain tumor patients who underwent FMISO PET/computed tomography before any treatments. According to the pathological diagnosis, the brain tumors were divided into three groups: astrocytomas (group 1), neuroepithelial tumors except for astrocytomas (group 2), and others (group 3). Two experienced neuropathologists evaluated the presence of necrosis in consensus. FMISO uptake in the tumor was evaluated visually and semi-quantitatively using the tumor-to-normal cerebellum ratio (TNR). RESULTS: In visual analyses, 26/27 cases in the FMISO-positive group presented with necrosis, whereas 28/32 cases in the FMISO-negative group did not show necrosis. Mean TNRs with and without necrosis were 3.49 ± 0.97 and 1.43 ± 0.42 (p < 0.00001) in group 1, 2.91 ± 0.83 and 1.44 ± 0.20 (p < 0.005) in group 2, and 2.63 ± 1.16 and 1.35 ± 0.23 (p < 0.05) in group 3, respectively. Using a cut-off value of TNR = 1.67, which was calculated by normal reference regions of interest, we could predict necrosis with sensitivity, specificity, and accuracy of 96.7, 93.1, and 94.9 %, respectively. CONCLUSIONS: FMISO uptake within the lesion indicated the presence of histological micro-necrosis. When we used a TNR of 1.67 as the cut-off value, intratumoral micro-necrosis was sufficiently predictable. Because the presence of necrosis implies a poor prognosis, our results suggest that FMISO PET could provide important information for treatment decisions or surgical strategies of any type of brain tumor.
  • Masayuki Sugimoto, Masato Wakabayashi, Yoichi Shimizu, Takeshi Yoshioka, Kenichi Higashino, Yoshito Numata, Tomohiko Okuda, Songji Zhao, Shota Sakai, Yasuyuki Igarashi, Yuji Kuge
    PLOS ONE 11 3 e0152191  2016年03月 [査読有り][通常論文]
     
    Obesity was reported to cause kidney injury by excessive accumulation of sphingolipids such as sphingomyelin and ceramide. Sphingomyelin synthase 2 (SMS2) is an important enzyme for hepatic sphingolipid homeostasis and its dysfunction is considered to result in fatty liver disease. The expression of SMS2 is also high in the kidneys. However, the contribution of SMS2 on renal sphingolipid metabolism remains unclear. Imaging mass spectrometry is a powerful tool to visualize the distribution and provide quantitative data on lipids in tissue sections. Thus, in this study, we analyzed the effects of SMS2 deficiency on the distribution and concentration of sphingomyelins in the liver and kidneys of mice fed with a normal-diet or a high-fat-diet using imaging mass spectrometry and liquid chromatography/electrospray ionization-tandem mass spectrometry. Our study revealed that high-fat-diet increased C18-C22 sphingomyelins, but decreased C24-sphingomyelins, in the liver and kidneys of wild-type mice. By contrast, SMS2 deficiency decreased C18-C24 sphingomyelins in the liver. Although a similar trend was observed in the whole-kidneys, the effects were minor. Interestingly, imaging mass spectrometry revealed that sphingomyelin localization was specific to each acyl-chain length in the kidneys. Further, SMS2 deficiency mainly decreased C22-sphingomyelin in the renal medulla and C24-sphingomyelins in the renal cortex. Thus, imaging mass spectrometry can provide visual assessment of the contribution of SMS2 on acyl-chain- and region-specific sphingomyelin metabolism in the kidneys.
  • Naoyuki Ukon, Naoki Kubo, Masayori Ishikawa, Songji Zhao, Nagara Tamaki, Yuji Kuge
    Results in Physics 6 659 - 663 2016年 [査読有り][通常論文]
     
    Focusing on whole-body uniformity in small-animal single-photon emission computed tomography (SPECT), we examined the optimal helical acquisition parameters using five-pinhole collimators for mouse imaging. SPECT images of an 80-mm-long cylindrical phantom with 99mTc solution were acquired using an Inveon multimodality imaging platform. The bed travels used in this study were 0, 30, 60, 90 and 120 mm, and the numbers of revolutions traversed during the SPECT scan were 1.0, 2.0, 3.0, 4.0, 5.0 and 7.0, respectively. Artifacts that degrade uniformity in reconstructed images were conspicuous when the bed travel was smaller than the object length. Regarding the distal-to-center ratio (DCR) of SPECT values in the object's axial direction, the DCR nearest to the ideal ratio of 1.00 was 1.02 in the optimal uniformity with 4.0 revolutions and a bed travel of 120 mm. Moreover, the helical acquisition using these parameters suppressed the formation of artifacts. We proposed the optimal parameters in whole-body helical SPECT; the bed travel was sufficiently larger than the object length; the 4.0 or more revolutions were required for a pitch of approximately 30 mm/revolution. The optimal acquisition parameters in SPECT to preserve uniformity would contribute to the accurate quantification of whole-body biodistribution. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Masayuki Sugimoto, Yoichi Shimizu, Takeshi Yoshioka, Masato Wakabayashi, Yukari Tanaka, Kenichi Higashino, Yoshito Numata, Shota Sakai, Akio Kihara, Yasuyuki Igarashi, Yuji Kuge
    Biochimica et biophysica acta 1851 12 1554 - 65 2015年12月 [査読有り][通常論文]
     
    Sphingomyelin (SM) is synthesized by SM synthase (SMS) from ceramide (Cer). SM regulates signaling pathways and maintains organ structure. SM comprises a sphingoid base and differing lengths of acyl-chains, but the importance of its various forms and regulatory synthases is not known. It has been reported that Cer synthase (CerS) has restricted substrate specificity, whereas SMS has no specificity for different lengths of acyl-chains. We hypothesized that the distribution of each SM molecular species was regulated by expression of the CerS family. Thus, we compared the distribution of SM species and CerS mRNA expression using molecular imaging. Spatial distribution of each SM molecular species was investigated using ultra-high-resolution imaging mass spectrometry (IMS). IMS revealed that distribution of SM molecular species varied according to the lengths of acyl-chains found in each brain section. Furthermore, a combination study using in situ hybridization and IMS revealed the spatial expression of CerS1 to be associated with the localization of SM (d18:1/18:0) in cell body-rich gray matter, and CerS2 to be associated with SM (d18:1/24:1) in myelin-rich white matter. Our study is the first comparison of spatial distribution between SM molecular species and CerS isoforms, and revealed their distinct association in the brain. These observations were demonstrated by suppression of CerS2 using siRNA in HepG2 cells; that is, siRNA for CerS2 specifically decreased C22 very long-chain fatty acid (VLCFA)- and C24 VLCFA-containing SMs. Thus, histological analyses of SM species by IMS could be a useful approach to consider their molecular function and regulative mechanism.
  • Kentaro Kobayashi, Kenji Hirata, Shigeru Yamaguchi, Osamu Manabe, Shunsuke Terasaka, Hiroyuki Kobayashi, Tohru Shiga, Naoya Hattori, Shinya Tanaka, Yuji Kuge, Nagara Tamaki
    European journal of nuclear medicine and molecular imaging 42 7 1071 - 80 2015年06月 [査読有り][通常論文]
     
    PURPOSE: (11)C-methionine (MET) PET is an established diagnostic tool for glioma. Studies have suggested that MET uptake intensity in the tumor is a useful index for predicting patient outcome. Because MET uptake is known to reflect tumor expansion more accurately than MRI, we aimed to elucidate the association between volume-based tumor measurements and patient prognosis. METHODS: The study population comprised 52 patients with newly diagnosed glioma who underwent PET scanning 20 min after injection of 370 MBq MET. The tumor was contoured using a threshold of 1.3 times the activity of the contralateral normal cortex. Metabolic tumor volume (MTV) was defined as the total volume within the boundary. Total lesion methionine uptake (TLMU) was defined as MTV times the mean standardized uptake value (SUVmean) within the boundary. The tumor-to-normal ratio (TNR), calculated as the maximum standardized uptake value (SUVmax) divided by the contralateral reference value, was also recorded. All patients underwent surgery (biopsy or tumor resection) targeting the tissue with high MET uptake. The Kaplan-Meier method was used to estimate the predictive value of each measurement. RESULTS: Grade II tumor was diagnosed in 12 patients (3 diffuse astrocytoma, 2 oligodendroglioma, and 7 oligoastrocytoma), grade III in 18 patients (8 anaplastic astrocytoma, 6 anaplastic oligodendroglioma, and 4 anaplastic oligoastrocytoma), and grade IV in 22 patients (all glioblastoma). TNR, MTV and TLMU were 3.1 ± 1.2, 51.6 ± 49.9 ml and 147.7 ± 153.3 ml, respectively. None of the three measurements was able to categorize the glioma patients in terms of survival when all patients were analyzed. However, when only patients with astrocytic tumor (N = 33) were analyzed (i.e., when those with oligodendroglial components were excluded), MTV and TLMU successfully predicted patient outcome with higher values associated with a poorer prognosis (P < 0.05 and P < 0.01, respectively), while the predictive ability of TNR did not reach statistical significance (P = NS). CONCLUSION: MTV and TLMU may be useful for predicting outcome in patients with astrocytic tumor.
  • Osamu Manabe, Naoya Hattori, Shigeru Yamaguchi, Kenji Hirata, Kentaro Kobayashi, Shunsuke Terasaka, Hiroyuki Kobayashi, Hiroaki Motegi, Tohru Shiga, Keiichi Magota, Noriko Oyama-Manabe, Ken-ichi Nishijima, Yuji Kuge, Nagara Tamaki
    European journal of nuclear medicine and molecular imaging 42 6 896 - 904 2015年05月 [査読有り][通常論文]
     
    PURPOSE: Previous radiological investigations have generally shown the superiority of metabolic imaging in distinguishing high-grade from low-grade glioma, but the presence of an oligodendroglial component may affect the diagnostic accuracy. We investigated the diagnostic accuracy of PET imaging using (11)C-methionine (MET) and (18)F-fluorodeoxyglucose (FDG) in distinguishing high-grade from low-grade glioma, in correlation with the oligodendroglial component. METHODS: The study population comprised adult patients who underwent preoperative PET imaging using both MET and FDG within 1 week and successful excision of the tumour tissue, which confirmed WHO grade II-IV glioma. We examined the tumour metabolic activity in terms of lesion-to-normal uptake ratios (L/N ratio) in both MET PET and FDG PET images. We assessed the correlation between the imaging results and the histological findings to determine the diagnostic accuracy of receiver operating characteristics (ROC) analysis in detecting high-grade tumours. RESULTS: We studied 46 patients with glioma (13 low-grade and 33 high-grade), including 26 with an oligodendroglial components. The L/N ratios of the PET images showed significantly higher metabolic activities in high-grade gliomas than in low-grade gliomas for both MET (4.29 ± 1.22 and 2.36 ± 0.72, respectively; p < 0.0001) and FDG (1.72 ± 0.91 and 0.77 ± 0.26, respectively; p = 0.0007) images, although significant overlaps in L/N ratio were observed between high-grade and low-grade gliomas. Excluding the 26 patents with an oligodendroglial component improved the separation for both MET (4.62 ± 1.14 vs. 2.16 ± 0.63; p < 0.001) and FDG (1.76 ± 0.87 vs. 0.71 ± 0.14; p < 0.05) images. The ROC analyses demonstrated the clinical utility of the metabolic radiotracers in distinguishing high-grade from low-grade gliomas, showing similar AUC values for MET (0.91) and FDG (0.92). Excluding the 26 patents with an oligodendroglial component also further improved the diagnostic accuracy for both MET (AUC 0.98), and FDG (AUC 1.00) images. The metabolic radiotracers were significantly correlated with the MIB-1 labelling index (R = 0.52, p < 0.05 for MET; R = 0.52, p < 0.05, for FDG) only in gliomas without an oligodendroglial component. CONCLUSION: For better characterization of gliomas and for risk assessment, the results of metabolic PET imaging should be revised after obtaining the pathological report, because oligodendroglial differentiation may positively influence the substrate metabolism and thus complicated the preoperative evaluation.
  • Yimin, Kohanawa M, Zhao S, Li M, Kuge Y, Tamaki N, Watanabe M
    J Interferon Cytokine Res 35 3 222 - 231 2015年 [査読有り][通常論文]
  • Zhao S, Li H, Nishijima K, Zhao Y, Akizawa H, Shimizu Y, Ohkura K, Tamaki N, Kuge Y
    Ann Nucl Med 29 7 582 - 587 2015年 [査読有り][通常論文]
  • Combined plasma and tissue proteomic study of atherogenic model mouse: approach to eucidate mlecular dterminants in aherosclerosis dvelopment
    Hanzawa H, Sakamoto T, Kaneko A, Manri N, Zhao Y, Zhao S, Tamaki N, Kuge Y
    J Proteome Res 14 10 4257 - 4269 2015年 [査読有り][通常論文]
  • Masaki Y, Shimizu Y, Yoshioka T, Tanaka Y, Nishijima K, Zhao S, Higashino K, Sakamoto S, Numata Y, Yamaguchi Y, Tamaki N, Kuge Y
    Sci Rep 5 16802  2015年 [査読有り][通常論文]
  • Kawashima H, Kimura H, Nakaya Y, Tomatsu K, Arimitsu K, Nakanishi H, Ozeki E, Kuge Y, Saji H
    Chem Pharm Bull (Tokyo) 63 9 737 - 740 2015年 [査読有り][通常論文]
  • Yamaguchi A, Hanaoka H, Fujisawa Y, Zhao S, Suzue K, Morita A, Tominaga H, Higuchi T, Hisaeda H, Tsushima Y, Kuge Y, Iida Y
    EJNMMI Res 5 29  2015年 [査読有り][通常論文]
  • Yamasaki K, Zhao S, Nishimura M, Zhao Y, Yu W, Shimizu Y, Nishijima K, Tamaki N, Takeda H, Kuge Y
    Mol Imaging 14 0 1 - 11 2015年 [査読有り][通常論文]
  • Zhao Y, Fukao K, Zhao S, Watanabe A, Hamada T, Yamasaki K, Shimizu Y, Kubo N, Ukon N, Nakano T, Tamaki N, Kuge Y
    Mol Imaging 14 0 1 - 8 2015年 [査読有り][通常論文]
  • Naoki Kubo, Katsutoshi Tsuchiya, Tohru Shiga, Shinichi Kojima, Atsuro Suzuki, Yuichiro Ueno, Keiji Kobashi, Nagara Tamaki
    IEEE TRANSACTIONS ON NUCLEAR SCIENCE 61 5 2489 - 2493 2014年10月 [査読有り][通常論文]
     
    A new design of collimator is proposed that has variable sensitivity and spatial resolution, eliminating the need for exchanging collimators in a gamma camera. Using Monte Carlo simulations, the present article evaluates the shielding of undesirable gamma rays in a parallel-hole collimator. It consists of a number of layers of rectangular holes. These layers consist of alternately stacked fixed and movable collimators. In high-resolution mode, the movable collimators are shifted by half the aperture pitch along the diagonal direction. The first collimator (type A) has 50 layers with fixed thicknesses of 1.2 mm. The second collimator (type B) has 25 layers with a thickness of 1.0 mm on the object side and 25 layers with a thickness of 1.4 mm on the opposite side. The third collimator (type C) has 20 layers with non-uniform thicknesses. The ratios of the maximum artificial peak to the main-peak are calculated for point-source responses. The ratios for types A, B, and C collimators are 0.78, 0.08, and 0.03, respectively. The same performance for shielding undesirable gamma rays is achieved in the type C collimator as for a conventional collimator.
  • Tsunehito Higashi, Yosuke Mai, Yoichi Noya, Takahiro Horinouchi, Koji Terada, Akimasa Hoshi, Prabha Nepal, Takuya Harada, Mika Horiguchi, Chizuru Hatate, Yuji Kuge, Soichi Miwa
    PLOS ONE 9 9 e107856  2014年09月 [査読有り][通常論文]
     
    Cigarette smoke consists of tar and gas phase: the latter is toxicologically important because it can pass through lung alveolar epithelium to enter the circulation. Here we attempt to establish a standard method for preparation of gas phase extract of cigarette smoke (CSE). CSE was prepared by continuously sucking cigarette smoke through a Cambridge filter to remove tar, followed by bubbling it into phosphate-buffered saline (PBS). An increase in dry weight of the filter was defined as tar weight. Characteristically, concentrations of CSEs were represented as virtual tar concentrations, assuming that tar on the filter was dissolved in PBS. CSEs prepared from smaller numbers of cigarettes (original tar concentrations <= 15 mg/ml) showed similar concentration-response curves for cytotoxicity versus virtual tar concentrations, but with CSEs from larger numbers (tar >= 20 mg/ml), the curves were shifted rightward. Accordingly, the cytotoxic activity was detected in PBS of the second reservoir downstream of the first one with larger numbers of cigarettes. CSEs prepared from various cigarette brands showed comparable concentration-response curves for cytotoxicity. Two types of CSEs prepared by continuous and puff smoking protocols were similar regarding concentration-response curves for cytotoxicity, pharmacology of their cytotoxicity, and concentrations of cytotoxic compounds. These data show that concentrations of CSEs expressed by virtual tar concentrations can be a reference value to normalize their cytotoxicity, irrespective of numbers of combusted cigarettes, cigarette brands and smoking protocols, if original tar concentrations are <= 15 mg/ml.
  • Chowdhury Nusrat Fatema, Songji Zhao, Yan Zhao, Wenwen Yu, Ken-ichi Nishijima, Koichi Yasuda, Yoshimasa Kitagawa, Nagara Tamaki, Yuji Kuge
    BMC CANCER 14 1 692  2014年09月 [査読有り][通常論文]
     
    Background: Radiotherapy is an important treatment strategy for head and neck cancers. Tumor hypoxia and repopulation adversely affect the radiotherapy outcome. Accordingly, fractionated radiotherapy with dose escalation or altered fractionation schedule is used to prevent hypoxia and repopulation. F-18-fluoromisonidazole (FMISO) and F-18-fluorothymidine (FLT) are noninvasive markers for assessing tumor hypoxia and proliferation, respectively. Thus, we evaluated the dynamic changes in intratumoral hypoxic and proliferative states following radiotherapy using the dual tracers of F-18-FMISO and H-3-FLT, and further verified the results by immunohistochemical staining of pimonidazole (a hypoxia marker) and Ki-67 (a proliferation marker) in human head and neck cancer xenografts (FaDu). Methods: FaDu xenografts were established in nude mice and assigned to the non-radiation-treated control and two radiation-treated groups (10- and 20-Gy). Tumor volume was measured daily. Mice were sacrificed 6, 24, and 48 hrs and 7 days after radiotherapy. F-18-FMISO, and H-3-FLT and pimonidazole were injected intravenously 4 and 2 hrs before sacrifice, respectively. Intratumoral F-18-FMISO and H-3-FLT levels were assessed by autoradiography. Pimonidazole and Ki-67 immunohistochemistries were performed. Results: In radiation-treated mice, tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. Visual inspection showed that intratumoral F-18-FMISO and H-3-FLT distribution patterns were markedly different. Intratumoral F-18-FMISO level did not show significant changes after radiotherapy among the non-radiation-treated control and radiation-treated groups, whereas H-3-FLT level markedly decreased to 59 and 45% of the non-radiation-treated control at 6 hrs (p < 0.0001) and then gradually increased with time in the 10- and 20-Gy-radiation-treated groups. The pimonidazole-positive hypoxic areas were visually similar in both the non-radiation-treated control and radiation-treated groups. No significant differences were observed in the percentage of pimonidazole-positive cells and Ki-67 index. Conclusion: Intratumoral F-18-FMISO level did not change until 7 days, whereas H-3-FLT level markedly decreased at 6 hrs and then gradually increased with time after a single dose of radiotherapy. The concomitant monitoring of dynamic changes in tumor hypoxia and proliferation may provide important information for a better understanding of tumor biology after radiotherapy and for radiotherapy planning, including dose escalation and altered fractionation schedules.
  • Yoichi Shimizu, Takashi Temma, Isao Hara, Akira Makino, Naoya Kondo, Ei-ichi Ozeki, Masahiro Ono, Hideo Saji
    CANCER SCIENCE 105 8 1056 - 1062 2014年08月 [査読有り][通常論文]
     
    Membrane type-1 matrix metalloproteinase (MT1-MMP) is a protease activating MMP-2 that mediates cleavage of extracellular matrix components and plays pivotal roles in tumor migration, invasion and metastasis. Because in vivo noninvasive imaging of MT1-MMP would be useful for tumor diagnosis, we developed a novel near-infrared (NIR) fluorescence probe that can be activated following interaction with MT1-MMP in vivo. MT1-hIC7L is an activatable fluorescence probe comprised of anti-MT1-MMP monoclonal antibodies conjugated to self-assembling polymer micelles that encapsulate NIR dyes (IC7-1, em: 858nm) at concentrations sufficient to cause fluorescence self-quenching. In aqueous buffer, MT1-hIC7L fluorescence was suppressed to background levels and increased approximately 35.5-fold in the presence of detergent. Cellular uptake experiments revealed that in MT1-MMP positive C6 glioma cells, MT1-hIC7L showed significantly higher fluorescence that increased with time as compared to hIC7L, a negative control probe lacking the anti-MT1-MMP monoclonal antibody. In MT1-MMP negative MCF-7 breast adenocarcinoma cells, both MT1-hIC7L and hIC7L showed no obvious fluorescence. In addition, the fluorescence intensity of C6 cells treated with MT1-hIC7L was suppressed by pre-treatment with an MT1-MMP endocytosis inhibitor (P<0.05). In vivo optical imaging using probes intravenously administered to tumor-bearing mice showed that MT1-hIC7L specifically visualized C6 tumors (tumor-to-background ratios: 3.8 +/- 0.3 [MT1-hIC7L] vs 3.1 +/- 0.2 [hIC7L] 48h after administration, P<0.05), while the probes showed similarly low fluorescence in MCF-7 tumors. Together, these results show that MT1-hIC7L would be a potential activatable NIR probe for specifically detecting MT1-MMP-expressing tumors.
  • Satoru Onoe, Takashi Temma, Yoichi Shimizu, Masahiro Ono, Hideo Saji
    CANCER MEDICINE 3 4 775 - 786 2014年08月 [査読有り][通常論文]
     
    Mitochondrial membrane potential (Delta Psi(m)) alteration is an important target for cancer diagnosis. In this study, we designed a series of near-infrared fluorescent cationic cyanine dyes with varying alkyl chain lengths (IC7-1 derivatives) to provide diverse lipophilicities and serum albumin-binding rates, and we evaluated the usefulness of these derivatives for in vivo Delta Psi(m) imaging. IC7-1 derivatives with side chains from methyl to hexyl (IC7-1-Me to IC7-1-He) were synthesized, and their optical properties were measured. Cellular uptake and intracellular distribution were investigated with depolarized HeLa cells from carbonyl cyanine m-chlorophenylhydrazone (CCCP) treatment using a spectro-fluorometer and a fluorescence microscope. Serum albumin-binding rates were evaluated using albumin-binding inhibitors. In vivo optical imaging was performed with HeLa cell xenograft mice following intravenous administration of IC7-1 derivatives with or without warfarin and CCCP as in vivo blocking agents. IC7-1 derivatives showing maximum excitation and emission wavelengths at 823 nm and similar to 845 nm, respectively, were synthesized. IC7-1-Me to -Bu showed fluorescence in mitochondria that decreased with CCCP treatment in a concentration-dependent manner, which showed that IC7-1-Me to -Bu successfully indicated Delta Psi(m). Tumors were clearly visualized after IC7-1-Bu administration. Treatment with warfarin or CCCP significantly decreased IC7-1-Bu fluorescence in the tumor region. In summary, IC7-1-Bu exhibited fluorescence localized to mitochondria dependent on Delta Psi(m), which enabled clear in vivo tumor imaging via serum albumin as a drug carrier for effective tumor targeting. Our data suggest that IC7-1-Bu is a promising NIR probe for in vivo imaging of the altered Delta Psi(m) of tumor cells.
  • Naoki Kubo, Kenji Hirata, Kazuki Matsuzaki, Yuichi Morimoto, Wataru Takeuchi, Naoya Hattori, Tohru Shiga, Yuji Kuge, Nagara Tamaki
    NUCLEAR MEDICINE COMMUNICATIONS 35 6 677 - 682 2014年06月 [査読有り][通常論文]
     
    Objective PET using semiconductor detectors provides high-quality images of the human brain because of its high spatial resolution. To quantitatively evaluate the delineation of image details in clinical PET images, we used normalized mutual information (NMI) to quantify the similarity with images obtained through MRI. NMI is used to evaluate image quality by determining similarity with a reference image. The aim of this study was to evaluate quantitatively the delineation of image details provided by semiconductor PET. Materials and methods To quantitatively evaluate anatomical delineation in clinical PET images, MRI scans of patients were used as T1-weighted images. [F-18]-fluorodeoxyglucose (F-18-FDG) PET brain images were obtained from six patients using (a) a Hitachi semiconductor PET scanner and (b) a ECAT HR+ scintillator PET scanner. The NMI calculated from the semiconductor PET and MRI was denoted by NMIsemic, whereas the NMI calculated from conventional scintillator PET and MRI was denoted by NMIconve. The higher the value of NMI, the greater the similarity to MRI. Results NMIsemic ranged from 1.22 to 1.29, whereas NMIconve ranged from 1.13 to 1.18 (P < 0.05). Furthermore, all the NMI values of the semiconductor PET were higher than those of the conventional scintillator PET. Conclusion Utilizing NMI, we quantitatively evaluated the delineation of image details in clinical PET images. The results reveal that semiconductor PET has superior anatomical delineation and physical performance compared with conventional scintillator PET. This improved delineation of image details makes semiconductor PET promising for clinical applications.
  • Yan Zhao, Ayahisa Watanabe, Songji Zhao, Tatsuo Kobayashi, Keita Fukao, Yoshikazu Tanaka, Toru Nakano, Tetsuya Yoshida, Hiroshi Takemoto, Nagara Tamaki, Yuji Kuge
    PLOS ONE 9 2 e89338  2014年02月 [査読有り][通常論文]
     
    Objectives: To investigate the effects of irbesartan on inflammation and apoptosis in atherosclerotic plaques by histochemical examination and molecular imaging using C-14-FDG and Tc-99m-annexin A5. Background: Irbesartan has a peroxisome proliferator-activated receptor gamma (PPAR gamma) activation property in addition to its ability to block the AT1 receptor. Accordingly, irbesartan may exert further anti-inflammatory and anti-apoptotic effects in atherosclerotic plaques. However, such effects of irbesartan have not been fully investigated. Molecular imaging using F-18-FDG and Tc-99m-annexin A5 is useful for evaluating inflammation and apoptosis in atherosclerotic plaques. Methods: Female apoE(-/-) mice were treated with irbesartan-mixed (50 mg/kg/day) or irbesartan-free (control) diet for 12 weeks (n = 11/group). One week after the treatment, the mice were co-injected with C-14-FDG and Tc-99m-annexin A5, and cryostat sections of the aortic root were prepared. Histochemical examination with Movat's pentachrome (plaque size), Oil Red O (lipid deposition), Mac-2 (macrophage infiltration), and TUNEL (apoptosis) stainings were performed. Dual-tracer autoradiography was carried out to evaluate the levels of C-14-FDG and Tc-99m-annexin A5 in plaques (% IDxkg). In vitro experiments were performed to investigate the mechanism underlying the effects. Results: Histological examination indicated that irbesartan treatment significantly reduced plaque size (to 56.4% +/- 11.1% of control), intra-plaque lipid deposition (53.6%+/- 20.2%) and macrophage infiltration (61.9% +/- 20.8%) levels, and the number of apoptotic cells (14.5%+/- 16.6%). C-14-FDG (43.0% +/- 18.6%) and Tc-99m-annexin A5 levels (45.9% +/- 16.8%) were also significantly reduced by irbesartan treatment. Irbesartan significantly suppressed MCP-1 mRNA expression in TNF-alpha stimulated THP-1 monocytes (64.8% +/- 8.4% of un-treated cells). PPAR gamma activation was observed in cells treated with irbesartan (134% +/- 36% at 3 mu M to 3329% +/- 218% at 81 mu M) by a PPAR gamma reporter assay system. Conclusions: Remissions of inflammation and apoptosis as potential therapeutic effects of irbesartan on atherosclerosis were observed. The usefulness of molecular imaging using F-18-FDG and Tc-99m-annexin A5 for evaluating the therapeutic effects of irbesartan on atherosclerosis was also suggested.
  • Nobuhiro Oshima, Hiromichi Akizawa, Songji Zhao, Yan Zhao, Ken-ichi Nishijima, Yoji Kitamura, Yasushi Arano, Yuji Kuge, Kazue Ohkura
    BIOORGANIC & MEDICINAL CHEMISTRY 22 4 1377 - 1382 2014年02月 [査読有り][通常論文]
     
    Our previous studies indicated that In-111-diethylenetriaminepentaacetic acid (In-111-DTPA)-octreotide derivatives with an additional negative charge by replacing N-terminal D-phenylalanine (D-Phe) with an acidic amino acid such as L-aspartic acid (Asp) or its derivative exhibited low renal radioactivity levels when compared with In-111-DTPA-D-Phe(1)-octreotide. On the basis of the findings, we designed, synthesized and evaluated two Asp-modified In-111-DTPA-conjugated octreotide derivatives, In-111-DTPA-Asp(1)-octreotide and In-111-DTPA-Asp(0)-D-Phe(1)-octreotide. While In-111-DTPA-Asp1-octreotide showed negligible AR42J cell uptake, In-111-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited AR42J cell uptake similar to that of In-111-DTPA-D-Phe(1)-octreotide. When administered to AR42J tumor-bearing mice, In-111-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited renal radioactivity levels significantly lower than did In-111-DTPA-D-Phe(1)-octreotide at 1 and 3 h post-injection. No significant differences were observed in tumor accumulation between In-111-DTPA-Asp(0)-D-Phe(1)-octreotide and In-111-DTPA-D-Phe(1)-octreotide after 1 and 3 h injection. The findings in this study suggested that an interposition of an Asp at an appropriate position in In-111-DTPA-D-Phe(1)-octreotide would constitute a useful strategy to develop In-111-DTPA-D-Phe(1)-octreotide derivatives of low renal radioactivity levels while preserving tumor accumulation. (C) 2014 Elsevier Ltd. All rights reserved.
  • Atsushi Yamashita, Yan Zhao, Yunosuke Matsuura, Kazuaki Yamasaki, Sayaka Moriguchi-Goto, Chihiro Sugita, Takashi Iwakiri, Nozomi Okuyama, Chihiro Koshimoto, Keiichi Kawai, Nagara Tamaki, Songji Zhao, Yuji Kuge, Yujiro Asada
    PLOS ONE 9 1 e86426  2014年01月 [査読有り][通常論文]
     
    Aims: Inflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages. Methods: Macrophage-rich or smooth muscle cell (SMC)-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS) and interferon-c (INF gamma) were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using F-18-fluorodeoxyglucose (F-18-FDG) and pimonidazole, a marker of hypoxia. Results: The levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20). The uptake of F-18-FDG in arterial walls measured by autoradiography positively correlated with macrophage-and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p<0.0001). Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor-1 alpha and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8) and pentose phosphate pathway (4 of 6) metabolites increased in LPS and INF gamma stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely associated with metabolic pathways in the macrophages. Conclusion: Infiltrative macrophages in atherosclerotic arteries might affect metabolic systems, and hypoxia but not classical activation might augment glycolytic and pentose phosphate pathways in macrophages.
  • Yoichi Shimizu, Takashi Temma, Isao Hara, Akira Makino, Ryo Yamahara, Ei-ichi Ozeki, Masahiro Ono, Hideo Saji
    NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 10 1 187 - 195 2014年01月 [査読有り][通常論文]
     
    Near-infrared (NIR: 800-1000 nm) fluorescent probes, which activate their fluorescence following interaction with functional biomolecules, are desirable for noninvasive and sensitive tumor diagnosis due to minimal tissue interference. Focusing on bioavailability and applicability, we developed a probe with a self-assembling polymer micelle, a lactosome, encapsulating various quantities of NIR dye (IC7-1). We also conjugated anti-HER2 single chain antibodies to the lactosome surface and examined the probe's capacity to detect HER2 in cells and in vivo. Micelles encapsulating 20 mol% IC7-1 (hIC7L) showed 30-fold higher fluorescence (lambda(em): 858 nm) after micelle denaturation compared to aqueous buffer. Furthermore, antibody modification allowed specific activation of the probe (HER2-hIC7L) following internalization by HER2-positive cells, with the probe concentrating in lysosomes. HER2-hIC7L intravenously administered to mice clearly and specifically visualized HER2-positive tumors by in vivo optical imaging. These results indicate that HER2-hIC7L is a potential activatable NIR probe for sensitive tumor diagnosis. From the Clinical Editor: Near-infrared probes that activate their fluorescence following interaction with specific biomolecules are desirable for noninvasive and sensitive tumor detection due to minimal tissue interference. This team of authors developed a probe termed hIC7L and demonstrate its potential in HER2 tumor diagnosis. (C) 2014 Elsevier Inc. All rights reserved.
  • Songji Zhao, Yuji Kuge, Yan Zhao, Satoshi Takeuchi, Kenji Hirata, Toshiki Takei, Tohru Shiga, Hirotoshi Dosaka-Akita, Nagara Tamaki
    BMC CANCER 13 1 525  2013年11月 [査読有り][通常論文]
     
    Background: The purpose of this study was to evaluate whether early changes in 3'-deoxy-3'-H-3-fluorothymidine (H-3-FLT) uptake can reflect the antiproliferative effect of gefitinib in a human tumor xenograft, in comparison with the histopathological markers, Ki-67 and phosphorylated EGFR (phospho-EGFR). Methods: An EGFR-dependent human tumor xenograft model (A431) was established in female BALB/c athymic mice, which were divided into three groups: one control group and two treatment groups. Mice in the treatment groups were orally administered a partial regression dose (100 mg/kg/day) or the maximum tolerated dose of gefitinib (200 mg/kg/day), once daily for 2 days. Mice in the control group were administered the vehicle (0.1% Tween 80). Tumor size was measured before and 3 days after the start of treatment. Biodistribution of H-3-FLT and F-18-FDG (%ID/g/kg) was examined 3 days after the start of the treatment. Tumor cell proliferative activity with Ki-67 was determined. Immunohistochemical staining of EGFR and measurement of phospho-EGFR were also performed. Results: High expression levels of EGFR and Ki-67 were observed in the A431 tumor. After the treatment with 100 and 200 mg/kg gefitinib, the uptake levels of H-3-FLT in the tumor were significantly reduced to 67% and 61% of the control value, respectively (0.39 +/- 0.09, 0.36 +/- 0.06, 0.59 +/- 0.11% ID/g/kg for 100 mg/kg, 200 mg/kg, and control groups, respectively; p < 0.01 vs. control), but those of F-18-FDG were not. After the treatment with 100 and 200 mg/kg gefitinib, the expression levels of Ki-67 in the tumor were markedly decreased (4.6 +/- 2.4%, 6.2 +/- 1.8%,and 10.4 +/- 5.7% for 100 mg/kg, 200 mg/kg, and control groups, respectively, p < 0.01 vs. control). The expression levels of the phospho-EGFR protein also significantly decreased (29% and 21% of the control value for 100, and 200 mg/kg, respectively p < 0.01 vs. control). There was no statistically significant difference in tumor size between pre- and post-treatments in each group. Conclusion: In our animal model, H-3-FLT uptake levels significantly decreased after the treatment with two different doses of gefitinib before a significant change in tumor size was observed. These results were confirmed by the immunohistochemical staining of Ki-67 and phospho-EGFR protein immunoassay. Thus, it was indicated that early changes in H-3-FLT uptake may reflect the antiproliferative effect of gefitinib in a mouse model of a human epidermoid cancer.
  • Hisayasu Saito, Keiichi Magota, Songji Zhao, Naoki Kubo, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin, Nagara Tamaki, Satoshi Kuroda
    STROKE 44 10 2869 - 2874 2013年10月 [査読有り][通常論文]
     
    Background and Purpose This study was aimed to assess whether I-123-iomazenil (IMZ) single photon emission computed tomography can serially monitor the effects of bone marrow stromal cell (BMSC) transplantation on neuronal integrity in infarct brain of rats. Methods The BMSCs were harvested from green fluorescent protein-transgenic rats and were cultured. The rats were subjected to permanent middle cerebral artery occlusion. Their motor function was serially quantified throughout the experiments. The BMSCs or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 days after the insult. Using small-animal single photon emission computed tomography/computed tomography apparatus, the I-123-IMZ uptake was serially measured at 6 and 35 days after the insult. Finally, fluorescence immunohistochemistry was performed to evaluate the distribution of engrafted cells and their phenotypes. Results The distribution of I-123-IMZ was markedly decreased in the ipsilateral neocortex at 6 days postischemia. The vehicle-transplanted animals did not show a significant change at 35 days postischemia. However, BMSC transplantation significantly improved the distribution of I-123-IMZ in the peri-infarct neocortex as well as motor function. The engrafted BMSCs were densely distributed around cerebral infarct, and some of them expressed neuronal nuclear antigen and -aminobutyric acid type-A receptor. Conclusions The present findings strongly suggest that the BMSCs may enhance functional recovery by improving the neuronal integrity in the peri-infarct area, when directly transplanted into the infarct brain at clinically relevant timing. I-123-IMZ single photon emission computed tomography may be a promising modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situation.
  • Masaki Nagane, Hironobu Yasui, Tohru Yamamori, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hiromi Kameya, Hideo Nakamura, Hirotada Fujii, Osamu Inanami
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 437 3 420 - 425 2013年08月 [査読有り][通常論文]
     
    Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO(2) in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy x 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy. (C) 2013 Elsevier Inc. All rights reserved.
  • Sato J, Kitagawa Y, Yamazaki Y, Hata H, Okamoto S, Shiga T, Shindoh M, Kuge Y, Tamaki N
    J Nucl Med. 54 7 1060 - 1065 2013年07月 [査読有り][通常論文]
     
    Hypoxia is a common feature of cancer and a prognostic factor for many types of cancer. F-18-fluoromisonidazole (F-18-FMISO) PET can detect tumor hypoxia noninvasively. Hypoxia-inducible factor-1 (HIF-1) is a key player in the transcriptional response to low oxygen tension in many types of cancer. Its activity is mainly dependent on the stability and modification of HIF-1 alpha, which is a composition of HIF-1. However, it is unclear whether F-18-FMISO PET can identify HIF-1 alpha expression in oral squamous cell carcinoma (OSCC). The present study was performed to elucidate the correlation between F-18-FMISO PET findings and HIF-1 alpha expression in OSCC. Methods: Twenty-three patients (age range, 42-84 y; 15 men, 8 women) with OSCC were enrolled in this study. The T-stages of cancer were T1 in 1 patient, T2 in 9, T3 in 2, and T4a in 11. The N-stages were N0 in 13 patients, N1 in 5, and N2 in 5. Each patient underwent F-18-FMISO and F-18-FDG PET before surgery, and the maximum standardized uptake value (SUVmax) of both PET studies was measured. HIF-1 alpha expression in the operation materials was evaluated by immunohistochemical staining. The SUVmax of both PET studies and HIF-1 alpha findings were compared statistically. Results: F-18-FMISO PET detected uptake in the primary site in 14 of the 23 patients (61%). The median SUVmax of F-18-FMISO and F-18-FDG PET in the primary site was 1.83 (range, 0.8-2.7) and 16.5 (range, 1.0-32.3), respectively. There was a weak significant correlation between F-18-FMISO and F-18-FDG PET SUVmax (P = 0.02, r = 0.48). HIF-1 alpha expression was clearly detected in 11 of the 23 patients (48%). The F-18-FMISO PET SUVmax was significantly higher in the HIF-1 alpha-positive cases than in the HIF-1 alpha-negative cases (median, 2.1; range, 1.5-2.4, vs. median, 1.6; range, 0.8-2.0, respectively) (P = 0.002). However, there were no significant correlations between F-18-FDG PET SUVmax and HIF-1 alpha expression (median, 21.8; range, 7.7-29.1 vs. 1.0-32.2) (P = 0.06). Conclusion: F-18-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1 alpha expression.
  • Kawai T, Kawashima H, Kuge Y, Saji H
    Nucl Med Biol. 40 5 705 - 709 2013年07月 [査読有り][通常論文]
     
    Introduction: As a first trial for in vivo imaging of beta-secretase (BACE1) in Alzheimer's disease brain, we applied a novel non-peptidergic small molecule which has high affinity to the enzyme, naphthalene-1-carboxylic acid (3'-chloro-4'-fluoro-4-piperazin-1-yl-biphenyl-3-yl)amide (NCFB) into positron emission tomography (PET) probe. In the current study, N-C-11-methylated compound of NCFB, [C-11]Me-NCFB was synthesized and evaluated for the visualization of BACE1 in brain. Methods: BACE1 inhibitory constant was measured by FRET assay. [C-11]Me-NCFB was synthesized from NCFB with [C-11]methyl triflate. To evaluate properties of [C-11]Me-NCFB, log P value, stability in mouse plasma and brain uptake index were measured. The biodistribution in 6-week-old ddY mice was also studied. Results: BACE1 inhibitory constant showed an affinity of Me-NCFB to the enzyme (IC50 = 2.3 +/- 0.80 mu M). [C-11]Me-NCFB was synthesized in a 3.0% +/- 0.55% decay-corrected radiochemical yield. [C-11]Me-NCFB showed high lipophilicity, high stability in mouse plasma and blood-brain barrier (BBB) permeability. Injected to 6-week-old ddY mice, [C-11]Me-NCFB penetrated BBB and was retained in the brain (0.79% +/- 0.22% ID/g at 2 min and 0.75% +/- 0.08% ID/g at 60 min after injection, respectively), moreover, rapid blood clearance was observed. Conclusion: [C-11]Me-NCFB could have a potential as a PET probe for the imaging of BACE1 in the brain. (C) 2013 Elsevier Inc. All rights reserved.
  • Chowdhury Nusrat Fatema, Songji Zhao, Yan Zhao, Masahiro Murakami, Wenwen Yu, Ken-ichi Nishijima, Nagara Tamaki, Yoshimasa Kitagawa, Yuji Kuge
    ANNALS OF NUCLEAR MEDICINE 27 4 355 - 362 2013年05月 [査読有り][通常論文]
     
    Although radiotherapy is an important treatment strategy for head and neck cancers, it induces tumor repopulation which adversely affects therapeutic outcome. In this regard, fractionated radiotherapy is widely applied to prevent tumor repopulation. Evaluation of tumor proliferative activity using F-18-fluorothymidine (FLT), a noninvasive marker of tumor proliferation, may be useful for determining the optimal timing of and dose in the repetitive irradiation. Thus, to assess the potentials of FLT, we evaluated the sequential changes in intratumoral proliferative activity in head and neck cancer xenografts (FaDu) using FLT. FaDu tumor xenografts were established in nude mice and assigned to control and two radiation-treated groups (10 and 20 Gy). Tumor volume was measured daily. H-3-FLT was injected intravenously 2 h before killing. Mice were killed 6, 24, 48 h, and 7 days after the radiation treatment. Intratumoral H-3-FLT level was visually and quantitatively assessed by autoradiography. Ki-67 immunohistochemistry (IHC) was performed. In radiation-treated mice, the tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. In the visual assessment, intratumoral H-3-FLT level diffusely decreased 6 h after the radiation treatment and then gradually increased with time, whereas no apparent changes were observed in Ki-67 IHC. Six hours after the radiation treatment at 10 and 20 Gy, the intratumoral H-3-FLT level markedly decreased to 45 and 40 % of the control, respectively (P < 0.0001 vs control), and then gradually increased with time. In each radiation-treated group, the H-3-FLT levels at 48 h and on day 7 were significantly higher than that at 6 h. The intratumoral H-3-FLT levels in both treated groups were 68 and 60 % at 24 h (P < 0.001), 71 and 77 % at 48 h (P < 0.001), and 83 and 81 % on day 7 (P = NS) compared with the control group. Intratumoral FLT uptake level markedly decreased at 6 h and then gradually increased with time. Sequential evaluation of intratumoral proliferative activity using FLT can be beneficial for determining the optimal timing of and dose in repetitive irradiation of head and neck cancer.
  • Masahito Kawabori, Satoshi Kuroda, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
    NEUROPATHOLOGY 33 2 140 - 148 2013年04月 [査読有り][通常論文]
     
    Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1x105 or 1x106) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.
  • Shozo Okamoto, Tohru Shiga, Koichi Yasuda, Yoichi M. Ito, Keiichi Magota, Katsuhiko Kasai, Yuji Kuge, Hiroki Shirato, Nagara Tamaki
    JOURNAL OF NUCLEAR MEDICINE 54 2 201 - 207 2013年02月 [査読有り][通常論文]
     
    Tumor hypoxia is well known to be radiation resistant. F-18-fluoromisonidazole (F-18-FMISO) PET has been used for noninvasive evaluation of hypoxia. Quantitative evaluation of F-18-FMISO uptake is thus expected to play an important role in the planning of dose escalation radiotherapy. However, the reproducibility of F-18-FMISO uptake has remained unclarified. We therefore investigated the reproducibility of tumor hypoxia by using quantitative analysis of F-18-FMISO uptake. Methods: Eleven patients with untreated head and neck cancer underwent 2 F-18-FMISO PET/CT scans (F-18-FMISO1 and F-18-FMISO2) with a 48-h interval prospectively. All images were acquired at 4 h after F-18-FMISO injection for 10 min. The maximum standardized uptake (SUVmax), tumor-to-blood ratio (TBR), and tumor-to-muscle ratio (TMR) of F-18-FMISO uptake were statistically compared between the 2 F-18-FMISO scans by use of intraclass correlation coefficients (ICCs). The hypoxic volume was calculated as the area with a TBR of greater than or equal to 1.5 or the area with a TMR of greater than or equal to 1.25 to assess differences in hypoxic volume between the 2 F-18-FMISO scans. The distances from the maximum uptake locations of the F-18-FMISO1 images to those of the F-18-FMISO2 images were measured to evaluate the locations of F-18-FMISO uptake. Results: The SUVmax (mean +/- SD) for F-18-FMISO1 and F-18-FMISO2 was 3.16 +/- 1.29 and 3.02 +/- 1.12, respectively, with the difference between the 2 scans being 7.0% +/- 4.6%. The TBRs for F-18-FMISO1 and F-18-FMISO2 were 2.98 +/- 0.83 and 2.97 +/- 0.64, respectively, with a difference of 9.9% +/- 3.3%. The TMRs for F-18-FMISO1 and F-18-FMISO2 were 2.25 +/- 0.71 and 2.19 +/- 0.67, respectively, with a difference of 7.1% +/- 5.3%. The ICCs for SUVmax, TBR, and TMR were 0.959, 0.913, and 0.965, respectively. The difference in hypoxic volume based on TBR was 1.8 +/- 1.8 mL, and the difference in hypoxic volume based on TMR was 0.9 +/- 1.3 mL, with ICCs of 0.986 and 0.996, respectively. The maximum uptake locations of the F-18-FMISO1 images were different from those of the F-18-FMISO2 images and were within the full width at half maximum of the PET/CT scanner, except in 1 case. Conclusion: The values for F-18-FMISO PET uptake and hypoxic volume in head and neck tumors between the 2 F-18-FMISO scans were highly reproducible. Such high reproducibility of tumor hypoxia is promising for accurate radiation planning.
  • Yamashita A, Zhao Y, Zhao S, Matsuura Y, Sugita H, Iwakiri T, Koshimoto C, Kawai K, Tamaki N, Kuge Y, Asada Y
    Circ J. 77 10 2626 - 35 2013年 [査読有り][通常論文]
  • Zhao Y, Zhao S, Kuge Y, Tamaki N
    J Nucl Med. 54 8 1384 - 8 2013年 [査読有り][通常論文]
  • Yi M, Kohanawa M, Zhao S, Ozaki M, Haga S, Nan G, Kuge Y, Tamaki N
    Plos One 8 9 e74287  2013年 [査読有り][通常論文]
  • Noya Y, Seki K, Asano H, Mai Y, Horinouchi T, Higashi T, Terada K, Hatate C, Hoshi A, Nepal P, Horiguchi M, Kuge Y, Miwa S
    Toxicology 314 1 1 - 10 2013年 [査読有り][通常論文]
  • Murakami M, Zhao S, Zhao Y, Fatema CN, Yu W, Nishijima K, Takiguchi M, Tamaki N, Kuge Y
    Oncology Letters. 6 3 667 - 672 2013年 [査読有り][通常論文]
  • Attenuation of apotosis by telmisartan in atherosclerotic plaques of apoE-/- mice: evaluation using 99mTc-annexin A5.
    Zhao Y, Zhao S, Kuge Y, Strauss WH, Blankenberg FG, Tamaki N
    Mol Imaging. 12 5 300 - 9 2013年 [査読有り][通常論文]
  • Hatano T, Zhao S, Zhao Y, Nishijima K, Kuno N, Hanzawa H, Sakamoto T, Tamaki N Kuge Y
    Int J Oncol. 42 3 823 - 30 2013年 [査読有り][通常論文]
  • Miyamoto M, Kuroda S, Zhao S, Magota K, Maruichi K, Ito M, Kawabori M, Shichinohe H, Houkin K, Kuge Y, Tamaki N
    J Nucl Med 54 1 145 - 50 2013年 [査読有り][通常論文]
  • Oashi K, Furukawa H, Nishihara H, Ozaki M, Oyama A, Funayama E, Hayashi T, Kuge Y, Yamamoto Y
    J Invest Dermatol. 133 2 537 - 44 2013年 [査読有り][通常論文]
  • Yasuda K, Onimaru R, Okamoto S, Shiga T, Katoh N, Tsuchiya K, Suzuki R, Takeuchi W, Kuge Y, Tamaki N, Shirato H
    Int J Radiat Oncol Biol Phys. 85 1 142 - 7 2013年 [査読有り][通常論文]
  • Kenji Hirata, Tohru Shiga, Noriyuki Fujima, Osamu Manabe, Reiko Usui, Yuji Kuge, Nagara Tamaki
    Acta radiologica (Stockholm, Sweden : 1987) 53 10 1155 - 7 2012年12月01日 [査読有り][通常論文]
     
    Encephalitis is generally diagnosed by clinical symptoms, cerebrospinal fluid examination, and imaging studies including CT, magnetic resonance imaging (MRI), and perfusion single photon emission tomography (SPECT). However, the role of positron emission tomography (PET) in diagnosis of encephalitis remains unclear. A 49-year-old woman presenting with coma and elevated inflammatory reaction was diagnosed as having encephalitis according to slow activity on electroencephalogram, broad cortical lesion in MR fluid attenuated inversion recovery image, and increased blood flow demonstrated by SPECT. PET revealed increased accumulation of (11)C-methionine (MET) in the affected brain tissues. After the symptom had improved 2 months later, the accumulation of MET as well as the abnormal findings of MR imaging and SPECT was normalized. This case indicated that MET PET may monitor the activity of encephalitis.
  • Masahiro Murakami, Songji Zhao, Yan Zhao, Nusrat Fatema Chowdhury, Wenwen Yu, Ken-Ichi Nishijima, Mitsuyoshi Takiguchi, Nagara Tamaki, Yuji Kuge
    INTERNATIONAL JOURNAL OF ONCOLOGY 41 5 1593 - 1600 2012年11月 [査読有り][通常論文]
     
    The mechanistic dissociation of 'tumor starvation' versus 'vascular normalization' following anti-angiogenic therapy is a subject of intense controversy in the field of experimental research. In addition, accurately evaluating changes of the tumor microenvironment after anti-angiogenic therapy is important for optimizing treatment strategy. Sorafenib has considerable anti-angiogenic effects that lead to tumor starvation and induce tumor hypoxia in the highly vascularized renal cell carcinoma (RCC) xenografts. F-18-fluoromisonidazole (F-18-FMISO) is a proven hypoxia imaging probe. Thus, to clarify early changes in the tumor microenvironment following anti-angiogenic therapy and whether F-18-FMISO imaging can detect those changes, we evaluated early changes in the tumor microenvironment after sorafenib treatment in an RCC xenograft by sequential histological analysis and F-18-FMISO autoradiography (ARG). A human RCC xenograft (A498) was established in nude mice, for histological studies and ARG, and further assigned to the control and sorafenib-treated groups (80 mg/kg, per os). Mice were sacrificed on Days 1, 2, 3 and 7 in the histological study, and on Days 3 and 7 in ARG after sorafenib treatment. Tumor volume was measured every day. F-18-FMISO and pimonidazole were injected intravenously 4 and 2 h before sacrifice, respectively. Tumor sections were stained with hematoxylin and eosin and immunohistochemically with pimonidazole and CD31. Intratumoral F-18-FMISO distribution was quantified in ARG. Tumor volume did not significantly change on Day 7 after sorafenib treatment. In the histological study, hypoxic fraction significantly increased on Day 2, mean vessel density significantly decreased on Day 1 and necrosis area significantly increased on Day 2 after sorafenib treatment. Intratumoral F-18-FMISO distribution significantly increased on Days 3 (10.2-fold, p<0.01) and 7 (4.1-fold, p<0.01) after sorafenib treatment. The sequential histological evaluation of the tumor microenvironment clarified tumor starvation in A498 xenografts treated with sorafenib. F-18-FMISO hypoxia imaging confirmed the tumor starvation. F-18-FMISO PET may contribute to determine an optimum treatment protocol after anti-angiogenic therapy.
  • Watanabe A, Nishijima KI, Zhao S, Zhao Y, Tanaka Y, Takemoto H, Strauss HW, Blankenberg FG, Tamaki N, Kuge Y
    J Nucl Med. 53 10 1585 - 1591 2012年10月 [査読有り][通常論文]
     
    Type 1 diabetes mellitus is characterized by a significant deficit in pancreatic beta-cell mass, presumably caused by beta-cell apoptosis. We investigated the incidence of beta-cell apoptosis in streptozotocin-treated mice and nonobese diabetic (NOD) mice with Tc-99m-annexin A5. Methods: Vehicle-treated mice, streptozotocin-treated mice, and NOD mice at the ages of 5, 9, 16, and 20 wk (5-8 mice per group) were injected with Tc-99m-annexin A5 and sacrificed 6 h later for autoradiography, and the regional Tc-99m-annexin A5 level in the pancreas was evaluated. Pancreatic islets were identified by insulin immunohistochemical staining, and apoptotic cells were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The Tc-99m-annexin A5 level in pancreatic islets was expressed as the percentage injected dose per area of pancreatic islets and normalized by animal body weight (%ID x 10(6)/mm(2)/kg). The level of apoptotic cells in pancreatic islets was expressed as the number of TUNEL-positive cells per area of pancreatic islets (cells/mm(2)). Results: The Tc-99m-annexin A5 accumulation level was significantly higher (2.5 +/- 0.7 vs. 0.7 +/- 0.1 %ID x 106/mm(2)/kg, P < 0.05) and the number of TUNEL-positive cells was significantly higher (1,170 +/- 535 vs. 5 6 cells/mm(2), P < 0.05) in the pancreatic islets of the streptozotocin-treated mice than in those of the vehicle-treated mice. The Tc-99m-annexin A5 accumulation level was significantly higher (1.1 +/- 0.4 vs. 0.5 +/- 0.1 %ID x 10(6)/mm(2)/kg, P < 0.05) and the number of TUNEL-positive cells was significantly higher (152 +/- 82 vs. 4 +/- 9 cells/mm(2), P < 0.05) in the pancreatic islets of 16-wk-old NOD mice than in those of 5-wk-old NOD mice. In addition, the level of Tc-99m-annexin AS correlated with the number of TUNEL-positive cells in the pancreatic islets of the streptozotocin-treated mice (r = 0.821, P < 0.001) and NOD mice (r = 0.721, P < 0.001). Conclusion: There is significant islet cell apoptosis with Tc-99m-annexin A5 accumulation in the pancreas of both streptozotocin and NOD mice.
  • Ohte N, Narita H, Iida A, Fukuta H, Iizuka N, Hayano J, Kuge Y, Tamaki N, Kimura G
    Eur J Nucl Med Mol Imaging. 39 8 1246 - 1253 2012年08月 [査読有り][通常論文]
     
    After myocardial infarction (MI), left ventricular (LV) remodelling is observed in noninfarcted LV myocardium. LV remodelling is closely associated with systolic heart failure. Since myocardial dysfunction is related to the downregulation of cardiac postsynaptic beta-adrenergic receptors (beta-AR), we hypothesized that a reduction in beta-AR density may be manifested in the remote noninfarcted region and such reduction may be related to myocardial systolic dysfunction. Accordingly, we assessed beta-AR density with a focus on the remote noninfarcted region. Cardiac PET was performed in 15 patients with a prior MI and 10 age-matched healthy controls using C-11-CGP 12177, a radioligand for beta-receptors. The maximum number of available specific C-11-CGP 12177 binding sites per gram of tissue was calculated in regions of interest using an established graphical method. LV regional systolic function was assessed based on peak systolic myocardial strain on the LV wall in the longitudinal direction using two-dimensional ultrasound speckle tracking imaging. LV volumes and LV ejection fraction (EF) were also measured. The LV end-diastolic volume index was significantly larger in patients than in controls (67.8 +/- 16.9 vs. 49.1 +/- 12.3 ml/m(2), p < 0.01). Significant differences in beta-AR density were observed among three areas: the apical area in controls (where the lowest beta-AR density was observed), the remote noninfarcted region of patients and LVEF a parts per thousand yen55 %, and the remote noninfarcted region of patients and LVEF < 55 % (5.8 +/- 2.1 vs. 4.2 +/- 0.7 vs. 3.3 +/- 0.7 pmol/ml, p < 0.01, ANOVA). Peak systolic myocardial strain was significantly reduced in the remote noninfarcted LV wall in patients with a prior anterior wall MI compared with that in the corresponding wall in controls (-15.5 +/- 2.5 vs. -20.1 +/- 2.2 %, p < 0.001). A similar finding was also observed in patients with a prior inferior wall MI. In the remote noninfarcted region in patients, beta-AR downregulation was observed, which was related to deterioration of local myocardial systolic function.
  • Kanegawa N, Kiyono Y, Sugitaa T, Kuge Y, Fujibayasi Y, Saji H
    Mol Imaging. 11 4 280 - 285 2012年07月 [査読有り][通常論文]
     
    To visualize the norepinephrine transporters (NETs) in various brain diseases, we developed radioiodinated (2S,alpha S)-2-(alpha-(2-iodophenoxy)benzyl) morpholine ((S,S)-IPBM). This radioligand achieved the basic requirements for NET imaging. In this study, we assessed the potential of radioiodinated (S,S)-IPBM as an imaging biomarker of NET to obtain diagnostic information about depression in relation to NET expression in the brain using a rat depression model. The ex vivo autoradiographic experiments using the (S,S)[[I-125]IPBM showed significantly lower accumulation of radioactivity in the locus coeruleus (LC) and the anteroventricular thalamic nucleus (AVTN) of the depression group than in those of the control group. Consequently, in vitro autoradiographic experiments showed that NET maximum binding (B-max) values in the LC and AVTN, known as NET-rich regions, were significantly decreased in the rat model of depression when compared to those of the control rats. In addition, there was an extremely good correlation between NET B-max and (S,S)-IPBM accumulation (r = .98), an indication of radioiodinated IPBM as a quantitative NET imaging biomarker. The reduction in (S,S)-[I-125]IPBM accumulation in the rat model of depression correlated with that of NET density. These results suggest that (S,S)-[I-123]IPBM has potential as an imaging biomarker of NET to obtain diagnostic information about major depression.
  • Masahito Kawabori, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
    NEUROPATHOLOGY 32 3 217 - 226 2012年06月 [査読有り][通常論文]
     
    Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 x 10(6) cells) or intravenously (3 x 10(6) cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.
  • Kenji Hirata, Shunsuke Terasaka, Tohru Shiga, Naoya Hattori, Keiichi Magota, Hiroyuki Kobayashi, Shigeru Yamaguchi, Kiyohiro Houkin, Shinya Tanaka, Yuji Kuge, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 39 5 760 - 770 2012年05月 [査読有り][通常論文]
     
    Purpose Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that F-18 fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas. Methods This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and 18F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated. Results Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p <= 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 +/- 0.60, range 1.71-3.81) than in non-GBM patients (1.22 +/- 0.06, range 1.09-1.29, p <= 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also higher in GBM patients (1.46 +/- 0.75, range 0.91-3.79) than in non-GBM patients (1.07 +/- 0.62, range 0.66-2.95, p <= 0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. The uptake volume of FMISO was larger in GBM ( 27.18 +/- 10.46%, range 14.02- 46.67%) than in non- GBM ( 6.07 +/- 2.50%, range 2.12- 9.22%, p <= 0.001). Conclusion These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas.
  • Ichiro Yabe, Sachiko Tsuji-Akimoto, Tohru Shiga, Shinsuke Hamada, Kenji Hirata, Mika Otsuki, Yuji Kuge, Nagara Tamaki, Hidenao Sasaki
    JOURNAL OF THE NEUROLOGICAL SCIENCES 315 1-2 55 - 59 2012年04月 [査読有り][通常論文]
     
    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neuron and various cognitive deficits including writing errors. C-11-flumazenil (FMZ), the positron emission tomography (PET) GABA(A) receptor ligand, is a marker of cortical dysfunction. The objective of this study was to investigate the relationship between cognitive deficits and loss of neuronal integrity in ALS patients using C-11-FMZ PET. Ten patients with ALS underwent both neuropsychological tests and C-11-FMZ-PET. The binding potential (BP) of FMZ was calculated from C-11-FMZ PET images. There were no significant correlations between the BP and most test scores except for the writing error index (WEI), which was measured by the modified Western Aphasia Battery - VB (WAB-IVB) test. The severity of writing error was associated with loss of neuronal integrity in the bilateral anterior cingulate gyrus with mild right predominance (n = 9; x = 4 mm, y = 36 mm, z = 4 mm, Z = 5.1). The results showed that writing errors in our patients with ALS were related to dysfunction in the anterior cingulate gyrus. (c) 2011 Elsevier B.V. All rights reserved.
  • Toshiya Osanai, Satoshi Kuroda, Taku Sugiyama, Masahito Kawabori, Masaki Ito, Hideo Shichinohe, Yuji Kuge, Kiyohiro Houkin, Nagara Tamaki, Yoshinobu Iwasaki
    Neurosurgery 70 2 435 - 44 2012年02月 [査読有り][通常論文]
     
    BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders. OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats. METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry. RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation. CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization.
  • Yin Lin, Hiroaki Furumaki, Shiho Matsuoka, Toshihiro Sakurai, Masashi Kohanawa, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hitoshi Chiba
    LABORATORY INVESTIGATION 92 2 265 - 281 2012年02月 [査読有り][通常論文]
     
    Not-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steritosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factoor (TNF)-alpha mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-alpha and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-alpha: and inflammatory cell accumulation is dependent on HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In his model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxl DL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH. Laboratory Investigation (2012) 92, 265-281; doi:10.1038/labinvest.2011.159; published online 7 November 2011
  • Ayahisa Watanabe, Ken-ichi Nishijima, Songji Zhao, Yoshikazu Tanaka, Takeshi Itoh, Hiroshi Takemoto, Nagara Tamaki, Yuji Kuge
    ANNALS OF NUCLEAR MEDICINE 26 2 184 - 191 2012年02月 [査読有り][通常論文]
     
    Glycosylation is generally applicable as a strategy for increasing the activity of bioactive proteins. In this study, we examined the effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1 (GLP-1) as a bioactive peptide for type 2 diabetes. Noninvasive imaging studies were performed using a gamma camera after the intravenous administration of I-123-GLP-1 or I-123-alpha 2, 6-sialyl N-acetyllactosamine (glycosylated) GLP-1 in rats. In ex vivo biodistribution studies using I-125-GLP-1 or I-125-glycosylated GLP-1, organ samples were measured for radioactivity. Plasma samples were added to 15% trichloroacetic acid (TCA) to obtain TCA-insoluble and TCA-soluble fractions. The radioactivity in the TCA-insoluble and TCA-soluble fractions was measured. In the noninvasive imaging studies, a relatively high accumulation level of I-123-GLP-1 was found in the liver, which is the major organ to eliminate exogenous GLP-1. The area under the time-activity curve (AUC) of I-123-glycosylated GLP-1 in the liver was significantly lower (89%) than that of I-123-GLP-1. These results were consistent with those of ex vivo biodistribution studies using I-125-labeled peptides. The AUC of I-125-glycosylated GLP-1 in the TCA-insoluble fraction was significantly higher (1.7-fold) than that of GLP-1. This study demonstrated that glycosylation significantly decreased the distribution of radiolabeled GLP-1 into the liver and increased the concentration of radiolabeled GLP-1 in plasma. These results suggested that glycosylation is a useful strategy for decreasing the distribution into the liver of bioactive peptides as desirable pharmaceuticals.
  • Yi M, Tao H, Kohanawa M, Zhao S, Kuge Y, Tamaki N
    Biol Pharm Bull. 34 12 2214 - 2223 2012年 [査読有り][通常論文]
  • Kohei Sano, Takashi Temma, Takashi Azuma, Ryusuke Nakai, Michiko Narazaki, Yuji Kuge, Hideo Saji
    MOLECULAR IMAGING AND BIOLOGY 13 6 1196 - 1203 2011年12月 [査読有り][通常論文]
     
    Purpose: We aimed to establish a magnetic resonance imaging (MRI) protocol for the sensitive and specific imaging of functional molecules with a pre-targeting strategy utilizing the streptavidin-biotin interaction. Membrane type-1 matrix metalloproteinase (MT1-MMP) was selected as the target molecule. Procedures: The biotinylated polyamidoamine dendrimer (PAMAM)-based contrast agent (Bt-PAMAM-DTPA(Gd)) was prepared, and its proton relaxivity (r1) and affinity to streptavidin were evaluated. Tumor-bearing mice were pre-targeted with streptavidin-conjugated anti-MT1-MMP monoclonal antibody (mAb), streptavidin-conjugated negative control IgG, or saline and 3 days later were injected with Bt-PAMAM-DTPA(Gd) followed immediately by MRI for a period of 3 h. Results: High r1 (15.5 L mmol(-1) s(-1)) and 1.9-fold higher affinity than d-biotin were obtained. Significantly higher relative tumor signals were observed in mice pre-targeted with streptavidin-conjugated anti-MT1-MMP mAb (165% at 3 h vs. pre-administration) than with saline or streptavidin-conjugated negative control IgG (P < 0.0001). Conclusions: This pre-targeting approach can accomplish sensitive and specific in vivo MRI of functional molecules.
  • Hua Li, Songji Zhao, Yongnan Jin, Ken-ichi Nishijima, Hiromichi Akizawa, Kazue Ohkura, Nagara Tamaki, Yuji Kuge
    NUCLEAR MEDICINE COMMUNICATIONS 32 12 1211 - 1215 2011年12月 [査読有り][通常論文]
     
    Objectives We have developed a radiolabeled uracil derivative, 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil (IIMU) as a novel single photon emission computed tomography probe for thymidine phosphorylase (TP). This radioiodinated IIMU has a high affinity for TP and highly accumulates in the TP-expressing tumor cell line A431 (human epidermoid carcinoma). To evaluate the specificity of the cellular uptake of IIMU to TP expression, we examined the effects of TP knockdown on the uptake of (125)I-labeled IIMU ((125)I-IIMU) in the tumor cells. Methods TP-specific small interfering RNA (siRNA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-specific siRNA (positive control), and negative control siRNA were transfected into A431 cells, respectively. Target-mRNA and protein expression levels of TP and GAPDH were examined 48 and 72 h after transfection, respectively. The cellular uptake level of (125)I-IIMU was also evaluated 72 h after transfection. The results were compared after normalization with the corresponding negative controls. Results After TP-specific and GAPDH-specific siRNA transfection, the expression levels of TP and GAPDH mRNA decreased significantly to 41 and 29%, respectively, compared with the negative control (P < 0.001 for both). The expression levels of TP and GAPDH protein also significantly decreased to 34 and 30%, respectively (P < 0.001 for both). After TP-specific siRNA transfection, the cellular uptake level of (125)I-IIMU decreased significantly to 66% (P < 0.001). In contrast, GAPDH siRNA transfection did not significantly affect the cellular uptake level of (125)I-IIMU. Conclusion siRNA-mediated TP knockdown significantly decreased the cellular uptake level of (125)I-IIMU. This finding indicates that the uptake of IIMU in tumor cells is TP specific and directly corresponds to TP expression levels. Nucl Med Commun 32: 1211-1215 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Nuclear Medicine Communications 2011, 32: 1211-1215
  • Songji Zhao, Yuji Kuge, Min Yi, Yan Zhao, Toshiyuki Hatano, Keiichi Magota, Ken-ichi Nishijima, Masashi Kohanawa, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 38 10 1876 - 1886 2011年10月 [査読有り][通常論文]
     
    We evaluated whether the dynamic profile of L-C-11-methionine (C-11-MET) may have an additional value in differentiating malignant tumors from granulomas in experimental rat models by small animal positron emission tomography (PET). Rhodococcus aurantiacus and allogenic rat C6 glioma cells were inoculated, respectively, into the right and left calf muscles to generate a rat model bearing both granulomas and tumors (n = 6). Ten days after the inoculations, dynamic C-11-MET PET was performed by small animal PET up to 120 min after injection of C-11-MET. The next day, after overnight fasting, the rats were injected with F-18-2-deoxy-2-fluoro-D-glucose (F-18-FDG), and dynamic F-18-FDG PET was performed up to 180 min. The time-activity curves, static images, and mean standardized uptake value (SUV) in the lesions were calculated. C-11-MET uptake in the granuloma showed a slow exponential clearance after an initial distribution, while the uptake in the tumor gradually increased with time. The dynamic pattern of C-11-MET uptake in the granuloma was significantly different from that in the tumor (p < 0.001). In the static analysis of C-11-MET, visual assessment and SUV analysis could not differentiate the tumor from the granuloma in all cases, although the mean SUV in the granuloma (1.48 +/- 0.09) was significantly lower than that in the tumor (1.72 +/- 0.18, p < 0.01). The dynamic patterns, static images, and mean SUVs of F-18-FDG in the granuloma were similar to those in the tumor (p = NS). Dynamic C-11-MET PET has an additional value for differentiating malignant tumors from granulomatous lesions, which deserves further elucidation in clinical settings.
  • Takashi Kudo, Masashi Ueda, Hiroaki Konishi, Hidekazu Kawashima, Yuji Kuge, Takahiro Mukai, Azusa Miyano, Shotaro Tanaka, Shinae Kizaka-Kondoh, Masahiro Hiraoka, Hideo Saji
    MOLECULAR IMAGING AND BIOLOGY 13 5 1003 - 1010 2011年10月 [査読有り][通常論文]
     
    We aimed to evaluate the feasibility of using streptavidin-biotin-based pretargeting for positron emission tomography (PET) imaging of hypoxia-inducible factor (HIF)-1-active tumors. We used POS, a genetically engineered form of streptavidin that selectively stabilizes in HIF-1-active cells, and (4-F-18-fluorobenzoyl)norbiotinamide (F-18-FBB), a radiolabeled biotin derivative, for performing a biodistribution study and for PET imaging. The tumoral F-18-FBB accumulation was compared to the HIF-1-dependent luciferase bioluminescence and HIF-1 alpha immunohistochemical signal. F-18-FBB accumulation was observed in POS-pretargeted tumors in mice (2.85 +/- 0.55% injected dose per gram at 3 h), and clear PET images were obtained at the same time point. The tumoral F-18-FBB accumulation positively correlated with luciferase bioluminescence (R = 0.72, P < 0.05), and most of the area showing F-18-FBB accumulation corresponded to HIF-1 alpha-positive areas. Pretargeting with POS and F-18-FBB is an effective approach for PET imaging of HIF-1-active areas in tumors.
  • Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-Ichi Nishijima, Toshiyuki Hatano, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita
    ONCOLOGY REPORTS 26 3 725 - 730 2011年09月 [査読有り][通常論文]
     
    We investigated whether F-18-fluorothymidine-positron-emission tomography/computed tomography (F-18-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, F-18-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, F-18-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p=0.01). These results suggest that F-18-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuxima.b at an earlier time point than the change of tumor size.
  • Yan Zhao, Songji Zhao, Yuji Kuge, William H. Strauss, Francis G. Blankenberg, Nagara Tamaki
    MOLECULAR IMAGING AND BIOLOGY 13 4 712 - 720 2011年08月 [査読有り][通常論文]
     
    The aim of this study was to understand the relationship of lipid deposition to the macrophage content, macrophage metabolism, and apoptosis in plaque. We compared the uptake of 2-deoxy-2-fluoro-D-[C-14]glucose ([C-14]FDG) and [Tc-99m]HYNIC-annexin V ([Tc-99m]annexin A5) with the lesion histology in apolipoprotein E knockout (apoE(-/-)) mice. Male apoE(-/-) mice (n = 9) were injected with [C-14]FDG and [Tc-99m]annexin A5. Cryostat sections of aorta samples (n = 49) were used for dual-tracer autoradiography, and regional tracer uptake levels were evaluated. Lesions were identified histologically with Movat's pentachrome (AHA lesion phenotypes), Mac-2 staining (macrophage infiltration) and Oil Red O staining (lipid deposition). The highest uptakes of [C-14]FDG (3.10 +/- 1.50 %ID x kilogram per square millimeter) and [Tc-99m]annexin A5 (0.49 +/- 0.20 %ID x kilogram per square millimeter) were shown in atheromatous lesions (types III and IV). Each tracer uptake showed better correlation with macrophage infiltration than lipid deposition ([C-14]FDG, r = 0.44 vs. r = 0.14; [Tc-99m]annexin A5, r = 0.65 vs. r = 0.48). Both tracers were concentrated in type III and IV atheromatous lesions which corresponded to macrophage infiltration rather than lipid deposition.
  • Kenji Hirata, Yuji Kuge, Chiaki Yokota, Akina Harada, Koichi Kokame, Hiroyasu Inoue, Hidekazu Kawashima, Hiroko Hanzawa, Yuji Shono, Hideo Saji, Kazuo Minematsu, Nagara Tamaki
    NEUROSCIENCE LETTERS 495 3 210 - 215 2011年05月 [査読有り][通常論文]
     
    Although an enriched environment enhances functional recovery after ischemic stroke, the mechanism underlying this effect remains unclear. We previously reported that brain derived neurotrophic factor (BDNF) gene expression decreased in rats housed in an enriched environment for 4 weeks compared to those housed in a standard cage for the same period. To further clarify the relationship between the decrease in BDNF and functional recovery, we investigated the effects of differential 2-week housing conditions on the mRNA of BDNF and protein levels of proBDNF and mature BDNF (matBDNF). After transient occlusion of the right middle cerebral artery of male Sprague-Dawley rats, we divided the rats into two groups: (1) an enriched group housed multiply in large cages equipped with toys, and (2) a standard group housed alone in small cages without toys. Behavioral tests before and after 2-week differential housing showed better neurological recovery in the enriched group than in the standard group. Synaptophysin immunostaining demonstrated that the density of synapses in the pen-infarct area was increased in the enriched group compared to the standard group, while infarct volumes were not significantly different. Real-time reverse transcription polymerase chain reaction. Western blotting and immunostaining all revealed no significant difference between the groups. The present results suggest that functional recovery cannot be ascribed to an increase in matBDNF or a decrease in proBDNF but rather to other underlying mechanisms. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Keiichi Magota, Naoki Kubo, Yuji Kuge, Ken-ichi Nishijima, Songji Zhao, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 38 4 742 - 752 2011年04月 [査読有り][通常論文]
     
    We investigated the performance of the Inveon small-animal PET/SPECT/CT system and compared the imaging capabilities of the SPECT and PET components. For SPECT, the energy resolution, tomographic spatial resolution and system sensitivity were evaluated with a (99m)Tc solution using a single pinhole collimator. For PET, the spatial resolution, absolute sensitivity, scatter fraction and peak noise equivalent count were evaluated. Phantoms and a normal rat were scanned to compare the imaging capabilities of SPECT and PET. The SPECT spatial resolution was 0.84 mm full-width at half-maximum (FWHM) at a radius of rotation of 25 mm using a 0.5-mm pinhole aperture collimator, while the PET spatial resolution was 1.63 mm FWHM at the centre. The SPECT system sensitivity at a radius of rotation of 25 mm was 35.3 cps/MBq (4 x 10(-3)%) using the 0.5-mm pinhole aperture, while the PET absolute sensitivity was 3.2% for 350-650 keV and 3.432 ns. Accordingly, the volume sensitivity of PET was three orders of magnitude higher than that of SPECT. This integrated PET/SPECT/CT system showed high performance with excellent spatial resolution for SPECT and sensitivity for PET. Based on the tracer availability and system performance, SPECT and PET have complementary roles in multimodality small-animal imaging.
  • Shozo Okamoto, Tohru Shiga, Naoya Hattori, Naoki Kubo, Toshiki Takei, Norio Katoh, Yutaka Sawamura, Kenichi Nishijima, Yuji Kuge, Nagara Tamaki
    ANNALS OF NUCLEAR MEDICINE 25 3 213 - 220 2011年04月 [査読有り][通常論文]
     
    (11)C-Methionine positron emission tomography (MET-PET) has been used to distinguish brain tumor recurrence from radiation necrosis. Because the spatial resolution of conventional PET scanners is low, partial volume effect (PVE) may decrease the detectability of small tumor recurrence. The aim of this study is to investigate the diagnostic value of MET-PET upon semiquantitative analyses in particular PVE-affected small lesions. First, we performed a phantom experiment to investigate what size lesion is affected by PVE. This study included 29 patients (33 lesions) suspected of recurrent brain tumors by magnetic resonance imaging (MRI) after radiation therapy. All of them received MET-PET. Semiquantitative analysis was performed using maximum standardized uptake value (SUVmax) and lesion-versus-normal ratio (L/N ratio). ROC analysis was also assessed about the diagnostic value of MET-PET. From the result of the phantom experiment, lesions smaller than 20 mm in brain mode or smaller than 30 mm in whole-body mode were defined as PVE-affected lesions. Histological analysis or clinical follow-up confirmed the diagnosis of tumor recurrence in 22 lesions, and radiation necrosis in 11 lesions. L/N ratios of recurrence and necrosis for overall lesions were 1.98 +/- A 0.62 and 1.27 +/- A 0.28, respectively (p < 0.01). In the PVE-affected lesions, L/N ratio for recurrence (1.72 +/- A 0.44) was also significantly higher than that for necrosis (1.20 +/- A 0.11) (p < 0.01). On the ROC analysis for the PVE-affected lesions, the area under the curve for L/N ratio (0.897) was significantly higher than that for SUVmax (0.718) (p < 0.05). These areas under the curve were almost equal to that of overall lesions for L/N ratio (0.886) and for SUVmax (0.738). Semiquantitative analysis of MET provided high diagnostic value even for PVE-affected small lesions. MET-PET enables early diagnosis of recurrence of brain tumor in the follow-up after the radiation therapy.
  • Taku Sugiyama, Satoshi Kuroda, Toshiya Osanai, Hideo Shichinohe, Yuji Kuge, Masaki Ito, Masahito Kawabori, Yoshinobu Iwasaki
    NEUROSURGERY 68 4 1036 - 1047 2011年04月 [査読有り][通常論文]
     
    BACKGROUND: Noninvasive imaging techniques would be needed to validate the therapeutic benefits of cell transplantation therapy for central nervous system disorders. OBJECTIVE: To evaluate whether near-infrared (NIR)-emitting fluorescence tracer, quantum dots, would be useful to noninvasively visualize the bone marrow stromal cells (BMSC) transplanted into the infarct brain in living animals. METHODS: Rat BMSCs were labeled with QD800. In vitro and in vivo conditions to visualize NIR fluorescence were precisely optimized. The QD800-labeled BMSCs were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Using the NIR fluorescence imaging technique, the behaviors of BMSCs were serially visualized during the 8 weeks after transplantation. RESULTS: NIR fluorescence imaging could noninvasively detect the NIR fluorescence emitted from the transplanted BMSCs engrafted in the peri-infarct neocortex through the scalp up to 8 weeks after transplantation. The intensity gradually increased and reached the peak at 4 weeks. The results were supported by the findings on ex vivo NIR fluorescence imaging and histological analysis. CONCLUSION: NIR fluorescence imaging is valuable in monitoring the behaviors of donor cells in the rodent brain. The results would allow new opportunities to develop noninvasive NIR fluorescence imaging as a modality to track the BMSCs transplanted into the brain.
  • Yuji Shono, Chiaki Yokota, Yuji Kuge, Shinsuke Kido, Akina Harada, Koichi Kokame, Hiroyasu Inoue, Mariko Hotta, Kenji Hirata, Hideo Saji, Nagara Tamaki, Kazuo Minematsu
    BRAIN RESEARCH 1376 60 - 65 2011年02月 [査読有り][通常論文]
     
    Recent studies have demonstrated that animals housed in an enriched environment after an experimental stroke obtained a better functional outcome than those housed in a standard cage; however, little is known about the gene expression associated with this functional recovery. The purpose of the present study was to elucidate the expression of genes in an enriched environment after experimental stroke in the ischemic and non-ischemic sides of the cortices. Transient focal brain ischemia was produced by the occlusion of the right middle cerebral artery (t-MCAO) in male Sprague Dawley rats. The rats were divided into 3 groups: ischemic rats housed in the enriched environment, ischemic rats housed in standard cages, and non-ischemic rats in standard cages. Four weeks after t-MCAO, the rats were sacrificed and gene expression was examined. Motor function was improved in ischemic rats housed in the enriched environment compared with those in standard cages; however, there were no significant differences in the size of the infarct area between the ischemic rats in the enriched environment and those in standard cages. Decreases in the expression of Egr-1, -2, and BDNF mRNA in both sides of the cortices were detected in rats housed in the enriched environment, indicating that gene expression was altered throughout the brain at 4 weeks after transient focal ischemia. (C) 2010 Elsevier B.V. All rights reserved.
  • Kenji Hirata, Naoya Hattori, Chietsugu Katoh, Tohru Shiga, Satoshi Kuroda, Naoki Kubo, Reiko Usui, Yuji Kuge, Nagara Tamaki
    NUCLEAR MEDICINE COMMUNICATIONS 32 1 63 - 70 2011年01月 [査読有り][通常論文]
     
    Objective Cerebral blood flow (CBF) estimation with C(15)O(2) PET usually assumes a single tissue compartment model and a fixed brain-blood partition coefficient of water. However, the partition coefficient may change in pathological conditions. The purpose of this study was to investigate the changes in the partition coefficient of water in pathological regions and its effect on regional CBF assessment. Methods The study protocol included 22 patients with occlusive cerebrovascular disease to compare the partition coefficients among three regions (infarction area, noninfarct hypoperfusion area, and contralateral area) in the pathological brain (analysis A), and to compare the CBF estimated by using a fixed partition coefficient and CBF estimated using floating partition coefficients (analysis B). Results The partition coefficient in the infarction area (0.55 +/- 0.07 ml/g) was lower than that in the contralateral normal cortex (0.68 +/- 0.05 ml/g), whereas noninfarct hypoperfusion area did not show a significant change (0.67 +/- 0.06 ml/g). As a result, the use of a fixed partition coefficient of normal volunteers (0.70 ml/g) resulted in an underestimation in regional CBF by 12% in infarction area (P<0.05), whereas the estimation errors were smaller and induced no significant difference in the noninfarct hypoperfusion area or in contralateral areas. Conclusion The partition coefficient is stable except for the infarction area, and CBF estimation using a fixed partition coefficient of normal volunteers provides clinically appreciable information in patients with cerebrovascular disease. Nucl Med Commun 32:63-70 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
  • Takashi Temma, Yuki Ogawa, Yuji Kuge, Seigo Ishino, Nozomi Takai, Kantaro Nishigori, Masashi Shiomi, Masahiro Ono, Hideo Saji
    JOURNAL OF NUCLEAR MEDICINE 51 12 1979 - 1986 2010年12月 [査読有り][通常論文]
     
    Tissue factor (TF), a transmembrane glycoprotein that acts as an essential cofactor to factor VII/VIIa, initiates the exogenous blood coagulation cascade leading to thrombin generation and subsequent thrombus formation in vivo. TF expression is closely related to plaque vulnerability, and high TF expression is shown in macrophage-rich atheromatous lesions, making TF a potential target for detecting atheromatous lesions in vivo. Thus, we prepared (99m)Tc-labeled anti-TF-monoclonal antibody (TF-mAb) IgG as a molecular probe and evaluated its usefulness to achieve TF-specific imaging using myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Methods: Anti-TF-mAb was created using a standard hybridoma technique and was labeled by (99m)Tc with 6-hydrazinonicotinic acid (HYNIC) as a chelating agent to obtain (99m)Tc-TF-mAb. The immunoreactivity of HYNIC-TF-mAb was estimated by flow cytometry. WHHLMI and control rabbits were injected intravenously with (99m)Tc-TF-mAb. Twenty-four hours after the injection, the aorta was removed and radioactivity was measured. Autoradiography and histologic studies were performed using serial aorta sections. Subclass matched antibody (IgG(1)) was used as a negative control. Results: HYNIC-TF-mAb showed 93% immunoreactivity of the anti-TF-mAb. The radioactivity accumulation in WHHLMI aortas was 6.1-fold higher than that of control rabbits. Auto-radiograms showed a heterogeneous distribution of radioactivity in the intima of WHHLMI aortas. Regional radioactivity accumulation was positively correlated with TF expression density (R = 0.64, P < 0.0001). The highest radioactivity accumulation in percentage injected dose x body weight/mm(2) x 10(2) was found in atheromatous lesions (5.2 +/- 1.9) followed by fibroatheromatous (2.1 +/- 0.7), collagen-rich (1.8 +/- 0.7), and neointimal lesions (1.8 +/- 0.6). In contrast, (99m)Tc-IgG(1) showed low radioactivity accumulation in WHHLMI aortas that was independent of the histologic grade of lesions. Conclusion: The TF-detecting ability and preferential accumulation in atheromatous lesions of (99m)Tc-TF-mAb were demonstrated, indicating its potential for selective imaging of macrophage-rich atheromatous lesions in vivo.
  • Yuji Kuge, Nozomi Takai, Yuki Ogawa, Takashi Temma, Yan Zhao, Kantaro Nishigori, Seigo Ishino, Junko Kamihashi, Yasushi Kiyono, Masashi Shiomi, Hideo Saji
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 37 11 2093 - 2104 2010年11月 [査読有り][通常論文]
     
    Purpose Membrane type 1 matrix metalloproteinase (MT1-MMP) activates pro-MMP-2 and pro-MMP-13 to their active forms and plays important roles in the destabilization of atherosclerotic plaques. This study sought to determine the usefulness of (99m)Tc-labelled monoclonal antibody (mAb), recognizing MT1-MMP, for imaging atherosclerosis in a rabbit model (WHHLMI rabbits). Methods Anti-MT1-MMP monoclonal IgG(3) and negative control IgG(3) were radiolabelled with (99m)Tc after derivatization with 6-hydrazinonicotinic acid (HYNIC) to yield (99m)Tc-MT1-MMP mAb and (99m)Tc-IgG(3), respectively. WHHLMI and control rabbits were injected with these radio-probes. The aorta was removed and radioactivity was measured at 24 h after the injection. Autoradiography and histological studies were performed. Results (99m)Tc-MT1-MMP mAb accumulation in WHHLMI rabbit aortas was 5.4-fold higher than that of control rabbits. Regional (99m)Tc-MT1-MMP mAb accumulation was positively correlated with MT1-MMP expression (r = 0.59, p < 0.0001), while (99m)Tc-IgG(3) accumulation was independent of MT1-MMP expression (r = 0.03, p = NS). The highest (99m)Tc-MT1-MMP mAb accumulation was found in atheromatous lesions (4.8 +/- 1.9, %IDxBW/mm(2) x 10(2)), followed in decreasing order by fibroatheromatous (1.8 +/- 1.3), collagen-rich (1.6 +/- 1.0) and neointimal lesions (1.5 +/- 1.5). In contrast, (99m)Tc-IgG(3) accumulation was almost independent of the histological grade of lesions. Conclusion Higher (99m)Tc-MT1-MMP mAb accumulation in grade IV atheroma was shown in comparison with neointimal lesions or other more stable lesions. Nuclear imaging with (99m)Tc-MT1-MMP mAb, in combination with CT and MRI, could provide new diagnostic imaging capabilities for detecting vulnerable plaques, although further investigations to improve target to blood ratios are strongly required.
  • Kohei Sano, Takashi Temma, Yuji Kuge, Takashi Kudo, Junko Kamihashi, Songji Zhao, Hideo Saji
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 33 9 1589 - 1595 2010年09月 [査読有り][通常論文]
     
    Since membrane type-1 matrix metalloproteinase (MT1-MMP) is exclusively expressed in tumors and is closely associated with metastasis and invasion, MT1-MMP is a potential target of radiotracers for the evaluation of tumor malignancy. In this study, we planned to visualize MT1-MMP in vivo by a two-step pre-targeting strategy using a streptavidin (SAv)-biotin system combined with anti-MT1-MMP monoclonal immunoglobulin (IgG) (anti-MT1-MMP monoclonal antibody (mAb)). Streptavidinylated anti-MT1-MMP mAb was synthesized by reacting biotinylated anti-MT1-MMP mAb with SAv. In the pre-targeting study, FM3A mouse breast carcinoma-implanted mice were injected with anti-MT1-MMP mAb-SAv, followed 72 h later with radioiodinated biotin, (3-[I-123/125]iodobenzoyl)norbiotinamide (I-123/125-IBB). Biodistribution and imaging (single photon emission computed tomography (SPECT)/CT) data were collected at several time points in the 24 h period following introduction of the tracer. The comparison groups were injected with I-125-IBB alone or with I-125-IBB pre-targeted with negative control IgG-SAv. In the pre-targeting study for MT1-MMP, within 1 h of tracer injection, rapid tumor uptake and abrupt clearance from the blood of radioactivity (2.22, 0.87% injected dose/g at 1 h) were observed. The tumor to blood (T/B) radioactivity ratios were significantly higher than those from mice dosed with the pre-targeting negative control (p<0.0001). I-125-IBB alone did not accumulate in tumors. SPECT/CT image analysis of FM3A bearing mice showed high-contrast tumor images after 3 h with minimal blood-pool activity. The present study that uses a pre-targeting method showed high T/B radioactivity ratios and clear tumor images of MT1-MMP. This imaging method may be useful for the clinical diagnosis of malignant tumors.
  • Masashi Ueda, Takashi Kudo, Yuji Kuge, Takahiro Mukai, Shotaro Tanaka, Hiroaki Konishi, Azusa Miyano, Masahiro Ono, Shinae Kizaka-Kondoh, Masahiro Hiraoka, Hideo Saji
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 37 8 1566 - 1574 2010年08月 [査読有り][通常論文]
     
    Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-(123)I-iodobenzoyl)norbiotinamide ((123)I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and (123)I-IBB for rapid imaging of HIF-1-active tumours. Tumour-implanted mice were pretargeted with POS. After 24 h, (125)I-IBB was administered and subsequently, the biodistribution of radioactivity was investigated at several time points. In vivo planar imaging, comparison between (125)I-IBB accumulation and HIF-1 transcriptional activity, and autoradiography were performed at 6 h after the administration of (125)I-IBB. The same sections that were used in autoradiographic analysis were subjected to HIF-1 alpha immunohistochemistry. (125)I-IBB accumulation was observed in tumours of mice pretargeted with POS (1.6%ID/g at 6 h). This result is comparable to the data derived from (125)I-IBB-conjugated POS-treated mice (1.4%ID/g at 24 h). In vivo planar imaging provided clear tumour images. The tumoral accumulation of (125)I-IBB significantly correlated with HIF-1-dependent luciferase bioluminescence (R=0.84, p < 0.01). The intratumoral distribution of (125)I-IBB was heterogeneous and was significantly correlated with HIF-1 alpha-positive regions (R=0.58, p < 0.0001). POS pretargeting with (123)I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours.
  • Hiromichi Akizawa, Songji Zhao, Masayuki Takahashi, Ken-ichi Nishijima, Yuji Kuge, Nagara Tamaki, Koh-ichi Seki, Kazue Ohkura
    NUCLEAR MEDICINE AND BIOLOGY 37 4 427 - 432 2010年05月 [査読有り][通常論文]
     
    Introduction: The expression of thymidine phosphorylase (TP) is closely associated with angiogenesis, tumor invasiveness and activation of. antitumor agents. We evaluated radioiodinated 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([(125)I]IIMU) having high TP-inhibitory potency as the new radiotracer for SPECT targeting of TP expression in tumors. Methods: The characteristics of the radioiodinated TP inhibitor IIMU were determined by evaluating the uptake by tumor cells in vitro and by biodistribution studies in vivo. The distribution of the radiotracer and the extent of TP-specific uptake by tumors were evaluated by a counting method in tumor-bearing mice. Results: The in vitro uptake of radiolabeled IIMU by A431 cells along with high TP expressions was attributed to the binding of the radiotracer to its target enzyme, i.e., TP. In vivo distribution of the radiotracer in A431 tumor-bearing mice revealed tumor/blood and tumor/muscle activity uptake ratios of 36 and 106, respectively, at 3 h after the radiotracer injection. On using low TP-expressing tumors and TP blocking studies as controls, minor TP-specific accumulation of the radiotracer was detected in these studies. Conclusion: According to the binding of radioiodinated IIMU to the angiogenic enzyme TP, it can be concluded that radioiodinated IIMU might be suitable as a SPECT tracer for tumor imaging. (C) 2010 Elsevier Inc. All rights reserved.
  • Koh-ichi Seki, Yoichi Noya, Yusuke Mikami, Shinji Taneda, Akira K. Suzuki, Yuji Kuge, Kazue Ohkura
    ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH 17 3 717 - 723 2010年03月 [査読有り][通常論文]
     
    We recently developed a new isolation method for diesel exhaust particles (DEP), involving successive extraction with H(2)O, sodium bicarbonate, and sodium hydroxide, in which the sodium hydroxide extract was found to consist of phenolic components. Analysis of the extract revealed that vasodilative-active nitrophenols are in DEP in significantly higher concentrations than those estimated by an earlier method involving a combination of solvent extraction and repeated chromatography. These findings indicated that our new procedure offers a simple, efficient, and reliable method for the isolation and identification of bioactive substances in DEP. This encouraged us to extend our work toward investigating new vasodilatory substances in the sodium bicarbonate extract. DEP were collected from the exhaust of a 4JB1-type engine (ISUZU Automobile Co., Tokyo, Japan). GC-MS analysis was performed with a GCMS-QP2010 instrument (Shimadzu, Kyoto, Japan). DEP dissolved in 1-butanol was successively extracted with water, sodium bicarbonate, and then aqueous sodium hydroxide. The sodium bicarbonate extract was neutralized and the resulting mixture of acidic components was subjected to reverse-phase (RP) column chromatography followed by RP-HPLC with fractions assayed for vasodilative activity. This led to the identification of terephthalic acid, p-hydroxybenzoic acid, isophthalic acid, phthalic acid, 3-hydroxy-4-nitrobenzoic acid, 4-hydroxy-3-nitrophenol, and 1,4,5-naphthalene tricarboxylic acid as components of DEP. The sodium bicarbonate extract was rich in aromatic carboxylic acid components. Repeated reverse-phase chromatography resulted in the successful isolation of several acidic substances including the new vasodilative materials, 4-hydroxy-3-nitrobenzoic acid, and 3-hydroxy-4-nitrobenzoic acid. Our new fractionation method for DEP has made possible the isolation of new vasodilative compounds from the sodium bicarbonate extract.
  • M. Ueda, Y. Iida, A. Tominaga, T. Yoneyama, M. Ogawa, Y. Magata, H. Nishimura, Y. Kuge, H. Saji
    BRITISH JOURNAL OF PHARMACOLOGY 159 6 1201 - 1210 2010年03月 [査読有り][通常論文]
     
    Background and purpose: Much interest is currently being focused on the anti-nociceptive effects mediated by nicotinic acetylcholine (nACh) receptors, including their location and mechanism of action. The purpose of this study was to elucidate these issues using 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), a nACh receptor agonist, and [125I]5IA. Experimental approach: We partially ligated the sciatic nerve of Sprague-Dawley rat to induce neuropathic pain [Seltzer's partial sciatic nerve ligation (PSL) model]. We then examined the changes in nACh receptor density in the CNS using [125I]5IA autoradiography and the involvement of nACh receptors in anti-nociceptive effects in the region where changes occurred. Key results: Autoradiographic studies showed that the accumulation of [125I]5IA and the number of nACh receptors in the thalamus of PSL rats were increased about twofold compared with those in the sham-operated rats. No change was observed in other brain regions. Rats injected in the ventral posterolateral thalamic nucleus (VPL) with 5IA demonstrated a significant and dose-dependent anti-allodynic effect and this effect was completely antagonized by mecamylamine, injected with 5IA, into the VPL. The blockade of nACh receptors in the VPL by mecamylamine decreased by 70% the anti-allodynic effect of 5IA, given i.c.v. Moreover, mecamylamine given intra-VPL by itself, induced significant hyperalgesia. Conclusions and implications: Our findings suggest that the nACh receptors expressed in the VPL play an important role in the anti-allodynic effects produced by exogenous and endogenous agonists.
  • Kazuki Aita, Takashi Temma, Yoichi Shimizu, Yuji Kuge, Koh-ichi Seki, Hideo Saji
    JOURNAL OF FLUORESCENCE 20 1 225 - 234 2010年01月 [査読有り][通常論文]
     
    Fluorescent analysis has been widely used in biological, chemical and analytical research. A useful fluorescent labeling agent should include NIR emission, a large Stoke's shift, and good labeling ability without interfering with the pharmacological profile of the labeled compound. Thus, we planned to develop an M-AMF-DOTA(Nd) derivative composed of an NIR fluorescent moiety and a maleimide conjugating moiety as a new NIR fluorescent labeling agent which fulfills these requirements. M-AMF-DOTA(Nd) was synthesized from 4-amino-fluorescein and was conjugated with an avidin molecule (Avidin-AMF-DOTA(Nd)) through Lys-side chains by reaction with 2-iminothiolane. The fluorescent features of M-AMF-DOTA(Nd) and Avidin-AMF-DOTA(Nd) were comparatively evaluated. A binding assay of Avidin-AMF-DOTA(Nd) with D-biotin and a tumor cell-uptake study were performed to estimate the effects of conjugation on the biological and physicochemical features of the protein. M-AMF-DOTA(Nd) was obtained in 22% overall yield. M-AMF-DOTA(Nd) had a typical NIR fluorescence from the Nd ion (880 nm and 900 nm from 488 nm excitation). Avidin-AMF-DOTA(Nd) was easily synthesized and also had typical NIR fluorescence from the Nd ion without loss of fluorescent intensity. The binding affinity of Avidin-AMF-DOTA(Nd) to D-biotin was equivalent to naive avidin. Avidin-AMF-DOTA(Nd) was taken up by tumor cells in the same manner as avidin conjugated with fluorescein isothiocyanate, an established, widely used fluorescent avidin. Results from this study indicate that M-AMF-DOTA(Nd) is a potential labeling agent for routine NIR fluorescent analysis.
  • Kazuki Aita, Takashi Temma, Yuji Kuge, Koh-ichi Seki, Hideo Saji
    LUMINESCENCE 25 1 19 - 24 2010年01月 [査読有り][通常論文]
     
    We have developed a new NIR fluorescent probe based on an ytterbium(III) (E)-1-(pyridin-2-yl-diazenyl)naphthalen-2-ol (PAN) complex. This probe emits near-infrared luminescence derived from the Yb ion through excitation of the PAN moiety with visible light (lambda(ex) = 530 lambda(em) = 975 nm). The results support the possible utility of the probe for in vivo fluorescence molecular imaging. Copyright (C) 2009 John Wiley & Sons, Ltd.
  • Yuji Kuge, Naoyuki Obokata, Hiroyuki Kimura, Yumiko Katada, Takashi Temma, Yukihiko Sugimoto, Kazuki Aita, Koh-ichi Seki, Nagara Tamaki, Hideo Saji
    NUCLEAR MEDICINE AND BIOLOGY 36 8 869 - 876 2009年11月 [査読有り][通常論文]
     
    Introduction: Despite extensive attempts to develop cyclooxygenase (COX)-2 imaging radiotracers, no suitable positron emission tomography (PET)/single photon emission computed tomography (SPECT) tracers are currently available for in vivo imaging of COX-2 expression. The aims of this study were to synthesize and evaluate a radioiodinated derivative of lumiracoxib, 2-[(2-fluoro-6-iodophenyl)-amino]-5-methylphenylacetic acid (FIMA), which is structurally distinct from other drugs in the class and has weakly acidic properties, as a SPECT tracer for imaging COX-2 expression. Methods: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation with hydrogen peroxide. Cell uptake characteristics of (125)I-FIMA were assessed in control and linterfero/interferon-gamma-stimulated macrophages. The biodistribution of (125)I-FIMA was determined by the ex vivo tissue counting method in rats. Results: The COX-2 inhibitory potency of FIMA (IC(50)=2.46 mu M) was higher than that of indomethacin (IC(50)=20.9 mu M) and was comparable to lumiracoxib (IC(50)=0.77 mu M) and diclofenac (IC(50)=0.98 mu M). The IC(50) ratio (COX-1/COX-2=182) indicated FIMA has a high isoform selectivity for COX-2. (125)I-FIMA showed a significantly higher accumulation in COX-2 induced macrophages than in control macrophages, which decreased with nonradioactive FIMA in a concentration dependent manner. The biodistribution Study showed rapid clearance of (125)I-FIMA from the blood and most organs including the liver and kidneys. No significant in vivo deiodination was observed with radioiodinated FIMA. Conclusions: FIMA showed high inhibitory potency and selectivity for COX-2. Radioiodinated FIMA showed specific accumulation into COX-2 induced macrophages, no significant in vivo deiodination and rapid blood clearance. Radioiodinated FIMA deserves further investigation as a SPECT radiopharmaceutical for imaging COX-2 expression. (C) 2009 Elsevier Inc. All rights reserved.
  • Ken Herrmann, Toshiki Takei, Kakuko Kanegae, Tohru Shiga, Andreas K. Buck, Jennifer Altomonte, Markus Schwaiger, Tibor Schuster, Kenichi Nishijima, Yuji Kuge, Nagara Tamaki
    MOLECULAR IMAGING AND BIOLOGY 11 5 356 - 363 2009年09月 [査読有り][通常論文]
     
    The aim of this study was to assess the clinical value of [C-11]methionine-PET (MET-PET) for detection and localization of parathyroid adenomas in patients without prior thyroidectomy. A retrospective analysis of patients with suspected parathyroid adenomas undergoing imaging with MET-PET was performed. Prior thyroidectomy was an exclusion criterion. Forty-one patients with a total of 49 MET-PET scans were included. MET-PET consisted of whole-body images obtained 15-20 min after injection of 430 +/- 81 MBq of MET using a dedicated PET scanner. Imaging findings were validated by histology or other imaging studies and clinical follow-up on a lesion, side, and location basis. Comparison of PET results to other imaging modalities including ultrasound, MIBI scintigraphy, and morphological imaging [computed tomography (CT) and/or magnetic resonance imaging] and subgroup analysis of primary vs. secondary hyperparathyroidism was performed. Twenty-three of 49 PET scans revealed pathologic findings, whereas 26 of 49 scans were negative. Validation of PET findings for detection and localization of parathyroid adenomas resulted in an overall sensitivity of MET-PET of 54%, 49%, and 35% on a lesion, side, and location basis, respectively. Sensitivity of MET-PET was inferior compared to ultrasonography (50% vs. 93%), MIBI scintigraphy (53% vs. 74%) and morphological imaging (52% vs. 74%). Subgroup analysis revealed higher sensitivity for MET-PET in secondary HPT (sHPT) than primary HPT (pHPT; 62% vs. 43%; side basis). In patients with initial diagnosis of hyperparathyroidism and no prior thyroidectomy, the sensitivity of MET-PET for detection and localization of parathyroid adenomas is markedly lower compared to previous reports. While performance was better in sHPT, we believe that MET-PET cannot be recommended for pHPT localization in this clinically relevant subcollective. The clinical value of MET/PET in patients with hyperparathyroidism should be further investigated in a prospective study utilizing anatometabolic imaging with a PET/CT device.
  • Takashi Temma, Kohei Sano, Yuji Kuge, Junko Kamihashi, Nozomi Takai, Yuki Ogawa, Hideo Saji
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 32 7 1272 - 1277 2009年07月 [査読有り][通常論文]
     
    Membrane type-1 matrix metalloproteinase (MT1-MMP) expressed on the tumor cell surface activates pro-MMP-2 and pro-MMP-13 to exacerbate the malignancy, suggesting its suitability as a target molecule for diagnosis by in vivo molecular imaging. Thus, we prepared radiolabeled anti-MT1-MMP monoclonal antibody (mAb) as a novel radiolabeled probe for detecting MT1-MMP in vivo and evaluated its usefulness in breast tumor-bearing rodents. Tc-99m-anti-MT1-MMP mAb was prepared using HYNIC as a bifunctional chelating agent and immunoreactivity was evaluated by flow cytometry. MT1-MMP expression in breast carcinoma cells (rat: Walker-256 and MRMT-1, mouse: FM3A) was measured by Western blotting. In vivo biodistribution was examined for 48 h using tumor-implanted rodents followed by estimation of radiation absorbed by a standard quantitation platform Organ Level Internal Dose Assessment (OLINDA). Tc-99m-anti-MT1-MMP mAb was obtained with 84% immunoreactivity to MT1-MMP and more than 92% radiochemical purity. MT1-MMP was highly expressed in all malignant cells. Tumor radioactivity increased with time after administration and reached 3 to 5 times higher values at 24 h post-injection than those at I h. Other organs, including the stomach, showed decreasing values over time. Tumor to blood ratios increased with time and reached more than 1.3 at 48 h. The effective dose was <5.0 mu Sv/MBq. The results suggest that Tc-99m-anti-MT1-MMP mAb is a promising probe for future diagnosis of breast tumors by in vivo nuclear medical imaging.
  • Takashi Kudo, Masashi Ueda, Yuji Kuge, Takahiro Mukai, Shotaro Tanaka, Maki Masutani, Yasushi Kiyono, Shinae Kizaka-Kondoh, Masahiro Hiraoka, Hideo Saji
    JOURNAL OF NUCLEAR MEDICINE 50 6 942 - 949 2009年06月 [査読有り][通常論文]
     
    Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumor progression and in the development of resistance to radiotherapy. We designed a novel fusion protein (PTD-ODD-SAV [POS]) consisting of a protein transduction domain (PTD), streptavidin (SAV), and a portion of the oxygen-dependent degradation domain (ODD) of HIF-1 alpha that confers the same oxygen-dependent regulation as HIF-1 alpha on POS. (3-(123/125)I-iodobenzoyl) norbiotinamide ((123/125)I-IBB) was conjugated to the SAV moiety of POS to synthesize (123/125)I-IBB-labeled POS ((123/125)I-IPOS). The purpose of this study was to evaluate the feasibility of (123)I-IPOS as an imaging probe for HIF-1-active tumor hypoxia. Methods: After a 24-h incubation of (125)I-IPOS with various tumor cell lines under either normoxic (20% O(2)) or hypoxic (0.1% O(2)) conditions, the intracellular radioactivity was investigated. Then, the biodistribution of (123/125)I-IPOS was examined with tumor-implanted mice, and an in vivo imaging study was performed. The tumoral accumulation of (125)I-IPOS was compared with HIF-1 activity using the mice carrying tumors with the HIF-1-dependent luciferase reporter gene. Furthermore, the intratumoral localization of (125)I-IPOS was examined by the autoradiographic study, and then the same slide was subjected to immunostaining for pimonidazole, which is the hypoxic marker. Results: The ratios of radioactivity in hypoxic cells to that in normoxic cells were more than 2. These results indicate incorporation of (125)I-IPOS into these cells and degradation of (125)I-IPOS by normoxic tumor cells. In the biodistribution study, (125)I-IPOS accumulated in the tumor (1.4 +/- 0.3 percentage injected dose per gram) 24 h after administration. At that time, (125)I-IPOS showed high tumor-to-blood and tumor-to-muscle ratios (5.1 +/- 0.3 and 14.0 +/- 3.9, respectively). The tumors were clearly visualized by in vivo imaging 24 h after (123)I-IPOS injection (tumor-to-muscle ratio was 9.6). The tumoral accumulation of (125)I-IPOS correlated with HIF-1 activity (R = 0.71, P < 0.05), and its intratumoral distribution coincided with the hypoxic regions. Conclusion: (123)I-IPOS is a potential probe for the imaging of HIF-1 activity in tumors. Given the role of HIF-1 in tumor biology, its detection may be considered an indicator of aggressive cancer phenotypes.
  • Masanao Naya, Takahiro Tsukamoto, Koichi Morita, Chietsugu Katoh, Kenichi Nishijima, Hiroshi Komatsu, Satoshi Yamada, Yuji Kuge, Nagara Tamaki, Hiroyuki Tsutsui
    JOURNAL OF NUCLEAR MEDICINE 50 2 220 - 225 2009年02月 [査読有り][通常論文]
     
    We evaluated whether myocardial P-adrenergic receptor (beta-AR) density, as determined by (11)C-CGP12177 PET, could predict improvement of cardiac function by P-blocker carvedilol treatment in patients with idiopathic dilated cardiomyopathy (IDC). Methods: Ten patients with IDC (left ventricular ejection fraction [LVEF] < 45%) were studied. Myocardial PAR density was estimated using (11)C-CGP12177 PET before treatment with carvedilol. Changes of LVEF in response to dobutamine infusion (ALVEF-dobutamine) were also measured by echocardiography. Changes of LVEF (Delta LVEF-carvedilol) were evaluated after 20 mo of carvedilol treatment. Results: Baseline myocardial PAR density significantly correlated with Delta LVEF-carvedilol (r = -0.88, P < 0.001). In contrast, Delta LVEF-clobutamine did not correlate with Delta LVEF-carvedilol (P = 0.65). Myocardial PAR density was the significant multivariate independent predictor of Delta LVEF-carvedilol (p = -0.88, P < 0.001) among univariate predictors, including functional class (r = 0.76, P < 0.05), plasma norepinephrine (r = 0.85, P < 0.01), LVEF (r = -0.64, P < 0.05), and age as confounding factors. Furthermore, myocardial PAR density was significantly correlated with plasma norepinephrine (r = -0.79, P < 0.01) and LVEF (r = 0.70, P < 0.05). Conclusion: Myocardial PAR density is more tightly related to improvement of LVEF-carvedilol than is cardiac contractile reserve in patients with IDC. Patients with decreased myocardial PAR have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may receive greater benefit from being treated by antiadrenergic drugs.
  • Temma T, Kuge Y, Sano K, Kamihashi J, Obokata N, Kawashima H, Magata Y, Saji H
    Brain Res. 1212 18 - 24 2008年 [査読有り][通常論文]
  • Takahashi M, Seki K, Nishijima K, Kuge Y, Tamaki N, Ohkura K
    Heterocycles 76 1 237 - 241 2008年 [査読有り][通常論文]
  • Wu YW, Naya M, Tsukamoto T, Komatsu H, Morita K, Yoshinaga K, Kuge Y, Tsutsui H, Tamaki N
    Circ J. 72 5 786 - 792 2008年 [査読有り][通常論文]
  • Masayuki Takahashi, Koh-ichi Seki, Ken-ichi Nishijima, Songji Zhao, Yuji Kuge, Nagara Tamaki, Kazue Ohkura
    J Labelled Compounds and Radiopharmaceuticals. 51 11 384 - 387 2008年 [査読有り][通常論文]
  • Yan Zhao, Yuji Kuge, Songji Zhao, H. William Strauss, Francis G. Blankenberg, Nagara Tamaki
    J Nucl Med 49 10 1707 - 1714 2008年 [査読有り][通常論文]
  • Ishino S, Mukai T, Kuge Y, Kume N, Ogawa M, Abe J, Takai N, Shiomi M, Minami M, Kita T, Saji H
    J Nucl Med 49 10 1677 - 1685 2008年 [査読有り][通常論文]
  • Zhao S, Kuge Y, Kohanawa M, Takahashi T, Zhao Y, Yi M, Kanegae K, Seki KI, Tamaki N
    J Nucl Med. 49 1 135 - 141 2008年 [査読有り][通常論文]
  • Evaluation of radioiodinated (2S,alphaS)-2-(alpha-(2-iodophenoxy)benzyl)morpholine as a radioligand for imaging of norepinephrine transporter in the heart.
    Kiyono Y, Sugita T, Ueda M, Kawashima H, Kanegawa N, Kuge Y, Fujibayashi Y, Saji H
    Nucl Med Biol. 35 2 213 - 218 2008年 [査読有り][通常論文]
  • Kuge Y, Kume N, Ishino S, Takai N, Ogawa Y, Mukai T, Minami M, Shiomi M, Saji H
    Biol Pharm Bul. 31 8 1475 - 1482 2008年 [査読有り][通常論文]
  • Yi M, Kohanawa M, Ozaki M, Haga S, Fujikawa K, Zhao S, Kuge Y, Tamaki N
    Microbes Infect. 10 14-15 2008年 [査読有り][通常論文]
  • Songji Zhao, Yuji Kuge, Masashi Kohanawa, Toshiyuki Takahashi, Hidekazu Kawashima, Takashi Temma, Toshiki Takei, Yan Zhao, Koh-ichi Seki, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 34 12 2096 - 2105 2007年12月 [査読有り][通常論文]
     
    Introduction Increased F-18-fluorodeoxyglucose (FDG) uptake in inflammatory lesions, particularly in granulomatous inflammation (e.g., sarcoidosis), makes it difficult to differentiate malignant tumors from benign lesions and is the main source of false-positive FDG-PET findings in oncology. Here, we developed a rat granuloma model and examined FDG uptake in the granuloma. The effects of corticosteroid on FDG uptake in the granuloma were compared with those in a malignant tumor. Methods Rats were inoculated with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or allogenic hepatoma cells, and subdivided into control and pretreated (methylprednisolone acetate, 8 mg/kg i.m.) groups. Radioactivity in tissues was determined 1 h after the FDG injection. FDG-PET was performed in rats bearing BCG granulomas or tumors before and after prednisolone treatment. Results Mature epithelioid cell granuloma-formation and massive lymphocyte-infiltration were observed in the control group of granuloma, histologically similar to sarcoidosis. The mean FDG uptake in the granuloma was comparable to that in the hepatoma. Prednisolone reduced epithelioid cell granuloma-formation and lymphocyte-infiltration. Prednisolone significantly decreased the level of FDG uptake in the granuloma (52% of control), but not in the hepatoma. The FDG uptake levels in the granulomas and tumors were clearly imaged with PET. Conclusion We developed an intramuscular granuloma rat model that showed a high FDG uptake comparable to that of the tumor. The effect of prednisolone pretreatment on FDG uptake was greater in the granuloma than in the tumor. These results suggest that BCG-induced granuloma may be a valuable model and may provide a biological basis for FDG studies.
  • Takahiro Tsukamoto, Koichi Morita, Masanao Naya, Masayuki Inubushi, Chietsugu Katoh, Kenichi Nishijima, Yuji Kuge, Hiroshi Okamoto, Hiroyuki Tsutsui, Nagara Tamaki
    JOURNAL OF NUCLEAR MEDICINE 48 11 1777 - 1782 2007年11月 [査読有り][通常論文]
     
    Cardiac sympathetic function plays an important role in the regulation of left ventricular (LV) function and the pathophysiology of LV dysfunction. C-11-CGP-12177 (C-11-CGP) has been used to assess myocardial beta-adrenergic receptor (P-AR) density in vivo using PET. The aim of this study is to measure myocardial P-AR density in patients with nonischemic cardiomyopathy and to compare the measurements with various standard parameters of heart failure (HF), particularly with presynaptic function assessed by I-123-metaiodobenzy(guanidine (I-123-MIBG) imaging. Methods: C-11-CGP PET was performed on 16 patients with nonischemic cardiomyopathy and 8 age-matched healthy volunteers using a double injection method. A C-11-CGP dynamic scan for 75 min was performed after the injection of C-11-CGP with a high specific activity. After 30 min, C-11-CGP with a low specific activity was injected. The P-AR density of the whole LV was calculated on the basis of the graphical analysis method. Additionally, beta-AR density was compared with LV ejection fraction (LVEF), sympathetic presynaptic function assessed using I-123-MIBG kinetics, and neurohormonal parameters. Results: The P-AR density of patients was significantly lower than that of healthy volunteers (3.80 +/- 0.96 vs. 7.70 +/- 1.92 pmol/mL; P < 0.0001). In the patients, P-AR density correlated significantly with LVEF (r = 0.62, P < 0.05). Furthermore, P-AR density correlated significantly with the I-123-MIBG washout rate (r = -0.68, P < 0.01) and delayed heart-to-mediastinum ratio (H/M ratio) (r = 0.61, P < 0.05). On the other hand, the correlation between P-AR density and early H/M ratio was not significant (r = 0.40, P = 0.13). The beta-AR density of patients with severe HF (New York Heart Association functional [NYHA] class III) was significantly lower than that of those with NYHA functional class I or class II HIF (3.24 +/- 0.96 vs. 4.24 +/- 0.73 pmol/mL; P < 0.05). Conclusion: A reduction in P-AR density measured by C-11-CGP PET was observed in patientswith nonischemic cardiomyopathy. This downregulation may be due to the increased presynaptic sympathetic tone as assessed by I-123-MIBG imaging.
  • Yan Zhao, Yuji Kuge, Songji Zhao, Koichi Morita, Masayuki Inubushi, H. William Strauss, Francis G. Blankenberg, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 34 11 1747 - 1755 2007年11月 [査読有り][通常論文]
     
    Purpose Tc-99m-annexin A5, a marker of ongoing apoptosis, and F-18-FDG, a marker of the increased metabolism of inflammatory cells, are supposed to be useful in the detection of metabolically active atheroma. This study reports a comparison of the intralesional distribution of these tracers in relation to lesion development in ApoE-/- mice. Methods Male ApoE-/- mice (n = 12-14/group) were maintained on a Western-type diet after the age of 5 weeks. At 25 weeks, 99mTc-annexin A5 or 18F-FDG was injected and the aortas were harvested for autoradiography (ARG) and Oil Red O staining. Regional radioactivity accumulation was compared in relation to the Oil Red O staining score (ranging from 0 to 3, a semiquantitative parameter for evaluating lesion development). Results Both Tc-99m-annexin A5 and 18F-FDG showed preferential uptake into atherosclerotic lesions, with higher uptake levels for 18F-FDG ( mean, 56.07 % ID x kg/m(2)) than for Tc-99m-annexin A5 (mean, 10.38 % ID x kg/m2). The regional uptake levels of each tracer correlated with the Oil Red O staining score (r = 0.65, p<0.05 for Tc-99m-annexin A5; r=0.56, p<0.05 for 18F-FDG). The uptake ratios of advanced lesions ( score >0.5) to early lesions ( score <0.5) were significantly higher for Tc-99m-annexin A5 than for F-18-FDG (f = 4.73, p=0.03). Conclusion Both Tc-99m-annexin A5 and 18F-FDG accumulate in atherosclerotic lesions and correlate with the severity of each lesion. The higher absolute uptake levels of F-18-FDG may be advantageous for lesion detection, whereas the preferential uptake of 99mTc-annexin A5 in advanced lesions may be a useful indicator of late-stage lesions or vulnerable plaque transformation.
  • Seigo Ishino, Takahiro Mukai, Noriaki Kume, Daigo Asano, Mikako Ogawa, Yuji Kuge, Manabu Minami, Toru Kita, Masashi Shiomi, Hideo Saji
    ATHEROSCLEROSIS 195 1 48 - 56 2007年11月 [査読有り][通常論文]
     
    Lectin-like oxidized LDL receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL (Ox-LDL), has been implicated in vascular cell dysfunction related to atherosclerotic plaque instability, according to cell culture experiments. In the present study, we investigated the relationship between LOX-1 expression and plaque instability in hypercholesterolemic rabbits by immunohistological analyses in vivo. We prepared thirty series of cross sections of the thoracic aorta from six myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits (12-24 months), in which seventy atherosclerotic plaques were observed. LOX-1, matrix metal loproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1) expression, apoptotic events, plaque instability index (an index of the morphological destabilization of atherosclerotic plaques) and fibromuscular cap thickness in each atherosclerotic plaque were determined by immunohistochemical staining, TUNEL staining and Azan-Mallory staining. LOX-1 expression was positively correlated with the plaque instability index and MMP-9 expression. LOX-1 expression was more prominent in atherosclerotic plaques with thinner fibromuscular cap (< 100 mu m). Furthermore, LOX-1 expression was shown in the macrophage-rich lipid core area where MCP-1 expression and apoptotic events were prominent. These results indicate that enhanced LOX-1 expression was associated with histologically unstable atherosclerotic plaques in hypercholesterolemic rabbits, suggesting the involvement of LOX-1 in the destabilization of atherosclerotic plaques in vivo. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Kazuki Aita, Takashi Temma, Yuji Kuge, Hideo Saji
    LUMINESCENCE 22 5 455 - 461 2007年09月 [査読有り][通常論文]
     
    We developed a novel fluorescent probe that contains the neodymium(III) complex moiety and fluorescein moiety. This probe can emit long-lived near-infrared luminescence derived from a Nd ion through excitation of the fluorescein moiety with visible light (lambda(ex) = 488 nm, lambda(em) = 880 nm, lifetime = 2.3 mu s). These results indicate the possibility of the probe as a candidate for in vivo fluorescence molecular imaging. Copyright (C) 2007 John Wiley & Sons, Ltd.
  • Kakuko Kanegae, Ikuo Nakano, Kiyonobu Kimura, Hiroshi Kaji, Yuji Kuge, Tohru Shiga, Songji Zhao, Shouzo Okamoto, Nagara Tamaki
    ANNALS OF NUCLEAR MEDICINE 21 6 331 - 337 2007年08月 [査読有り][通常論文]
     
    Objective The aim of this study was to evaluate and compare the ability of C-11-methionine (MET) and F-18 fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) to diagnose lung cancer in patients with pneumoconiosis. Methods Twenty-six subjects underwent both whole-body MET-PET and FDG-PET on the same day. The first group was a lung cancer group, which consisted of 15 patients, and included those with pneumoconiosis with increased nodules (13 cases), hemoptysis (I case), and positive sputum cytology (I case). The second group was a no-malignancy control group, consisting of I I patients with pneumoconiosis. Results Sianificant correlations between nodule size and the maximum standardized uptake value (SUVmax) of the two PET tracers were observed in the control group. The larger the nodule size, the greater were the amounts of these tracers accumulated (MET: r = 0.771, P < 0.0001; FDG: r = 0.903, P < 0.0001). The SUVmax of MET was significantly lower than that of FDG in the pneumocomotic nodules (P < 0.0001). Lung cancer was found in 5 of 19 nodules (two with adenocarcinoma, one with squamous cell carcinoma, one with small cell carcinoma, and one with large cell carcinoma) in the first group. As for nodules equal to or less than 3 cm in diameter, the SUVmax of MET was significantly higher in the lung cancer than in the pneumoconiotic nodules, with 3.48 +/- 1.18 (mean SE) for the lung cancer and 1.48 +/- 0.08 for the pneumoconiotic nodules (P < 0.01), similar to the SUVmax of FDG, with 7.12 +/- 2.36 and 2.85 +/- 0.24 (P < 0.05), respectively. On the basis of the criteria for the control group, FDG and MET identified lung cancer with sensitivities of 60% and 80%, specificities of 100% and 93%, accuracies of 90% and 90%, positive predictive values of 100% and 80%, and negative predictive values of 88% and 93%, respectively. Conclusions Our results indicate that nodules with an intense uptake of MET and FDG relative to their size should be carefully observed because of a high risk for lung cancer.
  • Seigo Ishino, Yuji Kuge, Nozomi Takai, Nagara Tamaki, H. William Strauss, Francis G. Blankenberg, Masashi Shiomi, Hideo Saji
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 34 6 889 - 899 2007年06月 [査読有り][通常論文]
     
    Apoptosis is commonly observed in advanced atherosclerotic lesions. Tc-99m-annexin A5 (Tc-99m-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of Tc-99m-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. Methods The WHHLMI and control rabbits were injected intravenously with Tc-99m-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. Results Tc-99m-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of Tc-99m-annexin A5 in WHHLMI rabbits. Tc-99m-Annexin A5 accumulation was highest in the atheromatous lesions (6.2 +/- 2.5, %IDxBW/mm(2) 10(3)), followed in decreasing order by neointimal (4.9 +/- 1.3), fibroatheromatous (4.5 +/- 1.9), and collagen-rich lesions (3.3 +/- 1.4). The regional Tc-99m-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and "vulnerability index," an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. Conclusion The present study in WHHLMI rabbits showed higher Tc-99m-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. Tc-99m-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.
  • A novel and efficient synthesis of [2-C-11]5-fluorouracil for prognosis of cancer chemotherapy
    Koh-ichi Seki, Ken-ichi Nishijima, Yuji Kuge, Nagara Tamaki, Leonard I. Wiebe, Kazue Ohkura
    JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES 10 2 212 - 216 2007年06月 [査読有り][通常論文]
     
    Purpose: In order to facilitate the use of the PET- based ' Strauss test' for 5- FU sensitivity, a rapid and facile synthesis of [ 2-C-11] 5- fluorouracil ([ 2- C-11] 5- FU), based on [ C-11] phosgene ([ C-11] COCl2), is reported. Methods: The key intermediate ( E)-beta- benzoylamino- alpha- fluoroacrylamide ( 1) and [ C-11] phosgene was submitted to cyclo-condensation to give [ 2- C-11] 5- fluorouracil. Results: [ 2- C-11] 5- Fluorouracil was synthesized in 17 min with high (similar to 25%) radiochemical yield. Conclusion: The present study provides a rapid, simple, and efficient synthesis of [ 2- C-11] 5- FU, that would serve as a useful prognostic PET tracer for 5- FU chemotherapy.
  • Yasushi Kiyono, Tomoko Yamashita, Hisako Doi, Yuji Kuge, Toshiya Katsura, Ken-Ichi Inui, Hideo Saji
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 34 4 448 - 452 2007年04月 [査読有り][通常論文]
     
    Purpose Radionuclide therapy with I-131-labelled meta-iodobenzylguanidine ([I-131]MIBG) is effective in cases where it is difficult to carry out surgical resection or debulking of neuroendocrine tumours (NETs). However, it has recently been reported that P-glycoprotein (P-gp) is expressed in these NETs. Therefore, it is important to clarify whether MIBG is a substrate of P-gp or not. In this study, using a human cell line which overexpresses P-gp, LLC-GA5-COL150, we investigated this question. Methods The transcellular transport and accumulation of [I-125]MIBG were measured using monolayer cultures grown in Transwell chambers. [I-125]MIBG was added to either the basolateral or the apical side, aliquots of the incubation medium on the other side were taken at specified times, and the radioactivity was measured. For accumulation experiments, the cells on the filters were solubilised and the radioactivity in aliquots was measured. Results There were no significant differences in the transport of MIBG between LLC-PK1 and LLC-GA5-COL150 monolayers in either direction until 60 min. With respect to the accumulation of MIBG, there were no significant differences between LLC-PK1 and LLC-GA5-COL150 cells in either direction. Conclusion MIBG is not a substrate of P-gp. Therefore, radionuclide therapy with MIBG would be useful in the treatment of NETs expressing P-gp.
  • Expression Profiles of MT1-MMP, MMP-2 and COX-2 in Rabbit Atherosclerosis: Comparison with Plaque Instability Analysis.
    Kuge Y, Takai N, Ishino S, Temma T, Shiomi M, Saji H
    Biol Pharm Bull 30 9 1634 - 40 2007年 [査読有り][通常論文]
  • Yasushi Kiyono, Yuji Kuge, Yumiko Katada, Yasuhiro Magata, Hideo Saji
    Nucl Med Commun. 28 9 736 - 741 2007年 [査読有り][通常論文]
  • All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors.
    Stephanie Darmanin, Jian Chen, Songji Zhao, Hongyan Cui, Reza Shirkoohi, Naoki Kubo, Yuji Kuge, Nagara Tamaki, Koji Nakagawa, Jun-ichi Hamada, Tetsuya Moriuchi, Masanobu Kobayashi
    J Immunology 179 7 4616 - 25 2007年 [査読有り][通常論文]
  • Kazue Ohkura, Takeshi Yamaguchi, Ken-ichi Nishijima, Yuji Kuge, Koh-ichi Seki
    HETEROCYCLES 70 501 - + 2006年12月 [査読有り][通常論文]
     
    UV-irradiation of 6-chloro-l-methyluracil with benzene in the presence of TFA resulted in 1,2-cycloaddition and susequent elimination of HCl gave a cyclooctapyrimidine-2,4-dione. Similar acid catalyzed photoreaction with substituted benzenes bearing two or three methyl groups afforded the corresponding cyclooctapyrimidines and two novel pentacyclic compounds, 9,11-diazapentacyclo[6.4.0.0(1,3).0(2,5).0(4,8)]dodecanes and 9.11diazapentacyclo[6.4.0.0(1,3).0(2,6).0(4,8)]dodcanes, in fair yields.
  • Takashi Temma, Yasuhiro Magata, Yuji Kuge, Sayaka Shimonaka, Kohei Sano, Yumiko Katada, Hidekazu Kawashima, Takahiro Mukai, Hiroshi Watabe, Hidehiro Iida, Hideo Saji
    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 26 12 1577 - 1583 2006年12月 [査読有り][通常論文]
     
    The threshold of cerebral blood flow (CBF) into infarction in rats has been indicated to be similar to that in patients. However, CBF does not reflect metabolic function, and so estimations of oxygen metabolism have been required. Here, we estimated changes in oxygen metabolism after occluding the right middle cerebral artery (MCA) in rats using an injectable O-15-O-2 we developed. A decrease in CBF (left: 0.67 +/- 0.22 mL/min/g, right: 0.44 +/- 0.17 mL/min/g, P < 0.05) and compensatory increase in the oxygen extraction fraction (OEF) (left: 0.42 +/- 0.13, right: 0.50 +/- 0.19, P < 0.05) were observed at 1-h after occlusion. In contrast, a marked decrease in CBF and the cerebral metabolic rate for oxygen and a collapse of the compensatory OEF mechanism were found at 24 h after occlusion. Injectable O-15-O-2 could be used to reliably estimate oxygen metabolism in an infarction rat model with positron emission tomography.
  • Takahiro Tsukamoto, Koichi Morita, Masanao Naya, Chietsugu Katoh, Masayuki Inubushi, Yuji Kuge, Hiroyuki Tsutsui, Nagara Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 10 1150 - 1156 2006年10月 [査読有り][通常論文]
     
    Purpose: Myocardial flow reserve (MFR) measurement has an important role in assessing the functional severity of coronary artery stenosis. However, a discrepancy between the anatomical severity of coronary artery stenosis and MFR is often observed. Such a discrepancy may be explained by coronary risk factors. In this study, we aimed to investigate the influence of coronary artery stenosis severity and risk factors on MFR. Methods: Seventy-four patients suspected to have coronary artery disease and seven age-matched healthy volunteers were enrolled. Myocardial blood flow (MBF) and MFR were measured using O-15-labelled water PET. Regional MFR was calculated in regions with significant coronary artery stenosis (stenotic regions) and in regions without significant stenosis (remote regions). The contributions of coronary artery stenosis severity and coronary risk factors were assessed using univariate and multivariate analyses. Results: In stenotic regions, MFR correlated inversely with coronary artery stenosis severity (r=-0.50, p < 0.01). Univariate analysis did not show any significant difference in MFR between the patients with and the patients without each risk factor. In remote regions, however, MFR was significantly decreased in the diabetes and smoking groups (each p < 0.05). By multivariate analysis, diabetes and smoking were independent predictors of MFR (each p < 0.05). In the group with more than one risk factor, MFR was significantly lower (2.78 +/- 0.79) than in the other group (3.40 +/- 1.22, p < 0.05). Conclusion: MFR is influenced not only by coronary stenosis severity but also by coronary risk factors. In particular, the influence of risk factors should be considered in regions without severe coronary stenosis.
  • Kazue Ohkura, Ken-ichi Nishijima, Kimihito Sanoki, Yuji Kuge, Nagara Tamaki, Koh-ichi Seki
    TETRAHEDRON LETTERS 47 30 5321 - 5323 2006年07月 [査読有り][通常論文]
     
    beta-(N-Benzoylamino)methacrylamide, a key intermediate for the preparation of [2-C-11]thymine, was synthesized in three steps from ethyl alpha-formylpropionate and NH3. Reaction of the alkali metal salts of beta-(N-benzoylamino)methacrylamide with [C-11]phosgene gave [2-C-11]thymine. The yield of [2-11C]thymine was 362 +/- 53 MBq at EOS (n = 3) (18 MeV proton beam; 10 mu A, 10 min). The total synthesis was accomplished in just 16 min from the end of bombardment. (c) 2006 Elsevier Ltd. All rights reserved.
  • T Shiga, K Ikoma, C Katoh, H Isoyama, T Matsuyama, Y Kuge, H Kageyama, T Kohno, S Terae, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 7 817 - 822 2006年07月 [査読有り][通常論文]
     
    Purpose: Traumatic brain injury (TBI) causes brain dysfunction in many patients. However, some patients have severe brain dysfunction but display no abnormalities on magnetic resonance imaging (MRI). There have been some reports of hypometabolism even in such patients. The purpose of this study was to investigate the relationship between metabolic abnormality and loss of neuronal integrity in TBI patients with some symptoms but without MRI abnormalities. Methods: The study population comprised ten patients with TBI and ten normal volunteers. All of the patients were examined at least 1 year after the injury. O-15-labelled gas PET and [C-11]flumazenil (FMZ) positron emission tomography (PET) were carried out. The cerebral metabolic rate of oxygen (CMRO2) and binding potential (BP) images of FMZ were calculated. Axial T2WI, T2*WI and FLAIR images were obtained. Coronal images were added in some cases. Results: All of the patients had normal MRI findings, and all showed areas with abnormally low CMRO2. Low uptake on BP images was observed in six patients (60%). No lesions that showed low uptake on BP images were without low CMRO2. On the other hand, there were 14 lesions with low CMRO2 but without BP abnormalities. Conclusion: These results indicate that there are metabolic abnormalities in TBI patients with some symptoms after brain injury but without abnormalities on MRI. Some of the hypometabolic lesions showed low BP, indicating a loss of neuronal integrity. Thus, FMZ PET may have potential to distinguish hypometabolism caused by neuronal loss from that caused by other factors.
  • Naoki Kanegawa, Yasushi Kiyono, Hiroyuki Kimura, Taku Sugita, Satomi Kajiyama, Hidekazu Kawashima, Masashi Ueda, Yuji Kuge, Hideo Saji
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 6 639 - 647 2006年06月 [査読有り][通常論文]
     
    Purpose: Abnormality of the brain norepinephrine transporter ( NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S, S)-2-(alpha-(2-iodophenoxy) benzyl) morpholine [( S, S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. Methods: (S, S)-I-123/125-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of ( S, S)IPBM for NET was measured by assaying the displacement of H-3-nisoxetine and (S, S)-I-125-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S, S)-I-125-IPBM was also determined in rats. Furthermore, SPECT studies with (S, S)-I-123-IPBM were carried out in the common marmoset. Results: (S, S)-I-125-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (> 98%). ( S, S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S, S)-I-125-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S, S)-I-125-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S, S)-I-123-IPBM allowed brain NET imaging in the common marmoset with SPECT. Conclusion: These results suggest that (S, S)-I-123-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.
  • M Ogawa, Y Iida, M Nakagawa, Y Kuge, H Kawashima, A Tominaga, M Ueda, Y Magata, H Saji
    NUCLEAR MEDICINE AND BIOLOGY 33 2 249 - 254 2006年02月 [査読有り][通常論文]
     
    Cholinergic system in the central nervous system is involved in the memory function. Thus, because the dysfunction of cholinerglic system that project to the cerebral cortex from nucleus basalis of Meynert (nbM) Would be implicated in the memory function deficits in Alzheimer's disease (AD), evaluating cholinergic function may be useful for the early detection of AD. In this study, because the nucleus basalis magnocellularis (NBM) in rats is equivalent to nbM ill human, We investigated the change in cholinergic receptors in the frontal cortex of rats With unilateral lesion to the NBM to find an appropriate index for the early detection of AD using techniques Of nuclear medicine. The right NBM was injected with ibotenic acid. [F-18]FDG-PET images were obtained 3 days later. Some rats were sacrificed at 1 week, whereas others were subjected to a second [F-18]FDG-PET at 4 weeks then sacrificed for membrane preparation. The prepared membranes were Subjected to radioreceptor assays to Measure the density of nicotinic and muscarinic acetylcholine receptors. Glucose metabolism had decreased oil the damaged side compared to the control side at 3 clays, but at 4 weeks, there was no difference between the sides. Nicotinic acetylcholine receptors had significantly decreased in density compared to the control side at both I and 4 weeks. However, muscarinic receptors were not affected. These results suggested that neuronal dysfunction in AD could be diagnosed at all early stage by imaging nicotinic acetylcholine receptors. (c) 2006 Elsevier Inc. All rights reserved.
  • Smoking Cessation Normalizes Coronary Endothelial Vasomotor Response Assessed with 15O-Water and PET in Healthy Young Smokers.
    Morita K, Tsukamoto T, Naya M, Noriyasu K, Inubushi M, Shiga T, Katoh C, Kuge Y, Tsutsui H, Tamaki N
    J Nucl Med. 47 12 1914 - 1920 2006年 [査読有り][通常論文]
  • Y Kuge, Y Katada, S Shimonaka, T Temma, H Kimura, Y Kiyono, C Yokota, K Minematsu, K Seki, N Tamaki, K Ohkura, H Saji
    NUCLEAR MEDICINE AND BIOLOGY 33 1 21 - 27 2006年01月 [査読有り][通常論文]
     
    Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a I-125-labeled celecoxib analogue with a sulfonamide moiety (I-125-IATP). Methods: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of I-125-IMTP and I-125-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured. Results: The COX-2 inhibitory potency of IMTP (IC50=5.16 mu M) and IATP (IC50=8.20 mu M) was higher than that of meloxicam (IC50-29.0 mu M) and comparable to that of SC-58125 (IC50=1.36 mu M). The IC50 ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of I-125-IMTP and 125 MATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of I-125-IMTP was much faster than that of I-125-IATP. Distribution of (125) I-IATP to blood cells (88.0%) was markedly higher than that of I-125-IMTP (18.1%), which was decreased by CA inhibitors. Conclusions: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in I-125-IMTP. I-123-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression. (c) 2006 Elsevier Inc. All rights reserved.
  • N Kubo, S Zhao, Y Fujiki, A Kinda, N Motomura, C Katoh, T Shiga, H Kawashima, Y Kuge, N Tamaki
    ANNALS OF NUCLEAR MEDICINE 19 7 633 - 639 2005年10月 [査読有り][通常論文]
     
    Objectives: Small animal imaging has recently been focused on basic nuclear medicine. We have designed and built a small animal SPECT imaging system using a semiconductor camera and a newly designed collimator. We assess the performance of this system for small object imaging. Methods: We employed an MGC1500 (Acrorad Co.) camera including a CdTe semiconductor. The pixel size was 1.4 mm/pixel. We designed and produced a parallel-hole collimator with 20-mm hole length. Our SPECT system consisted of a semiconductor camera with the subject holder set on an electric rotating stage controlled by a computer. We compared this system with a conventional small animal SPECT system comprising a SPECT-2000H scanner with four Anger type cameras and pinhole collimators. The count rate linearity for estimation of the scatter was evaluated for a pie-chart phantom containing different concentrations of Tc-99m. We measured the FWHM of the Tc-99m SPECT line source along with scatter. The system volume sensitivity was examined using a flood source phantom which was 35 mm long with a 32-mm inside diameter. Additionally, an in vivo myocardial perfusion SPECT study was performed with a rat. Results: With regards to energy resolution, the semiconductor camera (5.6%) was superior to the conventional Anger type camera (9.8%). In the count rate linearity evaluation, the regression lines of the SPECT values were y = 0.019x + 0.031 (r(2) = 0.999) for our system and y = 0.018x + 0.060 (r(2) = 0.997) for the conventional system. Thus, the scatter count using the semiconductor camera was less than that using the conventional camera. FWHMs of our system and the conventional system were 2.9 +/- 0.1 and 2.0 +/- 0.1 mm, respectively. Moreover, the system volume sensitivity of our system [0.51 kcps/(MBq/ml)/cm] was superior to that of the conventional system [0.44 kcps/(MBq/ml)/cm]. Our system provided clear images of the rat myocardium, sufficient for practical use in small animal imaging. Conclusions: Our SPECT system, utilizing a semiconductor camera, permits high quantitative analysis by virtue of its low scatter radiation and high sensitivity. Therefore, this system may contribute to molecular imaging of small animals and basic medical research.
  • K Morita, C Katoh, K Yoshinaga, K Noriyasu, M Mabuchi, T Tsukamoto, H Kageyama, T Shiga, Y Kuge, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 32 7 806 - 812 2005年07月 [査読有り][通常論文]
     
    Purpose: Myocardial glucose utilization (MGU) is altered in various heart diseases. The aim of this study was to quantitatively assess regional myocardial glucose utilization in patients with left ventricular (LV) dysfunction by dynamic F-18-fluorodeoxyglucose positron emission tomography (FDG PET). Methods: A total of 18 subjects were studied, including ten with LV dysfunction ( seven with idiopathic dilated cardiomyopathy and three with aortic regurgitation; NYHA II in 8 and III in 2) and eight healthy normal volunteers. Patients with diabetes mellitus were excluded. A dynamic PET study was performed for 40 min following the injection of 370 MBq of FDG after 50-g glucose loading. On the basis of a three-compartment model, MGU, K-1, k(2), and k(3) were computed on a pixel by pixel basis to generate LV myocardial parametric maps. FDG standardized uptake value (SUV) was also calculated using static images obtained 40 min after FDG injection. These metabolic values were compared with myocardial flow distribution (% Flow), LVEF, LV volumes, and LV wall thickening (WT) determined by gated myocardial single-photon emission computed tomography using QGS software in eight myocardial segments. Results: MGU correlated positively with LV volumes and negatively with LVEF. K1 was significantly higher in the segments of the patients than in those of the normal volunteers ( 0.082 +/- 0.055 vs 0.041 +/- 0.017 ml min(-1) g(-1), p< 0.05), although there was no difference in MGU between the groups. On the other hand, SUV, k(2), and k(3) did not differ significantly between the groups. Among the patients, the K-1 values were significantly higher in the areas with impaired WT (% WT< 17%) (0.109 +/- 0.063 vs 0.069 +/- 0.062 ml min(-1) g(-1), p< 0.05) and in the areas with flow reduction (% Flow< 71%) (0.112 +/- 0.076 vs 0.071 +/- 0.046 ml min(-1) g(-1), p< 0.05). Conclusion: These results indicate that glucose utilization was preserved in the patients with LV dysfunction, mainly due to an increase in glucose transport, particularly in the regions with severely impaired LV function. Thus, the quantitative assessment of myocardial glucose utilization by FDG dynamic PET may provide useful information for assessing the regional myocardial metabolic status in patients with LV dysfunction.
  • C Yokota, Y Kuge, H Inoue, N Tamaki, K Minematsu
    JOURNAL OF THE NEUROLOGICAL SCIENCES 234 1-2 11 - 16 2005年07月 [査読有り][通常論文]
     
    Cyclooxygenase-2 (COX-2) was reported to be induced in the infarcted human brain. Spreading depression (SD) is thought to play a role in this induction. In this study, we correlated the expression of SD-associated genes with COX-2 production in brains after SD. Rats were divided into 3 groups: rats that did not undergo SD (group I saline controls, n=7), rats that underwent unilateral SD as a result of KCl application (group II, n=9), and rats that were pretreated with the selective COX-2 inhibitor, JTE-522 3 h before the induction of SD (group III, n=7). The expression of the SD-associated genes, S-100A9, and mitogen-activated proteinkinase phosphatase (cpg21) was analyzed 2 h later using a cDNA array. In group II, COX-2 and cpg21 mRNA expression, as determined by RT-PCR, were significantly upregulated in the hemisphere undergoing SD. While the expression of S-100A9 mRNA was bilaterally upregulated in these animals, this expression was significantly reduced in group III, and was accompanied by reduced bilateral production of PGE(2). Thus, the bilateral induction of expression of the S-100A9 gene in response to SD was associated with COX-2 activation. (c) 2005 Elsevier B.V. All rights reserved.
  • T Abumiya, C Yokota, Y Kuge, K Minematsu
    BRAIN RESEARCH 1049 1 95 - 103 2005年07月 [査読有り][通常論文]
     
    Vascular endothelial growth factor (VEGF) is a unique growth factor associated with angiogenesis, vascular permeability, and neuroprotection. The aim of this study was to observe the effects of early intraarterial infusion of low-dose VEGF on ischemia/reperfusion injury after transient focal cerebral ischemia in rats. Male Sprague-Dawley rats were subjected to 2 h of focal ischemia by middle cerebral artery occlusion. After the 2 It ischemia, the rats were infused with 0.3 mu g/kg of VEGF (n = 15), or the vehicle as a control (n = 15), via the reperfused internal carotid artery. The brains were collected after a I h, 6 It, or 72 h reperfused period. Severity of ischemic cellular injury, serum extravasation, hemorrhagic transformation, and matrix metalloproteinase (MMP)-2 and -9 expressions were compared between the VEGF-treated and control groups. No significant difference in the extent of ischemic cellular injury and serum extravasation was observed between the two groups. However, vessel numbers with hemorrhagic transformation were significantly greater in the VEGF-treated group than in the control group after the 72 h reperfusion (9.4 +/- 1.6 versus 2.6 +/- 1.5; P = 0.028). The severity of hemorrhagic transformation was not correlated with the extent of ischemic cellular injury or serum extravasation. MMP-2 and -9 expressions were not enhanced in the VEGF-treated group compared with the control group. These results suggest that exogenous VEGF administered intravascularly at a very early point in reperfusion aggravates hemorrhagic transformation. The aggravated hemorrhagic transformation does not seem to depend on the enlargement of ischemic cellular injury, serum extravasation, or overexpressions of MMP-2 and -9. (c) 2005 Elsevier B.V. All rights reserved.
  • Biological correlates of intratumoral heterogeneity in FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor.
    Zhao S, Kuge Y, Mochizuki T, Takahashi T, Nakada K, Sato M, Takei T, Tamaki N
    J Nucl Med. 46 4 675 - 682 2005年 [査読有り][通常論文]
  • Enhanced apoptotic reaction correlates with suppressed tumor glucose utilization following cytotoxic chemotherapy: using 99mTc-annexin V, 18F-FDG and histological evaluation.
    Takei T, Kuge Y, Zhao S, Sato M, Strauss HW, Blankenberg FG, Tait JF, Tamaki N
    J Nucl Med. 46 5 794 - 799 2005年 [査読有り][通常論文]
  • M Tsukamoto, C Katoh, T Shiga, T Kaji, Y Kuge, K Nakada, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 31 6 846 - 851 2004年06月 [査読有り][通常論文]
     
    To simplify the acquisition protocol of carbon-11 labeled flumazenil (FMZ) positron emission tomography (PET) for distribution volume (DV) images, we attempted to obtain standardized uptake value (SUV) images compatible with DV images, and assessed the applicability of this method in patients with unilateral cerebrovascular diseases (CVD). [C-11]FMZ PET was performed in ten normal subjects. A DV image and ten sequential 5-min SUV images were generated for each subject. We investigated the correlation coefficient (r) and standard estimation of error (SEE) between the latter ten static images and the DV image using the pixel-by-pixel method, thereby determining the optimum acquisition phase. The same FMZ PET procedure was performed in 15 patients with unilateral CVD. Twenty regions of interest (ROIs) were positioned both in lesioned areas and in symmetrical regions. DV and SUV in the optimum phase for each ROI were calculated to compare the lesion-to-normal (L/N) ratio of DV and that of SUV. The highest r and a low SEE (r=0.957, SEE=633) were observed from 30 to 35 min after tracer administration in the study of normal subjects. A high r (0.945) and a low SEE (0.0438) between the DV L/N ratio and the SUV L/N ratio were obtained in the study of patients. Our study suggests that SUV images acquired from 30 to 35 min after FMZ administration are a suitable alternative to DV images not only in normal subjects but also in patients with unilateral CVD. This simple method seems to be valuable for the identification of altered neuronal activity in patients with CVD.
  • C Yokota, T Kaji, Y Kuge, H Inoue, N Tamaki, K Minematsu
    NEUROSCIENCE LETTERS 357 3 219 - 222 2004年03月 [査読有り][通常論文]
     
    Substantial increases in cyclooxygenase-2 (COX-2) mRNA and protein levels were demonstrated in the peri-infarct and focal ischemic areas after 3-24 and 12-24 h, respectively, in rats. In the ischemic core, significant increases in COX-2 mRNA followed 6 h of ischemia, though the peak level was about one-third of that in the peri-infarct area. Increases in COX-2 protein in the ischemic core were not observed during ischemic periods. Diffuse, neuronal COX-2 staining was found in peri-infarct areas as well as in discrete, immunoreactive neurons in the ischemic core. Robust increases in prostaglandin E-2 levels in the peri-infarct area were demonstrated following 24 h of ischemia. Prostaglandin production as well as COX-2 expression in ischemic tissues depended on the degree and duration of the reduction in cerebral blood flow. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
  • Feasibility of Tc-99m-annexin V for repetitive detection of apoptotic tumor response to chemotherapy: An experimental study using a rat tumor model
    Y Kuge, M Sato, SJ Zhao, T Takei, K Nakada, K Seki, HW Strauss, FG Blankenberg, JF Tait, N Tamaki
    JOURNAL OF NUCLEAR MEDICINE 45 2 309 - 312 2004年02月 [査読有り][通常論文]
     
    Annexin V (annexin A5), a human protein with a high affinity for phosphatidylserine, labeled with Tc-99m can detect apoptosis in vivo. In the repetitive detection of apoptosis with Tc-99m-annexin V, however, the specific binding of annexin V to phosphatidyl-serine might affect the subsequent detection of apoptosis with this compound. To determine whether there is interference with repetitive doses of annexin V, we evaluated the effects of previous administration of cold annexin V on accumulation of 99mTc-annexin V in tumors in an experimental tumor model. Methods: Rats bearing hepatoma received cyclophosphamide (150 mg/kg, intraperitoneally) 11 d after the tumor inoculation. Cold annexin V (20 mug/kg, intravenously) was administered 24 h before or after the cyclophosphamide treatment (n = 7/group). Tc-99m-Annexin V was injected intravenously (radioactive dose, 5-23 MBq/kg; mass dose, 20 mug/kg), and radioactivity in tissues was determined 6 h later. Results: Accumulation of Tc-99m-annexin V in tumors was not significantly affected by previous treatment with cold annexin V before or after chemotherapy. Conclusion: These results demonstrate the feasibility of Tc-99m-annexin V imaging for repetitive detection of apoptosis, which is highly required in the clinical setting.
  • Time course of apoptotic tumor response following a single dose of chemotherapy: comparison with 99mTc-annexin V uptake and rates of positively immunostained cells in an experimental model.
    Takei T, Kuge Y, Zhao S, Sato M, Strauss HW, Blankenberg FG, Tait JF, Tamaki N
    J Nucl Med. 45 12 2083 - 2087 2004年 [査読有り][通常論文]
  • Reduced Oxidative Metabolic Response in Dysfunctional Myocardium with Preserved Glucose Metabolism but with Impaired Contractile Reserve.
    Yoshinaga K, Katoh C, Beanlands RS, Noriyasu K, Komuro K, Yamada S, Kuge Y, Morita K, Kitabatake A, Tamaki N
    J Nucl Med. 45 11 1885 - 1891 2004年 [査読有り][通常論文]
  • Characterization of [123I]iomazenil distribution in a rat model of focal cerebral ischemia in comparison with pathophysiological findings.
    Kaji T, Kuge Y, Yokota C, Tagaya M, Inoue H, Shiga T, Minematsu K, Tamaki N
    Eur J Nucl Med Mol Imaging. 31 1 64 - 70 2004年 [査読有り][通常論文]
  • Nishijima K, Kuge Y, Seki K, Ohkura K, Morita K, Nakada K, Tamaki N
    Nucl Med Commun. 25 8 845 - 849 2004年 [査読有り][通常論文]
  • Effect of steroids on [18F]Fluorodeoxyglucose uptake in experimental tumors.
    Zhao S, Kuge Y, Nakada K, Mochiduki T, Takei T, Nishijima K, Okada F, Tamaki N
    Nucl Med Commun. 25 7 727 - 730 2004年 [査読有り][通常論文]
  • Facile synthesis of 4a-fluoro-5,10-ethenobenzo[f]quinazolines through 1,4-photocycloaddition of 5-fluoro-1,3-dimethyluracil with substituted naphthalenes
    K Ohkura, T Sugaoi, T Ishihara, K Aizawa, K Nishijima, Y Kuge, K Seki
    HETEROCYCLES 61 377 - + 2003年12月 [査読有り][通常論文]
     
    UV-irradiation of 6-chloro-1,3-dimethyluracil with naphthalenes underwent 1,2-cycloaddition to give naphthocyclobutapyrimidines consisting of a cyclobutene ring, The same reaction of an aprotic solution of 5-fluoro-1,3-dimethyluracil and naphthalenes bearing various substituents underwent 1,4-cycloaddition mode-selectively to give the corresponding ethenobenzoquinazoline derivatives with H and F atoms remaining intact on the newly constructed barrelene moiety. In protic solvents, the reaction preferentially proceeded by way of a substitution reaction to afford 5-(1-naphthyl)uracil.
  • K Noriyasu, M Mabuchi, Y Kuge, K Morita, T Tsukamoto, T Kohya, A Kitabatake, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 30 12 1644 - 1650 2003年12月 [査読有り][通常論文]
     
    Several clinical studies have shown that iodine-123 labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) uptake is often lower than the uptake of perfusion tracers in patients with ischaemic heart disease. However, BMIPP accumulation may not decrease during the acute phase of a stunned myocardium in patients with acute coronary syndrome. We evaluated serial changes in BMIPP and perfusion tracer uptake in the myocardium after ischaemia. We performed a 20-min left coronary artery occlusion followed by reperfusion in male Wister rats. One hour after the reperfusion, echocardiography was performed. Intravenous injection of iodine-125 labelled BMIPP and thallium-201 was performed 1 day (acute group) and 5 days (subacute group) after the operation. To determine the myocardial distribution of I-125-BMIPP and Tl-201, dual-tracer autoradiography was conducted. We identified regions of interest in the anterolateral wall as an area at risk and in the inferoseptum as a remote control area. The anterolateral wall/inferosepturn ratio (A/I ratio) was calculated to compare the distributions of I-125-BMIPP and Tl-201. Coronary occlusion induced hypokinesia in the anterolateral region 1 h after the reperfusion. The A/I ratio of I-125-BMIPP was significantly higher than that of Tl-201 in the acute group (1.01+/-0.15 vs 0.80+/-0.23, P<0.001). On the other hand, there was no significant difference between the A/I ratios of I-125-BMIPP and Tl-201 in the subacute group (0.88+/-0.18 vs 0.85+/-0.18). Two rats showed a Significantly lower A/I ratio of I-125-BMIPP than Tl-201 in the subacute phase. These data suggest that BMIPP uptake is preserved despite a decrease in perfusion in the acute phase after ischaemia. In the subacute phase, on the other hand, BMIPP uptake is similar to or even lower than thallium uptake. Since BMIPP uptake may change with time after ischaemia, careful interpretation of BMIPP uptake after ischaemia is required in a clinical setting.
  • Characteristic brain distribution of 1-C-14-octanoate in a rat model of focal cerebral ischemia in comparison with those of I-123-IMP and I-123-iomazenil
    Y Kuge, K Hikosaka, K Seki, K Ohkura, K Nishijima, T Kaji, S Ueno, E Tsukamoto, N Tamaki
    JOURNAL OF NUCLEAR MEDICINE 44 7 1168 - 1175 2003年07月 [査読有り][通常論文]
     
    1-C-11-Octanoate is a potential tracer for studying astroglial function in PET. To evaluate the usefulness of 1-C-11-octanoate for studying ischemic stroke, we investigated the brain distribution of 1-C-14-octanoate and compared it with N-isopropyl-p-I-123-iodoamphetamine (I-123-IMP) distribution (cerebral blood flow), I-123-iomazenil (I-123-IMZ) distribution (neuronal viability based on I-123-IMZ binding to benzodiazepine receptors); and hematoxylin-eosin stain (morphologic changes) in a rat model of focal cerebral ischemia. Methods: The right middle cerebral artery of each rat was occluded intraluminally. The brain distribution of 1-C-14-octanoate and I-123-IMP (or I-123-IMZ) was determined 4 and 24 h after the insult using a dual-tracer autoradiographic technique (n = 4-7 in each group). Coronal brain sections adjacent to those used for autoradiography were stained with hematoxylin and eosin. Regions of interest (ROIs) were determined,for 3 coronal slices, and asymmetry indices (AIs, lesion/normal hemisphere) of the tracer uptake were calculated. ROIs on the hemisphere with the lesion were classified into 4 groups: In region A, widespread necrotic cells were observed; in region B, necrotic cells were occasionally observed; in region C1, no morphologic changes were observed and the AIs for I-123-IMP (or I-123-IMZ) were less than or equal to0.8; and in region C2, no morphologic changes were observed and the AIs for I-123-IMP (or I-123-IMZ) were >0.8. Results: 1-C-14-Octanoate uptake decreased in the regions where morphologic changes were observed (regions A and B) but was relatively preserved in the surrounding region without morphologic changes despite reduced I-123-IMP and I-123-IMZ uptake (region C1). In the region without morphologic changes (region C1), AIs for 1-(14C)-octanoate were significantly higher than those for I-123-IMP (4 h, 0.73 +/- 0.23 for 1-C-14-octanoate and 0.37 +/- 0.20 for I-123-IMP, P < 0.0001; 24 h, 0.84 +/- 0.11 for 1-C-14-octanoate and 0.44 +/- 0.15 for I-123-IMP, P < 0.0001) and those for I-123-IMZ (4 h, 0.83 +/- 0.19 for 1-C-14-octanoate and 0.57 +/- 0.13 for I-123-IMZ, P < 0.0001; 24 h, 0.91 +/- 0.13 for 1-C-14-octanoate and 0.73 +/- 0.06 for I-123-IMZ, P < 0.0001). Conclusion: 1-C-14-Octanoate uptake was relatively preserved in the regions without morphologic changes despite reduced I-123-IMP and I-123-IMZ uptake. 1-C-11-Octanoate may provide further functional information on the pathophysiology of ischemic stroke, reflecting astroglial function based on fatty acid metabolism.
  • K Yoshinaga, C Katoh, K Noriyasu, Y Iwado, H Furuyama, Y Ito, Y Kuge, T Kohya, A Kitabatake, N Tamaki
    JOURNAL OF NUCLEAR CARDIOLOGY 10 3 275 - 283 2003年05月 [査読有り][通常論文]
     
    Background. Myocardial perfusion single photon emission computed tomography (SPECT) occasionally fails to detect coronary stenosis in patients with coronary artery disease (CAD). We evaluated coronary flow reserve (CFR) using oxygen 15-labeled water in areas with and without ischemia on technetium 99m tetrofosmin stress perfusion SPECT in patients with angiographically documented CAD. Methods and Results. Twenty-seven patients with CAD and eleven age-matched normal subjects were studied. Baseline myocardial blood flow (MBF),and MBF during hyperemia induced by intravenous adenosine triphosphate infusion (0.16 mg (.) kg(-1) (.) min(-1)) were determined with the use of O-15-labeled water positron emission tomography, and the CFR was calculated. Tc-99m tetrofosmin stress/rest SPECT was performed for comparison. On the basis of the results of coronary angiography and SPECT, coronary segments were divided into 3 types: segments with coronary stenosis and a perfusion abnormality on stress SPECT imaging (group A, n = 16), segments with coronary stenosis without a perfusion abnormality (group B, n = 42), and remote segments with no coronary stenosis or perftision abnormality (group C, n 18). Baseline MBF values were similar among the 3 groups. CFR in group A was lower (1.82 +/- 0.54) than in group B (2.22 +/- 0.87, P < .05), in group C (2.92 +/- 1.21, P < .01), and in normal segments (3.86 +/- 1.24, P < .001). CFR in group B was lower than in group C (P < .02) and in normal segments (P < .001). CFR in group C was lower than in normal segments (P < .02). Conclusions. Areas with a perfusion abnormality on stress SPECT had reduced CFR. In the areas without a perfusion abnormality and with coronary stenosis, lowering of CFR was intermediate between the areas with a perfusion abnormality and remote segments. Moreover, CFR was slightly, but significantly, lower in remote segments in patients with CAD compared with normal segments.
  • C Yokota, H Inoue, Y Kuge, T Abumiya, M Tagaya, Y Hasegawa, N Ejima, N Tamaki, K Minematsu
    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 23 4 395 - 398 2003年04月 [査読有り][通常論文]
     
    The authors previously provided evidence that spreading depression (SD) can be evoked in primates. Cyclooxygenase-2 (COX-2) expression has been found to increase in the rodent cortex undergoing SD, and the authors sought to determine whether this association exists in primate brain. In the present study, neuronal COX-2 expression was induced during SD in the primate cortex. The mean expression ratio of COX-2 messenger RNA in animals with SD was significantly higher than that measured in controls (1.69 vs. 0.5; P = 0.02). Induction of COX-2 in these animals was also detected by human microarray analysis. Results show that, as in rodents, neuronal COX-2 is induced in the primate cortex in response to SD.
  • Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism
    J Chen, SJ Zhao, K Nakada, Y Kuge, N Tamaki, F Okada, JX Wang, M Shindo, F Higashino, K Takeda, M Asaka, H Katoh, T Sugiyama, M Hosokawa, M Kobayashi
    AMERICAN JOURNAL OF PATHOLOGY 162 4 1283 - 1291 2003年04月 [査読有り][通常論文]
     
    In the tumor cells exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1)-mediated adaptation responses such as angiogenesis and anaerobic metabolism are induced for their survival. We have recently reported that the constitutive expression of HIF-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and glucose deprivation. We then established dominant-negative HIF-1alpha (dnHIF-1alpha) transfectants and examined their susceptibility to apoptosis and growth inhibition induced by hypoxia and glucose deprivation in vitro and their tumorigenicity in SCID mice. We further examined the expressions of aldolase A and Glut-1 in vitro and Glut-1 expression and glucose uptake in the tumor tissues and microvessel counts in the tumor tissues. As a result, dnHIF-1alpha rendered the pancreatic cancer cells sensitive to apoptosis and growth inhibition induced by hypoxia and glucose deprivation. Also it abrogated the enhanced expression of Glut-1 and aldolase A mRNAs under hypoxia and reduced the expression of Glut-1 and the glucose uptake in the tumor tissues and consequently in vivo tumorigenicity. We found no significant difference in the microvessel counts among the tumor tissues. From these results, we suggest that the disruption of the HIF-1 pathway Iight be effective in the treatment of pancreatic cancers.
  • C Yokota, Y Kuge, H Inoue, M Tagaya, G Kito, T Susumu, N Tamaki, K Minematsu
    NEUROSCIENCE LETTERS 341 1 37 - 40 2003年04月 [査読有り][通常論文]
     
    We determined whether up to 24 h of ischemia could induce the expression of cyclooxygenase-2 (COX-2) in the brain of nonhuman primates. Randomized animals were subjected to either a 2 h ischemia (group II; n,= 3) or a 24 h ischemia (group 111; n = 3). Three animals in group I served as controls. In group 111, regional cerebral blood flow (CBF) and the cerebral glucose metabolic rate (CMRglc) were evaluated using positron emission tomography. Upregulation of COX-2 mRNA expression was observed after 2 h of ischemia, but disappeared by 24 h in the ischemic temporal cortex, in which both CMRglc and CBF were markedly reduced. In the ischemic parietal cortex, where CMRglc was preserved, COX-2 expression persisted even 24 h after ischemia. This study is the first to demonstrate neuronal COX-2 induction within potentially viable hypoperfused brain areas in nonhuman primates. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
  • Y Ito, C Katoh, K Noriyasu, Y Kuge, H Furuyama, K Morita, T Kohya, A Kitabatake, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 30 2 281 - 287 2003年02月 [査読有り][通常論文]
     
    We developed a noninvasive method to quantitatively estimate the myocardial blood flow (MBF) index and flow reserve (MFR) using dynamic and static data obtained with technetium-99m sestamibi, and compared the results with MBF and MFR measured by oxygen-15-labeled water ([O-15]H2O) PET. Twenty patients with coronary artery disease (CAD) and nine normal subjects underwent both Tc-99m-sestamibi and PET studies within 2 weeks. From the anterior view, dynamic data were acquired for 2 min immediately after the injection of Tc-99m-sestamibi, and planar static images were also obtained after 5 min at rest and during ATP stress (0.16 mg kg(-1) min(-1) for 5 min) on another day. The area under the time-activity curve on the aortic arch (Aorta ACU), myocardial weight with the SPET image (M), and the myocardial count on the planar image for 1 min (C-m) were obtained. The MBF index (MBFI) was calculated as follows: MBFI=C-m/Aorta ACUx100/M. MFR was measured by dividing the MBFI at ATP stress by MBFI at rest. The MBFI measured by Tc-99m-sestamibi was significantly correlated with MBF obtained using [O-15]H2O PET (MBFI=13.174+11.732xMBF, r=0.821, P<0.001). Furthermore, MFR measured by Tc-99m-sestamibi was well correlated with that obtained using [O-15]H2O PET, with some underestimation (r=0.845, P<0.001). MFR using Tc-99m-sestamibi in patients with CAD was significantly lower than that in normal subjects (CAD: 1.484+/-0.256 vs normal: 2.127+/-0.308, P<0.001). These data suggest that the MBFI and MFR can be measured with Tc-99m-sestamibi. This may be useful for the quantitative assessment of CAD, especially in those patients with diffuse coronary disease.
  • H Furuyama, Y Odagawa, C Katoh, Y Iwado, Y Ito, K Noriyasu, M Mabuchi, K Yoshinaga, Y Kuge, K Kobayashi, N Tamaki
    JOURNAL OF PEDIATRICS 142 2 149 - 154 2003年02月 [査読有り][通常論文]
     
    Objectives Coronary arterial lesions after Kawasaki disease (KD) may cause coronary endothelial dysfunction as the result of intimal hypertrophy. Our purpose was to assess myocardial flow reserve (MFR) and endothelial function in various myocardial regions after KD by using positron emission tomography. Study design Twenty-seven patients, 17.2 +/- 3.2 years of age, who had KD at 1.9 +/- 1.4 years, and 12 normal healthy subjects, 26.5 +/- 3.4 years of age, were evaluated by means of myocardial blood flow (MBF) with O-15-water positron emission tomography. MFR was estimated by MBF changes under adenosine triphosphate infusion and endothelial function by MBF changes under cold pressor testing. The left ventricle was divided into three coronary territories. Ten stenotic regions, 20 aneurysmal regions, 30 regressed aneurysmal regions, and 21 regions without coronary arterial lesions were compared with 36 control regions of the normal volunteers. Results MBF at rest was similar in each region. Hyperemic blood flow and MFR in each region after KD was significantly lower than those in the regions of normal volunteers. MBF during cold pressor testing was significantly reduced in each region after KD, as compared with no change in the control regions., Conclusions Our study indicates impaired MFR and endothelial function regardless of coronary artery status after KD.
  • Detection of apoptotic tumor response in vivo after a single dose of chemotherapy with Tc-99m-annexin V
    T Mochizuki, Y Kuge, SJ Zhao, E Tsukamoto, M Hosokawa, HW Strauss, FG Blankenberg, JF Tait, N Tamaki
    JOURNAL OF NUCLEAR MEDICINE 44 1 92 - 97 2003年01月 [査読有り][通常論文]
     
    Annexin V, a human protein with a high affinity for phosphatidylserine, has been labeled with Tc-99m to detect apoptosis in vivo. To determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy, we studied rats with an engrafted hepatoma. Methods: Annexin V was labeled with 99mTc (specific activity, 3.0 MBq/mug protein). Eleven days after being inoculated with allogenic hepatoma cells (KDH-8) in the left calf muscle, the rats were randomized to receive a single dose of cyclophosphamide (150 mg/kg intraperitoneally) or to serve as controls. Tc-99m-annexin V was injected 20 h later. Radioactivity in tissues was determined 6 h after injection of 99mTc-annexin V. Tumor uptake of C-14-iodoanitpyrine was determined as a marker of tumor blood flow. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) of tissue harvested at necropsy was performed to detect apoptosis in the tumor. Results: Cyclophosphamide treatment significantly increased the tumor uptake (percentage activity of injected dose per gram of tissue after normalization to the animal's weight [%ID/g/kg]) of Tc-99m-annexin V (0.070 +/- 0.007 %ID/g/kg for treated rats and 0.046 +/- 0.009 %ID/g/kg for controls, P < 0.001). C-14-iodoantipyrine uptake was similar in the treated and untreated groups. The number of TUNEL-positive cells in the tumor was significantly larger in the treated rats (297.70 +/- 50.34 cells/mm(2)) than in the control rats (168.45 +/- 23.60 cells/mm(2), P < 0.001). Tumor uptake of 99mTc-annexin V correlated with the number of TUNEL-positive cells in the tumor (r = 0.712; P < 0.001). Conclusion: Tumor uptake of Tc-99m-annexin V was Significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of TUNEL-positive cells in the tumor. The current results are suggestive of the utility of Tc-99m-annexin V as a noninvasive means to assess tumor response, although further testing, including clinical evaluation, is
  • T Kato, E Tsukamoto, Y Kuge, T Takei, T Shiga, N Shinohara, C Katoh, K Nakada, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 29 11 1492 - 1495 2002年11月 [査読有り][通常論文]
     
    Carbon-11 acetate positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of prostate cancer. However, no detailed analysis has yet been carried out on the physiological accumulation of [C-11]acetate in the prostate. The purpose of this study was to elucidate the physiological accumulation of [C-11]acetate in the prostate using dynamic PET. The study included 30 subjects without prostate cancer [21 with normal prostate and nine with benign prostatic hyperplasia (BPH)] and six patients with prostate cancer. A dynamic PET study was performed for 20 min after intravenous administration of 555 MBq of [C-11]acetate. The standardised uptake value (SUV) at 16-20 min post tracer administration and the early-to-late-activity ratio of the SUV (E/L ratio), which was determined by dividing the SUV6-10 min by the SUV16-20min, were calculated to evaluate the accumulation of [C-11]acetate. The prostate was clearly visualised and distinguished from adjacent organs in PET images in most of the cases. The SUV of the prostate (2.6+/-0.8) was significantly higher than that of the rectum (1.7+/-0.4) or bone marrow (1.3+/-0.3) (P<0.0001 in each case). The SUV of the normal prostate of subjects aged <50 years (3.4+/-0.7) was significantly higher than both the SUV for the normal prostate of subjects aged greater than or equal to50 years (2.3+/-0.7) and that of subjects with BPH (2.1+/-0.6) (P<0.01 in each case). The primary prostate cancer in six cases was visualised by [C-11]acetate PET. However, the difference in the SUV between subjects aged greater than or equal to50 with normal prostate or with BPH and the patients with prostate cancer (1.9+/-0.6) was not statistically significant. There was also no significant difference in the E/L ratio between subjects aged greater than or equal to50 with normal prostate (0.98+/-0.04) or BPH (0.96+/-0.08) and patients with prostate cancer (1.02+/-0.12). In conclusion, a normal prostate exhibits age-related physiological accumulation of [C-11]acetate. Careful interpretation of [C-11]acetate PET images of prostate cancer is necessary because the SUV and the E/L ratio for the normal prostate and for BPH overlap significantly with those for prostate cancer.
  • Thermodynamically controlled photocycloaddition of 5-fluoro-1,3-dimethyluracil to naphthalenes
    K Ohkura, T Sugaol, A Sakushima, K Nishijima, Y Kuge, K Seki
    HETEROCYCLES 58 595 - 600 2002年11月 [査読有り][通常論文]
     
    UV-Irradiation of 5-fluoro-1,3-dimethyluracil (5-FDMU) and 1-acetonaphthone (1a) afforded trans- 1,4-adduct, ethenobenzoquinazoline, (2) having an acetyl group at the C-10 bridgehead carbon, together with the cis-isomer (3). The cis-adduct (3) is more fragile than 2 in the dark at ambient temperature, and is more quickly converted back to the starting la and 5-FDMU through cycloreversion. Thus, the trans-adduct (2) comes to the predominant product when irradiation is prolonged. Similar irradiation of 1-naphthonitrile afforded cis-ethenobenzoquinazoline-10-carbonitrile (6) and the trans-isomer (7) as the kinetically controlled cycloadducts together with cis-ethenobenzoquinazoline with a CN group on the benzene moiety (5) as thermodynamically controlled product.
  • M Mabuchi, N Kubo, K Morita, K Noriyasu, Y Itoh, C Katoh, Y Kuge, N Tamaki
    NUCLEAR MEDICINE COMMUNICATIONS 23 9 879 - 885 2002年09月 [査読有り][通常論文]
     
    Single photon emission computed tomography (SPECT) using ultra-high energy collimators permits wide clinical application of 18 F-fluorodeoxyglucose (FDG) imaging without the use of expensive positron emission tomography (PET) cameras. This study was designed to evaluate the value of FDG SPECT using ultra-high energy collimators in assessing myocardial viability compared with FDG PET on a regional basis. We prospectively studied 33 patients with ischaemic heart disease. The patients were injected with 555 MBq of FDG under a hyperinsulinaemic glucose clamp, and FDG PET was performed 40 min later. FDG SPECT using ultra-high energy collimators was performed immediately after FDG PET. The images of the left ventricular myocardium were divided into nine segments and the regional defect score was assessed visually using a four-point scale (0 = normal to 3 = defect). Regional FDG uptake (%uptake) was quantitatively analysed using polar maps. In 297 segments of all the 33 patients, agreement between the defect scores based on FDG SPECT images and those based on FDG PET images was 70%, and agreement within one rank was 96% (kappa value= 0.52). The %uptake based on FDG SPECT images significantly correlated with that based on FDG PET images (r = 0.77, P < 0.01). However, the defect scores in the inferior wall based on FDG SPECT images were higher (1.41+/-1.14) than those based on FDG PET images (1.06+/-1.12, P<0.01). When the viable region is defined as %uptake greater than or equal to50% in FDG PET studies, the optimal cut-off level of %uptake based on FDG SPECT images was 60% in the anterior wall, apex, septum and lateral wall (accuracies, 97%, 93%, 96% and 99%, respectively), and 45% in the inferior wall (accuracy, 99%). It is concluded that FDG SPECT using ultra-high energy collimators can be used for the assessment of myocardial viability as accurately as FDG PET. However, a slight difference was observed in the defect scores mainly due to attenuation in the inferior wall. Therefore, a slightly different cut-off level for assessing myocardial viability should be applied to the inferior wall when using FDG SPECT. ((C) 2002 Lippincott Williams Wilkins).
  • Y Iwado, K Yoshinaga, H Furuyama, Y Ito, K Noriyasu, C Katoh, Y Kuge, E Tsukamoto, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 29 8 984 - 990 2002年08月 [査読有り][通常論文]
     
    Chronic cigarette smoking alters coronary vascular endothelial response. To determine whether altered response also occurs in young individuals without manifest coronary disease we quantified coronary blood flow at rest, following adenosine vasodilator stress and during the cold pressor test in healthy young smokers. Myocardial blood flow (MBF) was quantified by oxygen-15 labelled water positron emission tomography in 30 healthy men aged from 20 to 35 years (18 smokers and 12 non-smokers, aged 27.4 +/- 4.4 vs 26.3 +/- 3.3). The smokers had been smoking cigarettes for 9.4 +/- 4.9 pack-years, MBF was measured at rest, during intravenous adenosine triphosphate (ATP: 0.16 mg kg(-1) min(-1)) infusion (hyperaemic response), and during cold pressor test (CPT) (endothelial vasodilator response). Rest MBF and hyperaemic MBF did not differ significantly between the smokers and the non-smokers (rest: 0.86 +/- 0.11 vs 0.92 +/- 0.14 and ATP: 3.20 +/- 1.12 vs 3.69 +/- 0.76 ml g(-1) min(-1); P=NS). Coronary flow reserve was similar between the two groups (smokers: 3.78 +/- 1.83; non-smokers: 4.03 +/- 0.68; P=NS). Although CPT induced a similar increase in rate-pressure product (RPP) in the smokers and the non-smokers (10,430 +/- 1,820 vs 9,236 +/- 1,356 beats min(-1) mmHg(-1)), CPT MBF corrected by RPP was significantly decreased in the smokers (0.65 +/- 0.12 ml g(-1) min(-1)) compared with the non-smokers (0.87 +/- 0.12 ml g(-1) min(-1)) (P<0.05). In addition, the ratio of CPT MBF to resting MBF was inversely correlated with pack-years (r=-0.57, P=0.014). Endothelium-dependent coronary artery vasodilator function is impaired in apparently healthy young smokers.
  • T Kato, E Tsukamoto, Y Kuge, C Katoh, T Nambu, A Nobuta, S Kondo, M Asaka, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 29 8 1047 - 1054 2002年08月 [査読有り][通常論文]
     
    In extrahepatic bile duct cancer, preoperative evaluation is important because only surgical excision of all detectable tumours is associated with improvement in 5-year survival. However, morphological imaging techniques, including computed tomography (CT), are still insufficient for accurate staging. The purpose of this study was to assess the additional value, in relation to CT, of 2-[F-18]fluoro-2-deoxy-D-glucose positron emission tomography (F-18-FDG PET) for the evaluation of extrahepatic bile duct cancer. Thirty patients with extrahepatic bile duct cancer underwent both F-18-FDG PET and CT for initial staging. The results of the two modalities for evaluation of primary tumours and regional lymph nodes were compared with the final diagnoses based on pathological or clinical findings. The primary tumours were interpreted as malignant on the basis of CT in 24 (80%) of the patients, while F-18-FDG PET revealed increased F-18-FDG uptake in 18 (60%) of them. On the other hand, F-18-FDG PET showed focal accumulation of F-18-FDG in the bile duct in three of the six patients with equivocal findings on CT. The sensitivity, specificity and accuracy of CT for regional lymph node metastases were 54%, 59% and 57%, while those of F-18-FDG PET were 38%, 100% and 73%, respectively. The specificity of F-18-FDG PET for regional lymph node metastases was significantly higher than that of CT (P<0.01). Of 14 patients with N1 or N2 disease diagnosed by CT, only seven (50%) had a final diagnosis of regional lymph node metastasis. In these 14 patients, F-18-FDG PET accurately evaluated the N component of the disease in 12 patients (86%). In conclusion, in the initial staging of patients with extrahepatic bile duct cancer, F-18-FDG PET offers additional value in relation to CT in evaluating both the primary tumour and regional lymph nodes.
  • K Yoshinaga, C Katoh, K Noriyasu, S Yamada, Y Ito, Y Kuge, Y Kawai, T Kohya, A Kitabatake, N Tamaki
    EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 29 7 882 - 890 2002年07月 [査読有り][通常論文]
     
    The detection of viable myocardium is important for the prediction of functional recovery after revascularisation. However, a fixed perfusion defect often includes viable myocardium, and perfusion imaging then underestimates myocardial viability. We previously reported that low-dose dobutamine stress gated single-photon emission tomography (SPET) provides similar findings to dobutamine stress echocardiography in the assessment of myocardial viability. The present study investigated whether low-dose dobutamine stress gated SPET is of additional value as compared with stress-rest technetium-99m tetrofosmin SPET for the detection of myocardial viability. Standard stress-rest perfusion SPET, low-dose dobutamine stress gated SPET and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) were studied in 23 patients (mean age 67+/-7.6 years) with previous myocardial infarction. Twenty-one of them were successfully studied with each technique. FDG PET viability (FDG uptake greater than or equal to50%) was employed as the gold standard. One-day stress-rest Tc-99m-tetrofosmin myocardial SPET was performed. After the resting study, gated SPET was acquired following infusion of 7.5 mug kg(-1) min(-1) of dobutamine. Left ventricular wall motion in 16 segments was assessed by cine mode display using a four-point scale. Myocardial viability was considered present when there was improvement by one point. Of a total of 336 segments analysed, 53 had persistent defects on stress-rest perfusion SPET. FDG viability was seen in 16 of 17 dobutamine-responsive segments, but in only 11 of 36 dobutamine non-responsive segments (P<0.01). Thus, in the segments with persistent defects, viability findings on low-dose dobutamine stress gated SPET were concordant with those on FDG PET in 77% of segments (kappa value =0.55). For the detection of FDG-viable myocardium, the combination of stress-rest perfusion SPET and low-dose dobutamine stress gated SPET achieved a better sensitivity than stress-rest perfusion SPET alone (35/46, 76% vs 19/46, 41.3%, P<0.001), with a similar specificity (25/29, 86% vs 26/29, 90%, P=NS). We conclude that in the identification of viable myocardium, low-dose dobutamine stress gated SPET may provide additional information missed on a routine stress-rest perfusion scan. Dobutamine stress gated SPET may provide new insights into myocardial viability on the basis of ischaemia and contractile reserve.
  • Unique profile of spreading depression in a primate model
    C Yokota, Y Kuge, Y Hasegawa, M Tagaya, T Abumiya, N Ejima, N Tamaki, T Yamaguchi, K Minematsu
    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 22 7 835 - 842 2002年07月 [査読有り][通常論文]
     
    Spreading depression (SD) is considered to play a role in pathologic conditions of humans such as in the evolution of ischemic brain injury and migraine aura. Because many studies have demonstrated spreading hypoperfusion in patients with migraine and persistent hypoperfusion in nonprimate animal models of SD, these changes in cerebral blood flow (CBF) were regarded as an epiphenomenon of SD. However, there is no direct evidence of the occurrence of SD in primates. The authors attempted to elicit SD by applying 3.3 mol/L potassium chloride to the cerebral cortex of nine male cynomolgus monkeys. The CBF was monitored by positron emission tomography in five animals. Propagated direct-current shifts were found by the two neighboring microelectrodes only in one animal. The direct-current wave propagated at a speed of 4 mm/min and its amplitude was 20 mV, being consistent with the SD findings. Except in one animal with 6 SD episodes, SD waves were recorded infrequently at the rostral site (none in three animals, once in three, and twice in two). Focal hyperemia accompanied SD. Neither spreading hypoperfusion nor persistent hypoperfusion was found. These unique features of SD in primates raise a doubt as to whether the role of SD in nonprimate animals is the same as that in stroke and migraine in humans.
  • S Zhao, Y Kuge, E Tsukamoto, T Mochizuki, T Kato, K Hikosaka, K Nakada, M Hosokawa, M Kohanawa, N Tamaki
    NUCLEAR MEDICINE COMMUNICATIONS 23 6 545 - 550 2002年06月 [査読有り][通常論文]
     
    The expression of glucose transporters (GLUTs) and its relationship to fluorodeoxyglucose accumulation in malignant tun-tours have been well investigated, while such a relation has not been studied in inflammatory lesions. The aim of the present study was to investigate the effects of insulin and glucose loading on the expression of GLUTs in inflammatory lesions and compare them with those in malignant tumours in relation to fluorodeoxyglucose accumulation. All tissue specimens used in this study were obtained in our previous study, in which rats were inoculated with allogenic hepatoma cells (KDH-8), Staphylococcus aureus, or turpentine oil into the left calf muscle and divided into three subgroups: insulin loaded, glucose loaded, and control groups. The expression of glucose transporters (GLUT-1 to GLUT-5) was investigated by immunostaining the lesions (n = 5-6, for each group). In all control groups, the expression levels of GLUT-1 and GLUT-3 were significantly higher than those of GLUT-2, GLUT-4 and GLUT-5. Insulin loading did not significantly affect the expression levels of GLUT-1 and GLUT-3 in these lesions except for a significant but slight decrease in the GLUT-1 expression level in the inflammatory lesion of non-infectious origin (89% of the control value). Glucose loading significantly decreased the expression level of GLUT-1 in the inflammatory lesion of non-infectious origin (70% of the control value, P < 0.01), and that of GLUT-3 in the inflammatory lesion of infectious origin (70% of the control value, P < 0.05), while the expression levels of GLUT-1 and GLUT-3 in the tumour were not significantly affected. These results demonstrate the effects of insulin and glucose loading on the expression level of a molecule (GLUT proteins). The decreased GLUT-1 and GLUT-3 expression levels induced by glucose loading may partly explain the impaired FDG uptake observed in our previous study. ((C) 2002 Lippincott Williams Wilkins).
  • H Furuyama, Y Odagawa, C Katoh, Y Iwado, K Yoshinaga, Y Ito, K Noriyasu, M Mabuchi, Y Kuge, K Kobayashi, N Tamaki
    CIRCULATION 105 24 2878 - 2884 2002年06月 [査読有り][通常論文]
     
    Background-Coronary abnormalities after Kawasaki disease (KD) may be associated with endothelial dysfunction due to intimal hypertrophy. The purpose of this study was to evaluate myocardial flow reserve (MFR) and endothelial function in regressed aneurysmal regions after KD. Methods and Results-Subjects were 12 patients aged 16.0+/-2.6 years who suffered from KD at 1.7+/-1.5 years and 12 normal subjects aged 26.5+/-3.4 years. MFR and endothelial function were estimated, respectively, by changes in myocardial blood flow (MBF) during ATP infusion and by that during cold pressor test using O-15-water positron emission tomography. Data from 24 regressed aneurysmal regions were compared with those from the corresponding regions (n=36) in the control group. Although the MBF at rest in the regressed aneurysmal regions was similar to that in controls, the MBF at a hyperemic state induced by ATP infusion in the regressed aneurysmal regions was significantly lower than that in the control regions. Therefore, the MFR in regressed aneurysmal regions was significantly lower than that in controls (3.53+/-0.95 versus 4.60+/-1.14; P<0.05). MBF at rest and during the cold pressor test did not change in the control regions, but it was significantly reduced in regressed aneurysmal regions. The ratio of MBF during the cold pressor test to MBF at rest was significantly lower in regressed aneurysmal regions than in control regions (0.67+/-0.15 versus 1.00+/-0.15; P<0.05). Conclusions-MFR and endothelial function are often impaired in regressed aneurysmal regions after KD, and tomography enables the noninvasive evaluation of coronary function.
  • T Kato, Y Komatsu, E Tsukamoto, M Takei, T Takei, F Yamamoto, Y Kuge, M Asaka, N Tamaki
    CLINICAL NUCLEAR MEDICINE 27 5 376 - 377 2002年05月 [査読有り][通常論文]
     
    Menetrier's disease is a rare disorder that is characterized by significant hypertrophy of the gastric mucosa accompanied by hypoproteinemia caused by the loss of proteins from the gastric mucosa. To the authors' knowledge, the F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) findings of Menetrier's disease have not been reported. They present F-18 FDG-PET images of a patient with Menetrier's disease that show intense accumulation of F-18 FDG in the stomach that is likely to indicate a malignant disease of the stomach.
  • S Kohri, Y Hoshi, M Tamura, C Kato, Y Kuge, N Tamaki
    PHYSIOLOGICAL MEASUREMENT 23 2 301 - 312 2002年05月 [査読有り][通常論文]
     
    Combining spatially- and time-resolved spectroscopies, we attempted to quantitatively evaluate the contribution ratio of the partial mean pathlength of cerebral tissue to the observed overall mean pathlength, in which haemoglobin concentrations were selectively changed by administration of acetazolamide. When acetazolamide was administered, the observed increases in oxygenated haemoglobin depended on the probe distance, which became progressively larger at distances of 2, 3 and 4 cm. Increases in oxygen saturation were detected at 3 and 4 cm spacing, but not at 2 cm. Assuming that the modified Lambert-Beer's law can exist in the inhomogeneous structure of the head, then, we could estimate the contribution ratio of the cerebral tissue to optical signals at the probe distances of 2, 3 and 4 cm as 33%, 55% and 69%, respectively. Using these values, we recalculated acetazolamide-induced concentration changes in oxygenated-haemoglobin in the cerebral tissue, which resulted in the same values at distances of 2, 3 and 4 cm as expected. Thus, our present method opened the door to the possibility of selectively obtaining optical signals attributed to cerebral tissue.
  • K Ohkura, T Sugaoi, K Nishijima, Y Kuge, K Seki
    TETRAHEDRON LETTERS 43 17 3113 - 3115 2002年04月 [査読有り][通常論文]
     
    UV-irradiation of a solution of 5-fluoro-1,3-dimethyluracil (5-FDMU) in aprotic media effected a stereoselective 1,4-cycloaddition reaction to give a barrelene derivative in high yield. In direct contrast, irradiation of a solution of 5-FDMU and naphthalene in a protic medium afforded 5-(1-naphthyl)uracil as the major product. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Y Kuge, K Hikosaka, K Seki, K Ohkura, K Nishijima, E Tsukamoto, N Tamaki
    NUCLEAR MEDICINE AND BIOLOGY 29 3 303 - 306 2002年04月 [査読有り][通常論文]
     
    To clarify the contribution of glial cells to octanoate uptake into the brain, we determined the effects of fluoroacetate, a selective inhibitor of glial metabolism, on in vitro brain uptake of [1-C-14]octanoate, using rat brain slices. The [1-C-14]octanoate uptake significantly decreased, depending on the concentration of fluoroacetate (p = 0.001). The; [1-C-14] octanoate uptakes at 5 mM (0.23 +/- 0.05% uptake/mg slice) and 25 mM fluoroacetate (0.12 +/- 0.01% uptake/mg slice) were significantly lower than that at control (0.29 +/- 0.02% uptake/mg slice, p < 0.05 and p < 0.001, respectively). The results demonstrate the contribution of glial cells to octanoate uptake into the brain. The potential of [1-C-11]octanoate as a PET tracer for studying glial functions is suggested. (C) 2002 Elsevier Science Inc. All rights reserved.
  • Y Kuge, K Nishijima, K Nagatsu, K Seki, K Ohkura, A Tanaka, M Sasaki, E Tsukamoto, N Tamaki
    NUCLEAR MEDICINE AND BIOLOGY 29 2 275 - 279 2002年02月 [査読有り][通常論文]
     
    [F-18]FDG was produced by solid-phase F-18-fluorination (resin method) and chemical impurities were determined in the [F-18]FDG preparations by ion chromatography. The major chemical impurities were D-glucose (90.5 +/- 6.4 mug/mL), 2-chloro-2-deoxy-D-glucose (11.8 +/- 2.7 mug/mL), and D-mannose (1.7 +/- 0.7 mug/mL), which were expected to be present by considering the synthetic routes. An FDG mass (0.5 +/- 0.2 mug/mL) was also detected in the preparations. No notable radiochemical impurities, including 2-[F-18]fluoro-2-deoxy-D-mannose. were detected in the [F-18]FDG preparations. Thus, the levels of several chemical impurities were determined in the [F-18]FDG preparations produced by solid-phase F-18-fluorination. (C) 2002 Elsevier Science Inc. All rights reserved.
  • Nishijima K, Kuge Y, Tsukamoto E, Seki K, Ohkura K, Magata Y, Tanaka A, Nagatsu K, Tamaki N
    Appl Radiat Isot. 57 1 43 - 49 2002年 [査読有り][通常論文]
  • Synthesis of 9,11-diazapentacyclo[6.4.0.0(1,3).0(2,5).0(4,8)]dodecane-2,4-diones
    K Ohkura, K Nishijima, Y Kuge, K Seki
    HETEROCYCLES 56 1-2 235 - 244 2002年01月 [査読有り][通常論文]
     
    UV-Irradiation of 5,6-dihydrocyclobutaquinazoline-2,4-dione derivatives (1c-g) furnished the corresponding 9,11-diazapentacyclo[6.4.0.0(1,3).0(2,5).0(4,8)]dodecane-10,12-diones (2c-g) in fair yields, whereas photoreaction of cyclobutaquinazoline-2,4-dione (1h) produced quinazoline-2,4-dione (4) and cyclooctapyrimidine (5).
  • Nishijima K, Kuge Y, Seki K, Ohkura K, Motoki N, Nagatsu K, Tanaka A, Tsukamoto E, Tamaki N
    Nucl Med Biol. 29 3 345 - 350 2002年 [査読有り][通常論文]
  • オンカラム法(FDG MicroLabTM)を用いる18F-FDGの合成:エンドトキシン試験及び無菌試験に関する検討
    久下裕司, 西嶋剣一, 永津弘太郎, 田中 明, 塚本江利子, 玉木長良
    核医学 38 125 - 130 2001年 [査読有り][通常論文]
  • Low-dose dobutamine electrocardiograph-gated myocardial SPECT for identifying viable myocardium: comparison with dobutamine stress echocardiography and PET.
    Yoshinaga K, Morita K, Yamada S, Komuro K, Katoh C, Ito Y, Kuge Y, Kohya T, Kitabatake A, Tamaki N
    J Nucl Med. 42 838 - 844 2001年 [査読有り][通常論文]
  • Comparison of 18F-FDG, 131l-Na, and 201Tl in diagnosis of recurrent or metastatic thyroid carcinoma.
    Shiga T, Tsukamoto E, Nakada K, Morita K, Kato T, Mabuchi M, Yoshinaga K, Katoh C, Kuge Y, Tamaki N
    J Nucl Med. 42 414 - 419 2001年 [査読有り][通常論文]
  • FDG Uptake and Glucose Transporter Subtype Expressions in Experimental Tumor and Inflammation Models.
    Mochizuki T, Tsukamoto E, Kuge Y, Kanegae K, Zhao S, Hikosaka K, Hosokawa M, Kohanawa M, Tamaki N
    J Nucl Med. 42 10 1551 - 1555 2001年 [査読有り][通常論文]
  • Zhao S, Kuge Y, Tsukamoto E, Mochizuki T, Kato T, Hikosaka K, Hosokawa M, Kohanawa M, Tamaki N
    Eur J Nucl Med, 28 730 - 735 2001年 [査読有り][通常論文]
  • Serial Changes in Cerebral Blood Flow and Flow-Metabolism Uncoupling in Primates with Acute Thromboembolic Stroke.
    Kuge Y, Yokota C, Tagaya M, Hasegawa Y, Nishimura A, Kito G, Tamaki N, Hashimoto N, Yamaguchi T, Minematsu K
    J Cereb Blood Flow Metab. 21 202 - 210 2001年 [査読有り][通常論文]
  • Performance assessment of O-18 water purifier.
    Kitano H, Magata Y, Tanaka A, Mukai T, Kuge Y, Nagatsu K, Konishi J, Saji H
    Ann Nucl Med. 15 75 - 78 2001年 [査読有り][通常論文]
  • Kito G, Nishimura A, Susumu T, Nagata R, Kuge Y, Yokota C, Minematsu K
    J Neurosci Meth. 105 45 - 53 2001年 [査読有り][通常論文]
  • Y Miyake, Y Kuge, H Shimadzu, N Hashimoto, Y Ishida, M Shibakawa, T Nishimura
    NUCLEAR MEDICINE AND BIOLOGY 27 8 701 - 705 2000年11月 [査読有り][通常論文]
     
    Poly(adenosine diphosphate-ribose) synthetase (PARS) is a nuclear enzyme that is activated by deoxyribonucleic acid (DNA) strand breaks and participates in DNA repair, Excessive PARS activation, however, leads to cell death due to depletion of adenosine triphosphate (ATP). To evaluate whether it is possible to detect excessive activation of PARS with positron emission tomography (PET), we examined the pharmacokinetics of 3,4-dihydro-5-[C-11]methoxy-1(2H)-isoquinolinone ([C-11]MIQO), a potent poly(ADP-ribose) synthetase inhibitor, in the brain of rats and monkeys. Although the uptake of [C-11]MIQO in the brain of normal rats was low, [C-11]MIRO was rapidly incorporated into and then quickly washed out from the brain. The uptake of the radiotracer in the brain of normal monkeys was also row; however, [C-11]MIQO gave a distribution image that differed from that of cerebral blood flow obtained by [O-15]water-PET. No localization of [C-11]MIQO in the brain of normal monkeys was observed. Low accumulation of some radioactivity was also observed in muscles surrounding the brain of monkeys, but did not seem to interfere with measurement of [C-11]MIQO uptake in the brain with PET. Thus, detection of [C-11]MIQO uptake with PET may be useful for detecting PARS activity in ischemic injury. NUCL MED BIOL 27;8:701-705, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.
  • Y Kuge, Y Hasegawa, C Yokota, K Minematsu, N Hashimoto, Y Miyake, T Yamaguchi
    JOURNAL OF THE NEUROLOGICAL SCIENCES 176 2 114 - 123 2000年06月 [査読有り][通常論文]
     
    To clarify the effects of spread depression (SD) on cerebral circulation and metabolism, we elicited a single or repetitive episode of and evaluated CBF and CMRglc three-dimensionally in normal cats (n = 4, in each group) using a high-resolution positron emission tomography (PET) scanner. SD was evoked by applying KCl to the left occipital cor-tex, We then monitored DC potential changes with tungsten electrodes inserted into the left temporal cortex. CBF was measured twice before and three times (immediately, 30-60 min, and 60-120 min) following KCl application using [O-15]H2O, and CMRglc was determined using 2-[F-18]fluoro-2-deoxy-D-glucose immediately following the last CBF measurement, The following results were obtained: (1) a single episode of SD produced a temporary: CBF increase. followed by a long-lasting hypoperfusion in the cortex with no significant changes to CBF observed in the subcortex; (2) no significant CMRglc changes were observed in either cortical or subcortical regions following a single episode of SD; (3) a flow-metabolism uncoupling was observed in the cortical regions concurrently with persistent hypoperfusion; (4) repetitive SD produced significant CBF changes in the cortex, and (5) the cortical CMRglc increased as a result of repeated episodes of SD, with no significant changes observed in the subcortex. Thus, we succeeded in determining three-dimensionally the effects of single and repetitive SD on CBF and CMRglc in cats using a high-resolution PET scanner. The present study provides the first direct evidence of CBF-CMglc uncoupling occurring concurrently with persistent hypoperfusion following SD. (C) 2000 Elsevier Science B.V. All rights reserved.
  • Preliminary evaluation of [1-C-11]octanoate as a PET tracer for studying cerebral ischemia: A PET study in rat and canine models of focal cerebral ischemia
    Y Kuge, H Kawashima, T Hashimoto, M Imanishi, M Shiomi, K Minematsu, Y Hasegawa, T Yamaguchi, Y Miyake, N Hashimoto
    ANNALS OF NUCLEAR MEDICINE 14 1 69 - 74 2000年02月 [査読有り][通常論文]
     
    Octanoate is taken up into the brain and is converted in astrocytes to glutamine through the TCA cycle after beta-oxidation. We speculate that [1-C-11]octanoate may be used as a tracer for astroglial functions and/or fatty acid metabolism in the brain and may be useful for studying cerebral ischemia. In the present study we investigated brain distribution of [1-C-11]octanoate and compared it with cerebral blood flow (CBF) by using rat and canine models of middle cerebral artery (MCA) occlusion and a high resolution PET. In rats brain distribution of [O-15]H2O measured 1-2 h and 5-6 h after insult was compared with that of [1-C-11]octanoate measured 3-4 h after insult. Radioactivity ratios of lesioned to normal hemispheres determined with [O-15]H2O were lower than those determined with [1-C-11]octanoate. These results were confirmed by a study on a canine model of MCA-occlusion. Twenty-four hours after insult, CBF decreased in the MCA-territory of the occluded hemisphere, whereas normal or higher accumulation of [1-C-11]octanoate was observed in the ischemic regions. The uptake of [1-C-11]octanoate-derived radioactivity therefore increased relative to CBF in the ischemic regions, indicating that [1-C-11]octanoate provides functional information different from CBF. In conclusion, we found that [1-C-11]octanoate is a potential radiopharmaceutical for studying the pathophysiology of cerebral ischemia.
  • Kuge Y, Kawashima H, Minematsu K, Hasegawa Y, Yamaguchi T, Miyake Y, Hashimoto T, Imanishi M, Shiomi M, Tamaki N, Hashimoto N
    Biol Pharm Bull. 23 984 - 988 2000年 [査読有り][通常論文]
  • FDG MicroLabTMシステムを用いる18F-FDGの合成:臨床応用のための基礎的検討
    久下裕司, 塚本江利子, 加藤千恵次, 関興一, 大倉一枝, 大宮康明, 西嶋剣一, 田中明, 佐々木基仁, 玉木長良
    核医学 36 873 - 878 1999年 [査読有り][通常論文]
  • 全身FDG 検査における正常分布の検討
    加藤貴司, 塚本江利子, 杉並裕子, 高野晶寛, 馬淵恵, 吉永恵一郎, 志賀哲, 森田浩一, 加藤千恵次, 足立至, 久下裕司, 玉木長良
    核医学 36 971 - 977 1999年 [査読有り][通常論文]
  • H Kawashima, Y Kuge, K Yajima, Y Miyake, N Hashimoto
    NUCLEAR MEDICINE AND BIOLOGY 25 6 543 - 548 1998年08月 [査読有り][通常論文]
     
    To evaluate the potential of [1-C-11]-3-(R,S)-methyloctanoate (BMOA), [1-C-11]-2-octynoate, and [1-C-11]-2-decynoate as PET tracers for studying particular steps in fatty acid beta-oxidation, we examined the pharmacokinetics of these compounds in rats and a cat. In rats given these compounds, high levels of radioactivity accumulated in the heart, liver, and kidneys, suggesting their potential as tracers for studying beta-oxidation in these tissues. These organs were clearly visible with PET in a cat given BMOA, indicating the utility of BMOA for imaging these organs. NUCL MED BIOL 25;6:543-548, 1998. (C) 1998 Elsevier Science Inc.
  • 脳核医学診断用自動ROI設定システムの動物PET実験への応用
    久下裕司, 赤井信夫, 田村浩司, 山田学, 谷崎直昭, 橋本忠俊, 今西三明, 塩見美江, 石田良雄, 橋本直人
    核医学 35 733 - 740 1998年 [査読有り][通常論文]
  • H Kawashima, K Yajima, Y Kuge, N Hashimoto, Y Miyake
    JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 39 3 181 - 193 1997年03月 [査読有り][通常論文]
     
    [1-C-11]-2-Octynoic acid, [1-C-11]-2-decynoic acid and [1-C-11]-3-(R,S)-methyloctanoic acid have been synthesized in order to evaluate these compounds as PET (Positron Emission Tomography) tracers for imaging in vivo medium-chain acyl-CoA dehydrogenase and medium-chain fatty acid utilization. The synthesis was performed by the Grignard reaction between alkylmagnesium bromides and [C-11]CO2. The radiochemical yields of [1-C-11]-2-octynoic acid, [1-C-11]-2-decynoic acid, and [1-C-11]-3-(R,S)-methyloctanoic acid were 10, 7 and 1% based on the [C-11]CO2 used respectively. Radiochemical purity was >99% in all cases.
  • Y Kuge, K Minematsu, Y Hasegawa, T Yamaguchi, H Mori, H Matsuura, N Hashimoto, Y Miyake
    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 17 1 116 - 120 1997年01月 [査読有り][通常論文]
     
    To examine the reliability of quantitative positron emission tomography studies in the rat (Rat-PET), we assessed the influence of radioactivity accumulated in the Harderian glands on PET CMR(glc) determination. We measured CMR(glc) by PET and ex vivo dissection methods by using 2-[F-18]fluoro-2-deoxy-D-glucose in rats with and without focal brain ischemia. The CMR(glc) values obtained by PET, after correcting with recovery coefficients, were higher than those measured by the ex vivo method at rostral slices, and reduction of the CMR(glc) in the ischemic brain was not demonstrated by PET in the frontal cortex, The radioactivity accumulated in the Harderian glands prevents the quantitative determination of CMR(glc) using Rat-PET.
  • Kuge Y, Kawashima H, Yamazaki S, Hashimoto N, Miyake Y
    Nucl Med Biol. 23 1009 - 1012 1996年 [査読有り][通常論文]
  • Uptake of Radioactive Octanoate in Astrocytoma Cells: Basic Studies for Application of [1-11C]Octanoate as a PET Tracer.
    Yamazaki S, Fukui K, Kawashima H, Kuge Y, Miyake Y, Kangawa K
    Ann Nucl Med. 10 395 - 399 1996年 [査読有り][通常論文]
  • S YANAI, H OKADA, K SAITO, Y KUGE, Y OGAWA, H TOGUCHI
    INTERNATIONAL JOURNAL OF PHARMACEUTICS 123 2 237 - 245 1995年09月 [査読有り][通常論文]
     
    TNP-470 (6-O-(N-chloroacetylcarbamoyl)fumagillol AGM-1470) is an angiogenesis inhibitor, a new type of anticancer drug which prevents tumor neovascularization, thereby blocking the nutrient supply to tumors. In this study, we sought the optimal formulation of TNP-470 for arterial injection in order to achieve strong anticancer activity due to the tumor-selective targeting of the drug, by investigating in vitro release and stability and in vivo rabbit VX-2 antitumor activity. We found that a medium-chain triglyceride (MCT) solution containing TNP-470 facilitated the 2-week sustained release of TNP-470 in vitro and fairly good long-term stability of the agent, although it was very labile in aqueous solution. In a rabbit VX-2 tumor model, 3 weeks after inoculation on the inner side of the leg, the antitumor activities of various formulations of TNP-470 were evaluated by administration into the femoral artery feeding the tumor. Compared with Lipiodol solution or PLGA microspheres containing TNP-470, the MCT solution containing TNP-470 exerted stronger and more persistent antitumor activity accompanied by tumor regression for 3 weeks subsequently. The release sustainability of TNP-470 in the in vitro release test was suggested to be an important factor in the antitumor activity of each formulation. From these results, we conclude that the MCT solution is the most promising formulation of TNP-470 as an arterial injection for treatment of cancers.
  • S YANAI, H OKADA, K SAITO, Y KUGE, M MISAKI, Y OGAWA, H TOGUCHI
    PHARMACEUTICAL RESEARCH 12 5 653 - 657 1995年05月 [査読有り][通常論文]
     
    Using rabbits bearing VX-2 carcinoma on the inner side of the leg, we examined the antitumor activity of a medium-chain triglyceride (MCT) solution of an angiogenesis inhibitor, TNP-470 (AGM-1470, 6-O-(N-chloroacetylcarbamoyl)-fumagillol, following administration into the femoral artery feeding the tumor, The MCT solution of TNP-470 (1 and 5 mg) strongly suppressed tumor growth following a single intra-arterial (i. a.) injection 2 or 3 weeks after tumor inoculation. Moreover, remarkable regression of well-developed tumors, those 4 weeks after inoculation, was obtained by i. a. injection of the MCT solution containing 20 mg of TNP-470 without any influence on body weight. The antitumor effects were potentiated by coadministration of doxorubicin or mitomycin C (MMC) in the solution or microspheres containing MMC. In a shell-less chorioallantoic membrane (CAM) assay, angiogenesis was inhibited when a droplet of the MCT solution containing 25 mu g of TNP-470 was placed on the CAM for 2 days, suggesting that the prolonged antitumor effect resulted from the inhibition of tumor neovascularization by sustained drug release from the preparation. These results indicate that i. a. injection of the MCT solution of TNP-470 is promising for treating well-developed tumors.
  • Brain Uptake and Metabolism of [1-11C]Octanoate in Rats: Pharmacokinetic Basis for its Application as a Radiopharmaceutical for Studying Brain Fatty Acid Metabolism
    Kuge Y, Yajima K, Kawashima H, Yamazaki H, Hashimoto N, Miyake Y
    Ann Nucl Med. 9 137 - 142 1995年 [査読有り][通常論文]
  • Nylon Monofilament for Intraluminal Middle Cerebral Artery Occlusion in Rats.
    Kuge Y, Minematsu K, Yamaguchi T, Miyake Y
    Stroke. 26 1655 - 1658 1995年 [査読有り][通常論文]
  • ANTITUMOR-ACTIVITY OF A MEDIUM-CHAIN TRIGLYCERIDE SOLUTION OF THE ANGIOGENESIS INHIBITOR TNP-470 (AGM-1470) WHEN ADMINISTERED VIA THE HEPATIC-ARTERY TO RATS BEARING WALKER-256 CARCINOSARCOMA IN THE LIVER
    S YANAI, H OKADA, M MISAKI, K SAITO, Y KUGE, Y OGAWA, H TOGUCHI
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 271 3 1267 - 1273 1994年12月 [査読有り][通常論文]
     
    The antitumor effect of an angiogenesis inhibitor, TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), administered via the hepatic artery in a medium-chain triglyceride (MCT) solution, in which TNP-470 is very stable, was examined in rats bearing Walker 256 carcinosarcoma in the liver. The MCT solution containing 0.1 mg of TNP-470 completely suppressed tumor growth after a single arterial injection, and the solutions containing 0.5 similar to 5 mg of TNP-470 caused tumor regression without severe side effects on body weight gain or liver function. These antitumor effects lasted for at least 2 weeks. Moreover, the administration of the MCT solution containing 5 mg of TNP-470 also caused remarkable regression of well-developed enlarged tumors 2 weeks after inoculation, indicating potential in the treatment of unresectable hepatic cancer. When the MCT solution containing radiolabeled TNP-470 was injected via the hepatic artery, the initial radioactivity in the tumor was 22 times that in the normal part of the liver and 5.7 times that in the tumor when an aqueous solution of radiolabeled TNP-470 was injected. Also, in the case of the MCT solution, the radioactivity in the tumor was maintained at a relatively high level for over 2 weeks after injection. These results indicate that the remarkable antitumor effect resulted from the selective delivery and prolonged retention of TNP-470 at the tumor site.
  • H SAJI, Y KUGE, Y MAGATA, Y FUJIBAYASHI, A YOKOYAMA
    CHEMICAL & PHARMACEUTICAL BULLETIN 40 1 161 - 164 1992年01月 [査読有り][通常論文]
     
    To develop radiopharmaceuticals for pancreatic imaging, radioiodinated ethyl benzene derivatives containing various functional groups (amino, carboxyl, and methyl groups) were synthesized and the effects of these functional groups were compared in vitro and in vivo. At 2 min after intravenous injection, the amino derivative, 2-(4-iodophenyl)-N,N-dimethyl ethylamine, displayed about twice the pancreatic uptake and a more than 8-fold higher pancreas/liver ratio than the carboxyl and methyl derivatives. This high and selective in vivo accumulation on the amino derivative in the pancreas was well supported by in vitro studies on the uptake by pancreatic tissue slices. The mechanism promoting pancreatic accumulation of radiopharmaceuticals with an amino group is also discussed.
  • Accumulation of Radioactivity in the Pancreas After Intravenous Administration of [13N]Ammonia.
    Saji H, Kuge Y, Yamamoto K, Magata Y, Yonekura Y, Konishi J, Yokoyama A
    Nucl Med Biol. 19 531 - 537 1992年 [査読有り][通常論文]
  • Accumulation and Metabolism of [125I]HIPDM in the Rat Pancreas.
    Saji H, Kuge Y, Tsutsumi D, Yamamoto K, Konishi J, Yokoyama A
    Ann Nucl Med. 5 157 - 161 1991年 [査読有り][通常論文]
  • 新規カルシウム拮抗薬 Manidipine Hydrochloride [CV-4093(2HCl)]のラット、イヌにおける代謝
    吉田清志, 三谷政義, 塚本剛司, 久下裕司, 小林卓郎, 棚山薫晴
    薬理と治療 17 2119 - 2135 1989年 [査読無し][通常論文]
  • 遺伝子組換え型ヒトインターロイキン-2 (TGP-3) のラット、マウス、ウサギ、イヌ、サルにおける薬物動態
    小林卓郎, 久下裕司, 朴木英明, 飯沢祐史, 山本仁, 石古博昭, 棚山薫晴
    基礎と臨床 23 4309 - 4325 1989年 [査読無し][通常論文]

書籍

  • Radioimmunodetection of Atherosclerotic Lesions Focusing on the Accumulation Mechanism of Immunoglobulin G
    Shimizu Y, Hanzawa H, Zhao Y, Nishijima K, Fukura S, Sakamoto T, Zhao S, Tamaki N, Kuge Y (担当:共著範囲:pp.141-150)
    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. (Kuge Y, Shiga T, Tamaki N, eds.), Springer 2016年
  • Discovery and Evaluation of Biomarkers for Atherosclerosis
    Sakamoto T, Hanzawa H, Manri N, Sakakibara M, Shimizu Y, Zhao Y, Zhao S, Yamada S, Kamiya K, Eki Y, Suzuki A, Higuchi H, Sugano C, Tsutsui H, Tamaki N, Kuge Y (担当:共著範囲:pp.131-139)
    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. (Kuge Y, Shiga T, Tamaki N, eds.), Springer 2016年
  • Preclinical Evaluation of a Thymidine Phosphorylase Imaging Probe, [123I]IIMU, for Translational Research
    Nishijima K, Zhao S, Feng F, Shimizu Y, Akizawa H, Ohkura K, Tamaki N, Kuge Y (担当:共著範囲:pp.125-130)
    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. (Kuge Y, Shiga T, Tamaki N, eds.), Springer 2016年
  • Development of a Microreactor for Synthesis of 18F-Labeled Positron Emission Tomography Probe
    Kuno N, Manri N, Abo N, Asano Y, Nishijima K, Tamaki N, Kuge Y (担当:共著範囲:pp.113-124)
    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. (Kuge Y, Shiga T, Tamaki N, eds.), Springer 2016年
  • Semiconductor Detector-Based Scanners for Nuclear Medicine
    Takeuchi W, Suzuki A, Ueno Y, Shiga T, Hirata K, Okamoto S, Zhao S, Kuge Y, Kubo N, Kobayashi K, Watanabe S, Kobashi K, Umegaki K, Tamaki N (担当:共著範囲:pp.51-65)
    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. (Kuge Y, Shiga T, Tamaki N, eds.), Springer 2016年
  • Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy
    Kuge Y, Shiga T, Tamaki N (担当:共編者(共編著者))
    Springer 2016年
  • 放射線技術学シリーズ:核医学検査技術学 第3版 第2章 放射性医薬品
    久下裕司 (担当:分担執筆範囲:pp.38-45)
    日本放射線技術学会 監修、大西秀雄・市原 隆・山本智朗 共編。オーム社 2016年
  • わかりやすい核医学 ?核医学で知っておくべき最低限の基礎知識 B放射性医薬品
    久下裕司 (担当:分担執筆範囲:pp.9-15)
    玉木長良、真鍋治編。文光堂 2016年
  • わかりやすい核医学 ?核医学で知っておくべき最低限の基礎知識 A放射能・放射線の基礎
    久下裕司 (担当:分担執筆範囲:pp.2-8)
    玉木長良、真鍋治編。文光堂 2016年
  • 放射線技術学シリーズ:放射化学 第3版 第8章 5.分子イメージング
    久下裕司 (担当:分担執筆範囲:pp.163-166)
    日本放射線技術学会 監修、東 静香、久保直樹 共編。オーム社 2015年
  • 放射線技術学シリーズ:放射化学第3版 第8章 4. PETの化学
    久下裕司 (担当:分担執筆範囲:pp.152-163)
    日本放射線技術学会 監修、東 静香、久保直樹 共編。オーム社 2015年
  • BRAND NEW 心臓核医学 E心臓核医学の展望。?循環器疾患および動脈硬化の分子イメージング
    久下裕司, 玉木長良 (担当:分担執筆範囲:pp.248-254)
    西村恒彦 編。金原出版 2012年
  • 新・心臓病診療プラクティス16 動脈硬化の内科治療に迫る 核医学検査
    玉木長良, 久下裕司 (担当:分担執筆範囲:pp.133-138)
    吉川純一、笠貫宏、土師一夫、別府慎太郎、松崎益徳 編。文光堂 2011年
  • NEW 放射化学・放射薬品学 第9章 放射線と生体。9.1 身の回りの放射線とその生体への影響
    久下裕司, 関興一 (担当:分担執筆範囲:pp.209-213)
    佐治英郎 編。廣川書店 2011年
  • Non-invasive Optical Tracking of Bone Marrow Stromal Cells Transplanted into Rat Cerebral Infarct
    Sugiyama T, Kuroda S, Osanai T, Maruichi K, Chiba Y, Shichinohe H, Kuge Y, Tamaki N, Iwasaki Y (担当:共著範囲:pp.139-144)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Bone Marrow Stromal Cell Transplantation for Central Nervous System Disorders ?Perspective for Translational Research and Clinical Application
    Kuroda S, Kuge Y, Tamaki N, Iwasaki Y (担当:共著範囲:pp.126-138)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Molecular Imaging of Atherosclerotic Plaque Vulnerability: Comparison between 18F-FDG and 99mTc-Annexin A5
    Zhao Y, Kuge Y, Zhao S, Strauss HW, Blankenberg FG, Tamaki N (担当:共著範囲:pp.69-77)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Initial Performance Measurement of an Integrated PET/SPECT/CT System for Small Animal Imaging
    Magota K, Kubo N, Narihiro K, Suzuki K, Nishijima K, Zhao S, Kuge Y, TamakiN (担当:共著範囲:pp.60-68)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Molecular Imaging for the Assessment of Tumor Malignancy and Response to Therapy
    Kuge Y, Zhao S, Takei T, Tamaki N (担当:共著範囲:pp.19-29)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Advances in Molecular Imaging
    Tamaki N, Kuge Y (担当:共著範囲:pp.1-4)
    Molecular imaging for integrated medical therapy and drug development. (Tamaki N, Kuge Y, eds), Springer 2010年
  • Molecular imaging for integrated medical therapy and drug development
    Tamaki N, Kuge Y (担当:共編者(共編著者))
    Springer 2010年
  • 遺伝子医学MOOK, 創薬研究への分子イメージング応用 画像バイオマーカーとしての分子イメージングの利用 7)治療効果評価への分子イメージングの利用 ?動脈硬化治療薬開発のための分子イメージング. 創薬研究への分子イメージング応用
    玉木長良, 趙芫, 久下裕司 (担当:分担執筆範囲:pp.201-205)
    佐治英郎 編。メディカル ドゥ 2010年
  • 遺伝子医学MOOK 別冊, 創薬技術の革新 マイクロドーズからPET分子イメージングへの新展開 PETが着目する課題3)循環器領域の分子イメージング
    玉木長良, 吉永恵一郎, 久下裕司 (担当:分担執筆範囲:pp.126-131)
    杉山雄一、山下伸二、栗原千絵子編。メディカル ドゥ 2010年
  • 心・血管病の分子イメージング 第1章 心・血管病の分子イメージングの歴史、現状
    玉木長良, 吉永恵一郎, 久下裕司 (担当:分担執筆範囲:pp.1-5)
    Jagat Narula監修、田原宣広編。永井書店 2010年
  • 臨床医とコメディカルのための最新クリニカルPET 第18章 心臓核医学の分子イメージング 1.心筋交感神経・受容体イメージング
    久下裕司, 西嶋剣一, 玉木長良 (担当:分担執筆範囲:pp.288-291)
    編集主幹:米倉義晴。先端医療技術研究所 2010年
  • IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS SERIES No. 1. Technetium-99m Radiopharmaceuticals: Status and Trends. Chapter 11 Technetium-99m Annexin-A5 for Apoptosis Imaging
    Kuge Y (担当:分担執筆範囲:pp.241-253)
    INTERNATIONAL ATOMIC ENERGY AGENCY 2009年
  • 放射線技術学シリーズ:放射化学 第2版 第8章4. PETの化学
    久下裕司 (担当:分担執筆範囲:pp.150-160)
    日本放射線技術学会 監修、花田博之 編。オーム社 2008年
  • 放射線技術学シリーズ:放射化学 第2版 第8章5. 分子イメージング
    久下裕司 (担当:分担執筆範囲:pp.160-163)
    日本放射線技術学会 監修、花田博之 編。オーム社 2008年
  • 放射線技術学シリーズ:核医学検査技術学 第2版 第2章 放射性医薬品
    久下裕司 (担当:分担執筆範囲:pp.36-42)
    日本放射線技術学会 監修、大西英雄・松本政典・増田一孝 共編。オーム社 2008年
  • 遺伝子医学MOOK9, ますます広がる分子イメージング技術 第2章 生物学的応用編 4. 心疾患の分子イメージング 2) 神経伝達・受容体機能解析
    玉木長良, 久下裕司 (担当:分担執筆範囲:pp.232-235)
    佐治英郎、田畑泰彦 編。メディカル ドゥ 2008年
  • 臨床医のためのクリニカルPET−病期・病態診断のためのガイドブック− 第I部 基礎・技術編 第1章 PET薬剤の最先端 1. PET薬剤開発の進歩
    久下裕司 (担当:分担執筆範囲:pp.11-14)
    伊藤正敏 編、先端医療技術研究所 2007年
  • An ultra-high-energy collimator for small animal imaging in dual-isotope study of 18F and 99mTc.
    Kubo N, Zhao S, Kinda A, Motomura N, Katoh C, Kuge Y, Tamaki N (担当:共著範囲:pp.275-279)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Reduction of myocardial oxidative metabolism in dilated cardiomyopathy but not in remote areas in myocardial infarction.
    Noriyasu K, Tsukamoto T, Morita K, Kageyama H, Mabuchi M, Katoh C, Kuge Y, Kitabatake A, Tamaki N (担当:共著範囲:pp.271-274)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • In vitro and in vivo characterization of high specific activity S-(-) [11C]CGP-12177, a radioligand for β-adrenoceptors, in rats.
    Nishijima K, Kuge Y, Motoki N, Seki K, Ohkura K, Morita K, Tamaki N (担当:共著範囲:pp.261-266)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • The impact of coronary stenosis and risk factors on myocardial flow reserve.
    Tsukamoto T, Morita K, Noriyasu K, Katoh C, Kageyama H, Mabuchi K, Kuge Y, Nakada K, Okamoto H, Kitabatake A, Tamaki N (担当:共著範囲:pp.257-260)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Time course of apoptotic tumor response following a single dose of chemotherapy: Detection with 99mTc-annexin V and comparison with blood flow, caspase-3 expression and TUNEL staining in an experimental tumor model.
    Takei T, Kuge Y, Zhao S, Mochizuki T, Strauss HW, Blankenberg F, Tait JF, Tamaki N (担当:共著範囲:pp.249-252)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Methionine PET in differentiating recurrent brain tumor from radiation necrosis following cranial radiation.
    Katoh N, Nakada K, Takei N, Aoyama H, Shirato H, Kato C, Kuge Y, Tsukamoto E, Tamaki N (担当:共著範囲:pp.217-221)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Neuronal cyclooxygenase-2 induction associated with spreading depression and focal brain ischemia in primates.
    Yokota C, Kuge Y, Hasegawa Y, Inoue H, Tagaya M, Abumiya T, Kito G, Tamaki N, Minematsu K (担当:共著範囲:pp.191-196)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • The loss of neuronal integrity may be one of the causes of cognitive disturbances in the patients with brain traumatic injury and normal FLAIR and T2-weighted MRI.
    Shiga T, Ikoma K, Tsukamoto M, Katoh C, Matsuyama T, Kuge Y, Nakada K, Tamaki N (担当:共著範囲:pp.177-180)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Analysis of Neuronal and Glial Functions in Cerebral Ischemia: An Approach with Nuclear Medicine.
    Kuge Y, Kaji T, Hikosaka K, Yokota C, Seki K, Ohkura K, Shiga T, Minematsu K, Tamaki N (担当:共著範囲:pp.44-52)
    Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives, International Congress Series 1264 (Y. Kuge, N. Tamaki, eds), Elsevier Science B.V 2004年
  • Clinical Nuclear Cardiology --State of the Art and Future Directions-- (3rd Edition) Section VIII Tracer Specific Imaging Technique, Chapter 35 Fatty Acid Imaging
    Tamaki N, Morita K, Kuge Y (担当:分担執筆範囲:pp.559-575)
    Elsevier 2004年
  • Positron Emission Tomography and Molecular Imaging: State of the Art and Future Perspectives
    Tamaki N, Kuge Y (担当:共編者(共編著者))
    International Congress Series 1264, Elsevier Science B.V 2004年
  • クリニカルPET 一望千里 第6章 実用編
    河嶋秀和, 久下裕司 (担当:分担執筆範囲:pp.179-199)
    西村恒彦、佐治英郎、飯田秀博編。メジカルレビュー社 2004年
  • Brain ischemia and spreading depression in a primate model.
    Yokota C, Kuge Y, Tagaya M, Hasegawa Y, Abumiya T, Kito G, Yamaguchi T, Minematsu K (担当:共著範囲:pp.127-144)
    Strategic medical science against brain attack (Kikuchi H, ed.), Springer-Verlag 2002年
  • Annual Review 腎臓 「ポジトロン断層撮影法(PET)」
    玉木長良, 塚本江利子, 久下裕司 (担当:分担執筆範囲:pp.55-58)
    伊藤克巳、浅野 泰、遠藤 仁、御手洗哲也、東原英二 編。中外医学社 2002年
  • 放射線技術学シリーズ:核医学検査技術学 第2章 放射性医薬品
    久下裕司 (担当:分担執筆範囲:pp.34-44)
    日本放射線技術学会 監修、大西英雄・松本政典・増田一孝 共編。オーム社 2002年
  • 循環器疾患---state of arts, ver.2 全面改訂版, 別冊・医学のあゆみ 「診断法をめぐる最近の進歩, 虚血性心疾患, ポジトロン断層撮影法」
    玉木長良, 久下裕司 (担当:分担執筆範囲:pp. 277-279)
    矢崎義雄、島田和幸、井上博、永井良三 編。医歯薬出版 2001年 277-279
  • 放射線技術学シリーズ:放射化学 第6章5. PETの化学
    久下裕司 (担当:分担執筆範囲:pp.143-154)
    日本放射線技術学会 監修、花田博之 編。オーム社 2001年
  • クリニカルPETハンドブック 「心筋のバイアビリティ診断、心筋受容体の最近の知見」
    玉木長良, 久下裕司 (担当:分担執筆範囲:pp.117-123)
    鳥塚莞爾、小西淳二、増田康治、西村恒彦、玉木長良、伊藤健吾、佐治英郎 編。技術経済研究所 2001年
  • Animal PET Study in Development of Novel PET Tracers.
    Kuge Y, Kawashima H, Ejima N, Miyake Y, Hashimoto N, Hashimoto T, Imanishi M, Shiomi M, Minematsu K, Hasegawa Y, Yamaguchi T, Tamaki N (担当:共著範囲:pp.297-304)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Modified Method for Quantifying Regional Myocardial Blood Flow Using 15O-water with PET
    Katoh C, Kuge Y, Morita K, Tsukamoto E, Tamaki N, Knuuti J (担当:共著範囲:pp. 273-278)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Visualization of Normal Organs in Whole-Body PET Imaging with F-18 FDG
    Kato T, Tsukamoto E, Suginami Y, Mabuchi M, Yoshinaga K, Takano A, Adachi I, Shiga T, Morita K, Katoh C, Kuge Y, Tamaki N (担当:共著範囲:pp.221-224)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Clinical Usefulness of FDC-PET in the Patients with Differentiated Thyroid Cancer after Total Thyroidectomy
    Shiga T, Tsukamoto E, Kato T, Morita K, Adachi I, Mabuchi M, Yoshinaga K, Suginami Y, Takano A, Tamaki N, Katoh C, Kuge Y (担当:共著範囲:pp. 181-185)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Quantitative Analysis for Myocardial Glucose Utilization Using Positron Emission Tomography and F-18-Deoxyglucose
    Morita K, Katoh C, Yoshinaga K, Adachi I, Shiga T, Mabuchi M, Itoh Y, Konno M, Kohya T, Kitabatake A, Kuge Y, Tsukamoto E, Tamaki N (担当:共著範囲:pp. 141-145)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Clinical Utility of Combination of FDG-PET and CBF-SPECT in Extratemporal Lobe Epilepsy
    Takano A, Shiga T, Kobayashi J, Nakamura F, Adachi I, Katoh C, Kuge Y, Koyama T, Tsukamoto E, Tamaki N (担当:共著範囲:pp. 73-78)
    Positron Emission Tomography in the Millennium”, International Congress Series 1197 (Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K, eds.), Elsevier Science B.V. 2000年
  • Positron Emission Tomography in the Millennium
    Tamaki N, Tsukamoto E, Kuge Y, Katoh C, Morita K (担当:共編者(共編著者))
    International Congress Series 1197, Elsevier Science B.V 2000年

その他活動・業績

  • Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw.
    Kitagawa Y, Ohga N, Asaka T, Sato J, Hata H, Helman J, Tsuboi K, Amizuka N, Kuge Y, Shiga T Jpn Dent Sci Rev. 55 (1) 65 -67 2019年 [査読無し][招待有り]
  • The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment.
    Hirata K, Yamaguchi S, Shiga T, Kuge Y, Tamaki N J Clin Med. 8 (8) E1088 2019年 [査読有り][招待有り]
  • Nuclear Medicine Today 2018 最新トピックスから探る核医学の現在と未来 ?Theranosticsに向けた研究開発の最新トピックス 5.68Ge/68Gaジェネレータを用いるPET薬剤の研究開発と将来展望。
    久下裕司, 東川 桂, 岡本祥三, 志賀 哲 INNERVISION 33 (11) 58 -61 2018年 [査読無し][招待有り]
  • Nuclear Medicine Today 2018 最新トピックスから探る核医学の現在と未来 ?Theranosticsに向けた研究開発の最新トピックス 4.前立腺がんに対するPSMA-PETとPSMAによるアイソトープ治療の最新動向。
    岡本祥三, 志賀 哲, 久下裕司 INNERVISION 33 (11) 55 -57 2018年 [査読無し][招待有り]
  • 口腔癌における低酸素分子イメージング
    北川善政, 佐藤 淳, 大賀則孝, 浅香卓哉, 竹内康人, 犬伏正幸, 久下裕司, 志賀 哲 お茶の水醫學雑誌 66 193 -211 2018年 [査読無し][招待有り]
  • 特集 薬剤関連顎骨壊死の画像診断up to date。 薬剤関連顎骨壊死のPET検査。
    北川 善政, 浅香 卓哉, 佐藤 淳, 秦 浩信, 坪井 香奈子, 網塚 憲生, 久下 裕司, 志賀 哲 臨床放射線 63 (10) 1071 -1081 2018年 [査読無し][招待有り]
  • Shimizu Y, Kuge Y Nuclear Medicine and Molecular Imaging 50 (4) 284 -291 2016年 [査読有り][招待有り]
  • イメージングによる“がん”の治療効果予測−新規核医学診断薬([123I]IIMU)の臨床研究への歩み−
    久下裕司, 西嶋剣一, 大倉一枝, 志賀 哲, 玉木長良 ISOTOPE NEWS 729 16 -20 2015年 [査読無し][招待有り]
  • イメージング質量分析を用いたスフィンゴミエリンの組織内分布と制御機構の解明
    杉本正志, 志水陽一, 五十嵐靖之, 久下裕司 JSMI Report 9 (1) 43 -45 2014年 [査読無し][招待有り]
  • 久下裕司 血栓止血誌 25 (3) 363 -370 2014年 [査読無し][招待有り]
  • 新しいがんの放射線生物学を拓くイメージング技術
    安井博宣, 戒田篤志, 兵藤文紀, 三浦大典, 久下裕司, 松本孔貴 放射線生物研究 Radiation Biology Research Communications 49 (3) 263 -283 2014年 [査読無し][招待有り]
  • Molecular Imaging 2014 分子イメージングはどこまで進んだか ?分子イメージングの最新動向 1.核医学における分子イメージングの最新動向 5)製造標準化の現状と展望
    脇厚生, 久下裕司, 西嶋剣一, 藤林靖久 INNERVISION 29 (7) 23 -26 2014年 [査読無し][招待有り]
  • 久下裕司 呼吸と循環 61 (11) 1001 -1007 2013年 [査読無し][招待有り]
  • 特集 心血管イメージング最前線−エコー, CTからcoronary imagingまで−5.核医学検査 f. 分子イメージングの方向性
    久下裕司, 玉木長良 Heart View 17 (12(増刊号)) 320 -325 2013年 [査読無し][招待有り]
  • 特集 「百聞は一見にしかず 生体イメージングがもたらす診断と治療の戦略」セミナー 循環器領域の分子イメージング
    久下裕司, 玉木長良 ファルマシア 49 (7) 682 -687 2013年 [査読無し][招待有り]
  • 特集 不安定プラークの病態と診断 10.不安定プラークと分子イメージング
    久下裕司, 玉木長良 月刊循環器 3 (1) 69 -77 2013年 [査読無し][招待有り]
  • Molecular imaging in heart failure patients
    Tamaki N, Kuge Y, Yoshinaga K Clin Transl Imaging 1 (5) 341 -354 2013年 [査読無し][招待有り]
  • 特集1 心臓核医学の最先端 1.動脈硬化イメージング−実験的検討
    久下裕司, 趙 芫, 趙 松吉, 玉木長良 PETジャーナル 18 14 -16 2012年 [査読無し][招待有り]
  • 医薬品開発(又は創薬・育薬)における分子イメージング技術の現状と進歩
    久下裕司, 西嶋剣一, 孫田恵一, 趙 松吉, 玉木長良 医薬品医療機器レギュラトリーサイエンス 43 (4) 308 -313 2012年 [査読無し][招待有り]
  • 交感神経と循環器疾患 交感神経イメージング
    玉木長良, 吉永恵一郎, 久下裕司 Cardiac Practice 23 (2) 143 -147 2012年 [査読無し][招待有り]
  • 特集 冠動脈疾患の診断・治療における画像診断の進歩 分子イメージングによる冠動脈病変評価
    玉木長良, 吉永恵一郎, 久下裕司 Cardiac Practice 23 (1) 23 -27 2012年 [査読無し][招待有り]
  • 特集1 次世代腫瘍分子イメージング 4.アポトーシスイメージングプローブ
    久下裕司, 竹井俊樹, 趙 松吉 PETジャーナル 13 23 -25 2011年 [査読無し][招待有り]
  • 特集1 核医学検査の新しい展開〜治療戦略への応用 治療戦略に役立つ放射性薬剤の開発
    久下裕司, 西嶋剣一, 趙 松吉 映像情報メディカル 43 (11) 842 -849 2011年 [査読無し][招待有り]
  • 心不全の分子イメージング
    玉木長良, 吉永恵一郎, 久下裕司 日本心不全学会 News Letter 15 (2) 8 -9 2011年 [査読無し][招待有り]
  • SPECT、PETによるプラークイメージング
    玉木長良, 趙 芫, 久下裕司 動脈硬化予防 9 (2) 53 -57 2010年 [査読無し][招待有り]
  • Yuji Kuge, Songji Zhao, Toshiki Takei, Nagara Tamaki ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY 9 (9) 1003 -1011 2009年11月 [査読有り][招待有り]
     
    Apoptosis, or programmed cell death, is activated in the course of successful anti-neoplastic therapy. Determining baseline levels of apoptosis and the increment of apoptosis induced by therapy can serve as useful prognostic markers. Thus, non-invasive assessment of apoptosis would be desirable to provide clinicians with information on therapeutic efficacy as well as for the development and testing of new anticancer drugs. In these regards, apoptosis detecting radio-probes (radiopharmaceuticals) have been extensively studied. Annexin A5 (annexin V) is an endogenous protein that binds with high affinity and specificity to phosphatidylserine, which is presented on the cell surface in an early process of apoptosis. Accordingly, apoptotic cells can be detected in vivo using annexin A5 labeled with radionuclides, such as (99m)Tc and (18)F. To date, several annexin A5 radio-probes have been developed. Among these, (99m)Tc-HYNIC-annexin A5 is the best candidate for apoptosis imaging. The apoptosis imaging using radio-labeled annexin A5 has been applied for detecting apoptosis in vivo in the experimental and clinical evaluation of the tumor response to chemotherapy or radiotherapy. The present review describes apoptosis imaging with annexin A5 radio-probes, focusing on its application to the evaluation of the tumor response to chemotherapy. First, principles of apoptosis imaging with annexin A5 radio-probes are described. Next, experimental results with radio-labeled annexin A5 in the evaluation of therapeutic efficacy are discussed. Finally, clinical application of apoptosis imaging with radio-labeled annexin A5 is addressed.
  • PET核医学検査による評価
    玉木長良, 趙 芫, 久下裕司, 志賀哲 Mebio 26 (4) 114 -118 2009年 [査読無し][招待有り]
  • 核医学の軌跡(PETを中心に)
    玉木長良, 吉永恵一郎, 久下裕司 DIGITALMEDICINE 42 26 -29 2009年 [査読無し][招待有り]
  • Myocardial metabolic imaging in the clinical setting
    Tamaki N, Kuge Y, Yoshinaga K Eur Cardiolgy 5 (1) 15 -18 2009年 [査読無し][招待有り]
  • 放射線治療を指向したPET/SPECTプローブの開発〜低酸素イメージングを中心に〜
    久下裕司, 上田真史, 趙 松吉, 工藤 喬, 近藤科江, 田中正太郎, 玉木長良, 平岡眞寛, 佐治英郎 癌の臨床 54 (2) 105 -108 2008年 [査読無し][招待有り]
  • 分子イメージングとがん治療戦略:イメージングによるインビボ組織染色を目指して
    久下裕司, 佐治英郎, 玉木長良, 趙松吉, 関興一, 上田真史, 清野泰 INNERVISION 22 (7) 42 2007年 [査読無し][招待有り]
  • 心受容体イメージング
    玉木長良, 塚本隆裕, 犬伏正幸, 久下裕司 日本臨床 65 (2) 303 -307 2007年 [査読無し][招待有り]
  • PETの展望 「新しいPET用薬剤」
    久下裕司, 西嶋剣一 Pharma Medica 24 (10) 51 -54 2006年 [査読無し][招待有り]
  • 動脈硬化病態の解析と分子イメージング:プロスタグランジン合成酵素を標的として
    久下裕司, 佐治英郎, 清野泰, 横田千晶, 玉木長良, 関興一 INNERVISION 21 (7) 17 2006年 [査読無し][招待有り]
  • 動脈硬化の質的診断のための分子イメージング
    佐治英郎, 久下裕司, 向高弘, 多田村栄二, 久米典昭, 野原隆司 INNERVISION 21 (7) 27 2006年 [査読無し][招待有り]
  • ミニガンマカメラの基礎実験及び臨床への応用の可能性
    佐治英郎, 清野 泰, 久下裕司 Isotope News 606 2 -6 2004年 [査読無し][招待有り]
  • 玉木長良, 森田浩一, 竹井俊樹, 久下裕司 呼吸と循環 52 (7) 703 -707 2004年 [査読無し][招待有り]
  • 特集“再生医療と画像診断 −失われた機能の再生をめざして−” 遺伝子治療における画像診断
    久下 裕司, 佐治英郎, 清野 泰 映像情報メディカル 36 (8) 856 -860 2004年 [査読無し][招待有り]
  • PETとレセプター 〜脳と心筋のレセプター機能解析〜
    久下 裕司, 玉木 長良, 佐治 英郎 医薬ジャーナル 40 (5) 1451 -1457 2004年 [査読無し][招待有り]
  • 受容体イメージング
    玉木長良, 志賀 哲, 久下裕司 Medical Imaging Technology 21 (5) 344 -349 2003年 [査読無し][招待有り]
  • FDG-PET検査の改良による腫瘍の鑑別診断法の開発:膜輸送遺伝子による検討
    玉木長良, 久下裕司, 趙 松吉, 塚本江利子, 中駄邦博 INNERVISION 18 (8) 25 2003年 [査読無し][招待有り]
  • What is the clinical role of neuronal imaging? (INVITED COMMENTARY)
    Morita K, Kuge Y, Tamaki N J Nucl Med 44 (9) 1467 -1468 2003年 [査読無し][招待有り]
  • 久下裕司, 西嶋剣一, 玉木長良 RADIOISOTOPES 51 191 -195 2002年 [査読無し][招待有り]
  • PET Summer Seminar Highlights 2001
    久下裕司, 塚本江利子, 中駄邦博, 久保直樹, 玉木長良 映像情報メディカル 33 (12) 1204 -1210 2001年 [査読無し][招待有り]
  • 心筋脂肪酸代謝イメージング:123I-BMIPP SPECTと11C-palmitate PET
    森田浩一, 久下裕司, 加藤知恵次, 玉木長良 BME 15 (8) 40 -44 2001年 [査読無し][招待有り]
  • Tamaki N, Kuge Y, Katoh C Nucl Med Com 22 (8) 847 -850 2001年 [査読無し][招待有り]
  • Clinical roles of perfusion and metabolic imaging.
    Tamaki N, Kuge Y, Tsukamoto E J Cardiol 37 (Suppl I) 57 -64 2001年 [査読無し][招待有り]
  • The Road to Quantitation of Regional Myocardial Uptake of Tracer (INVITED COMMENTARY)
    Tamaki N, Kuge Y, Tsukamoto E J Nucl Med 42 780 -781 2001年 [査読無し][招待有り]
  • 特集“新世紀における核医学の展望―FDG-PETの有用性と経済効果を中心に―” ?-2.使い捨てFDG合成キットの利点と医療経済効果
    久下裕司, 塚本江利子, 玉木長良 INNERVISION 15 (12) 88 -93 2000年 [査読無し][招待有り]
  • 玉木長良, 森田浩一, 久下裕司 呼吸と循環 48 (10) 1055 -1059 2000年 [査読無し][招待有り]
  • ポジトロン断層撮影法(PET)の虚血性心疾患への応用
    玉木長良, 森田浩一, 久下裕司, 塚本江利子 循環器科 48 (4) 331 -335 2000年 [査読無し][招待有り]
  • 特集“21世紀におけるPET画像の役割” 心臓
    玉木長良, 森田浩一, 久下裕司 臨床放射線 45 1055 -1064 2000年 [査読無し][招待有り]
  • 久下裕司 RADIOISOTOPES 49 249 -251 2000年 [査読無し][招待有り]
  • The role of fatty acids in cardiac imaging.
    Tamaki N, Morita K, Kuge Y, Tsukamoto E J Nucl Med 41 (9) 1525 -1534 2000年 [査読無し][招待有り]
  • 動物用PET−脳機能の研究:疾患モデルを用いて
    久下裕司 PET通信 25 10 -12 1998年 [査読無し][招待有り]
  • 久下裕司 RADIOISOTOPES 46 697 -698 1997年 [査読無し][招待有り]
  • PETによる脳内AchEマッピング:アルツハイマー病診断の可能性
    久下裕司 ファルマシア 33 57 -58 1997年 [査読無し][招待有り]
  • Effects of Extracranial Radioactivity on Measurement of Cerebral Glucose Metabolism by Rat-PET with [18F]-2-fluoro-2-deoxy-D-glucose (Letter to the editor)
    Kuge Y, Miyake Y, Minematsu K, Yamaguchi T, Hasegawa Y J. Cereb. Blood Flow Metab 17 1261 1997年 [査読無し][通常論文]
  • ラットのPET
    久下裕司, 峰松一夫, 長谷川泰弘, 三宅可浩 循環器病研究の進歩 17 85 -91 1996年 [査読無し][招待有り]

特許

受賞

  • 2002年 第40回 日本核医学会賞
  • 2002年 The 40th award of the Japanese Society of Nuclear Medicine

共同研究・競争的資金等の研究課題

  • サイクロトロンで製造した68Gaを用いる前立腺がん診断用PET薬剤:68Ga-PSMAの標識合成法開発
    国立研究開発法人 日本医療研究開発機構:医療研究開発推進事業費補助金(橋渡し研究戦略的推進プログラム)シーズA支援費
    研究期間 : 2018年 -2018年 
    代表者 : 久下裕司
  • 文部科学省:科学研究費補助金(挑戦的研究(萌芽))
    研究期間 : 2017年 -2018年 
    代表者 : 久下 裕司
  • 補体複合体のin vivoイメージングによる慢性炎症病態評価法の開発
    国立研究開発法人 日本医療研究開発機構:医療研究開発推進事業費補助金(橋渡し研究戦略的推進プログラム)シーズA支援費
    研究期間 : 2017年 -2017年 
    代表者 : 久下裕司
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2014年 -2017年 
    代表者 : 久下 裕司
  • 補体因子Properdinのin vivo可視化による不安定プラーク検出法の開発
    北海道臨床開発機構:医療研究開発推進事業費補助金(橋渡し研加速ネットワークプログラム)シーズAに係る研究開発委託費(シーズ育成経費)
    研究期間 : 2016年 -2016年 
    代表者 : 久下裕司
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2015年 -2016年 
    代表者 : 久下 裕司
  • 新規放射線F-18ラベル法によるDNA取り込み型核酸代謝PET核医学診断薬の開発
    北海道臨床開発機構:医療研究開発推進事業費補助金(橋渡し研加速ネットワークプログラム)シーズAに係る研究開発委託費(シーズ育成経費)
    研究期間 : 2015年 -2015年 
    代表者 : 久下裕司
  • 慢性炎症の高精度イメージングを可能とする核医学診断材の開発
    科学技術振興機構:研究成果展開事業
    研究期間 : 2014年 -2015年 
    代表者 : 久下裕司
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2013年 -2014年 
    代表者 : 久下 裕司
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2011年 -2012年 
    代表者 : 久下 裕司
     
    心筋梗塞や脳梗塞の根幹的原因である"動脈内のプラーク"の不安定性を精度よく評価できる診断法の開発が臨床画像診断学の急務である。本研究の目的は、プレターゲティング法を取り入れ、動脈内プラークの破綻とそれに伴う血栓形成に深く関与する組織因子(Tissue Factor, TF)の選択的な描出により不安定プラーク(粥状動脈硬化巣)を特異的に検出しうる新しい核医学イメージング法を提案することにある。この目的達成のため、今年度は以下の研究を実施した。1)anti-TF-mAb-SAv/18F-FBBのシステムの合成検討 18F標識ビオチン誘導体18F-FBBは、プレターゲティングユニットであるanti-TF-mAb-SAvと高い親和性を持つポストプローブであるが、18Fの半減期が約2時間であるため迅速な合成が必要である。この18F-FBBの標識前駆体である18F標識スクシンイミド誘導体18F-SFBの迅速合成のため、合成条件(温度、時間、溶媒等)を詳細に検討した。その結果、[18F]SFBの収量として4.7 ± 0.7 GBq(照射条件25 A, 20 min)、放射化学的収率として33.6 ± 9.5%(減衰補正なし)を達成した。合成時間は約55分程度、HPLCで求めた放射化学的純度は95%以上であり、迅速かつ高純度の[18F]SFBを得ることに成功した。2)モデル動物におけるPET撮像条件・TF発現の検討 TFイメージング実験の前段階として、大腿動脈バルーン障害ウサギを用いて、18F-FDGによるPET撮像実験と、病変部位におけるTF発現の検討を行った。PET撮像実験により200 MBq/rabbit程度の投与量で、動脈硬化病変を明瞭に描出できることが分かった。また、免疫染色により病変部における高いTF発現を認めた。
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2009年 -2010年 
    代表者 : 成廣 賢史, 久下 裕司
     
    本研究は、腫瘍における低酸素領域とそれにともない発現する血管新生因子(チミジンボスホリラーゼ:TP)のダブルターゲットとするアイソトープ治療のためのI-131標識薬剤を合成し、その有効性と限界明らかにすることを目的とする。平成21年度において目的とする化合物(5I-6NIMUとI-AIMU)とその合成法を確立した。平成22年度は、その合成法を標識合成法へ応用すべく以下検討を行った。1.放射性ヨウ素標識体5-ヨード-6-ニトロイミダゾールメチルウラシル([^<125>I]5I-6NIMU)の合成6-ニトロイミダゾールメチルウラシルを[^<125>I]NISにより放射性ヨウ素標識化を行った。目的とする[^<125>I]5I-6NIMUの生成を高収率で確認できた。しかしながら単離精製後、溶媒留去の操作において放射化学的純度の低下(分解)が確認された。また、室温下1〜2時間の保存において放射化学的純度の低下を認めた。2.放射性ヨウ素標識体5-ヨード-6-アミノミダゾールメチルウラシル([^<125>I]I-AIMU)標品の合成経路と同様に、[^<125>I]5I-6NIMUをメタノール・アンモニア水中水素雰囲気下10%パラジウム炭素により還元反応を実施した。しかしながら[^<125>I]I-AIMUを得ることに成功していない。その原因として原料[^<125>I]5I-6NIMUおよび成績体[^<125>I]I-AIMUの不安定さが考えられた。5I-6NIMU及びI-AIMUの合成法に従い、放射性ヨウ素を用いた標識合成へ応用した。[^<125>I]5I-6NIMUの放射化学的純度は90%であったが、目的とする放射性ヨウ素化合物を得ることに成功し、アイソトープ治療のためのI-131標識薬剤への展開が示唆された。[^<125>I]I-AIMUを得ることに成功しておらず合成経路を再検討中である。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2008年 -2010年 
    代表者 : 久下 裕司
     
    本研究では、増殖能・低酸素等を画像化する分子イメージング法による癌の病態解析、及び分子標的治療・放射線治療に対する癌の反応解析の有効性を動物実験・臨床研究において実証した。さらに申請者らが開発してきた“血管新生因子を標的とする分子プローブ"の有効性・安全性を動物において示した。これらの研究成果は、悪性腫瘍の分子レベルの変化を画像化しうる分子イメージング法の特長を生かし、臨床診断への応用が可能な新しい癌の診断・治療法を構築するための重要な知見を提供するものである。
  • 文部科学省:科学研究費補助金(萌芽研究)
    研究期間 : 2007年 -2008年 
    代表者 : 久下 裕司
     
    本研究の目的は、脳卒中及びアルツハイマー病を対象として、PET・SPECTといった分子イメージング法を分子生物学的手法と融合させることにより脳機能の再生過程を解析し、これらの過程の臨床診断に有用な画像診断法を探索・考案することにある。今年度は、充実した環境(Enriched environment ; EE)及び通常環境の異なる環境下で飼育したラットを用いて、神経機能回復の観点から重要と考えられる梗塞周辺部において、シナプス新生のマーカーであるsynaptophysin (SYP)の発現変化を測定した。また、中枢神経細胞膜上に特異的に発現する中枢性ベンゾジアゼピン受容体を標的とし、これに選択的に結合する[^<125>I]iomazenilを用いたin vitro autoradiographyを行い、環境刺激による神経再構築イメージングの可能性を検討した。その結果、SYP発現密度は、EE群ではST群に比べ、皮質と線条体の梗塞周辺部でともに有意に高く、環境刺激によって梗塞周辺部のシナプス新生が亢進し、これが神経機能の回復に寄与している可能性が示された。また、EE群ではST群に比べ、皮質梗塞周辺部における[^<125>I]iomazenil集積が有意に高く、中枢性ベンゾジアゼピン受容体を指標とする神経機能イメージングにより脳機能の再生過程を解析できる可能性が示された。以上の結果より、放射性iomazenilなどのプローブを用いた核医学的手法により、脳虚血障害後の環境刺激による神経機能の回復を定量的に評価できる可能性が示された。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2005年 -2007年 
    代表者 : 久下 裕司
     
    本研究では、"がんの分子機構"や"がんの個性"に関する情報を、ポジトロンCTをはじめとする分子イメージング法を用いてインビボで画像として捉え、がんの治療戦略に役立てることを目的とし、以下の成果を得た。1.分子標的治療に関する研究動物実験において、FLT(核酸誘導体)は腫瘍細胞の増殖能を反映し、Iressaなど分子標的療法の早期治療効果判定に有用である可能性が示された。2.放射線治療に関する研究担がんモデルラットにおいて、放射線照射による炎症反応が惹起される前にFDGにより放射線治療の効果を評価しうる可能性が示唆された。3.がんの分子機構を標的とする新規分子イメージング剤の開発(1)がんの血管新生能の評価を目的とした分子イメージング用薬剤として、チミジンホスホリラーゼ(TP)阻害作用を有する核酸誘導体の合成、及びC-11, I-123標識に成功した。これらの化合物は母体化合物と同等のTP阻害能を有した。(2)Celecoxibの放射性ヨウ素標識体(IMTP)のシクロオキシゲナーゼ-2イメージング用薬剤としての有用性が示唆された。また、非特異的集積の低減を目指して設計・合成した、新規ヨウ素標識体はCOX-2に高い選択性と阻害活性、非特異的結合の低下を示し、[^<123>I]FIMAがCOX-2選択的イメージング剤となる得ることが示唆された。(3)[^<99m>Tc]標識抗MT1-MMP抗体は腫瘍への集積性を示し、Membrane-type 1 matrix metalloproteinase (MT1-MMP)を標的としたイメージング剤としての有用性が示唆された。また、プレターゲティング法を用いることで、S/N比が改善する可能性が示唆された。
  • 文部科学省:科学研究費補助金(萌芽研究)
    研究期間 : 2006年 -2006年 
    代表者 : 久下 裕司
     
    本研究では、マイクロリアクタを用いる合成技術をポジトロンプローブ合成に応用することにより、簡便・迅速な標識合成法を確立し、チップ型自動合成装置開発の可能性を探ることを目的とし、以下の検討を行った。すなわち、反応系の制御に優れたマイクロリアクターを用いることで、PET用ドパミンD2受容体イメージング薬である[11C]ラクロプライドを短時間内に効率的に合成しうるか否かを検討した。マイクロリアクターには、Y字型チャネル構造のチップ(200um(W)×20um(D)×250mm(L))を用いた。原料としてデスメチルラクロプライド(2mg/800ul)と[11C]ヨウ化メチルの各DMSO溶液を用意し、これを2つの注入口からそれぞれ導入し、反応させた。チップの出口より採取した反応液をHPLCにて分析し、[11C]ラクロプライドの収率を算出した。また、原料の注入速度、反応温度と収率との関係を検討した。その結果、マイクロリアクターでの室温における収率は20secで11.7±4.3%、60secで14.5±2.3%であり、短時間での高収率、かつ良好な再現性を認めた。一方、60℃における収率は、20secで20.3±2.0%であり、加温による収率のさらなる上昇を認めた。以上の結果は、マイクロリアクターを用いた効率的な[11C]ラクロプライド合成を示すものであり、本システムを応用することで、今後放射性プローブを簡便に供給できる可能性が示された。
  • 文部科学省:科学研究費補助金(萌芽研究)
    研究期間 : 2004年 -2005年 
    代表者 : 久下 裕司
     
    本研究では、動脈硬化モデルにおいて放射性標識COX-2阻害薬の動態を解析し、分子生物学的評価結果と対比することにより、COX-2を標的とする動脈硬化病態診断の可能性を検証することを目的とし、本年度は以下の検討を行った。1.COX-2を標的とする放射性薬剤の開発に関する検討昨年度までに、選択的COX-2阻害薬であるCelecoxibのヨウ素置換体(IMTP)をデザイン・合成した。今年度は、IMTPの分子イメージング剤としての有用性をさらに検証するため、ラットを用いてインビボでの評価を行った。その結果、IMTPは速やかな血中クリアランスを示し、優れた標的/血液比を示した。これらの結果より、IMTPのCOX-2選択的イメージング剤としての可能性がインビボ実験において示された。2.動脈硬化モデルウサギにおけるCOX-2発現の検討動脈硬化病態、特に、プラーク破綻には、細胞外マトリックス分解酵素(MMP)が深く関与している。最近、MMPがプロスタグランジン(PG)E2依存性の経路により産生されることが示され、PGE2合成の律速酵素であるCOX、特に誘導型であるCOX-2の役割が注目されつつある。そこで、動脈硬化モデル家兎においてCOX-2発現を解析し、MMP-2の発現と対比することにより、COX-2を標的とする動脈硬化病態診断の有用性を検証した。その結果、MMP-2は、最も不安定性を示すアテローム性病変に強く発現していた。一方、COX-2は初期病変から進行性病変にわたって広く発現していた。これらの結果は、COX-2を標的とする分子イメージングにより動脈硬化病変の早期検出が可能であり、他方、MMP-2イメージングでは進行性病変の描出が可能であることを示唆している。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 2002年 -2004年 
    代表者 : 久下 裕司
     
    分子生物学的研究にインビボ分子イメージングの手法を組み入れ、(1)局所脳虚血病態に対するシクロオキシゲナーゼ-2 (COX-2)の組織障害性作用と脳組織再生作用を解析し、COX-2の作用とその阻害薬の役割を明らかにすること、(2)COX-2を標的とした分子イメージング法による脳虚血病態診断の可能性を探ることを目的として研究を遂行し、以下の成果を得た。1.脳虚血モデル動物における脳循環代謝、神経受容体機能の経時的変化の検討ベンゾジアゼピン受容体機能が保たれた虚血領域では、DNA断片化や細胞構築の破壊は見られなかった。他方、ベンゾジアゼピン受容体機能低下の見られない虚血領域にもCOX-2発現が認められた。2.脳虚血モデル動物におけるCOX-2,プロスタグランジン類の経時的変化の検討(1)COX-2 mRNA, COX-2 proteinの発現パターンは、血流低下の著しい虚血中心部とその周辺部では明らかに異なっており、COX-2発現が虚血の程度と時間によりダイナミックに変化していることが示唆された。(2)選択的COX-2阻害薬によるCOX-2活性の抑制は、SD誘発側皮質のIL1β、IL6発現とS100A9遺伝子の両側性発現抑制を伴うことが示唆された。3.COX-2を標的とした分子イメージング法に関する検討構造-活性相関学的検討から、選択的COX-2阻害薬であるCelecoxibのヨウ素置換体、5-(4-[^<123>I]iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl- 1H-pyrazole([^<123>I]IMTP)をデザイン・合成した。さらに、本化合物の分子イメージング剤としての有用性を検討した結果、IMTPがCOX-2に対して高い選択性と阻害活性を有することを見い出し、その放射性ヨウ素標識に成功した。
  • 文部科学省:科学研究費補助金(萌芽研究)
    研究期間 : 2002年 -2003年 
    代表者 : 久下 裕司
     
    腫瘍と炎症を精度良く鑑別し、治療方針の決定に役立てることが、診断医学の最重要課題の一つである。申請者らは、核酸合成及びプロスタグランジン合成酵素(COX)を標的とし、ポジトロン断層撮影法(PET)、シングルフォトン断層撮影法(SPECT)による腫瘍/炎症の鑑別診断能を向上させることを目的として本研究を計画した。この目的を達成するため、本年度は以下の検討を行った。(1)[C-11]ホスゲンを用いる核酸誘導体の簡便な標識合成法の開発研究数種の標識前駆物質を合成し、チミン、チミジンの非標識合成及びC-11標識合成を試みた。その結果、新規に合成された標識前駆物質により非標識チミンの合成に成功した。さらに、この標識前駆物質と[C-11]ホスゲンとの反応により[C-11]チミン、[C-11]チミジンの合成に成功した。(2)COX阻害薬の放射標識合成法の開発研究構造-活性相関学的検討から、選択的COX-2阻害薬であるCelecoxibのヨウ素置換体をデザインした。さらに、放射性ヨウ素標識体を得るため、数種の標識前駆物質の合成、及びヨウ素置換体の合成を試み、これらに成功した。(3)モデル動物に関する検討核酸合成及びプロスタグランジン合成酵素を標的とする腫瘍診断の有用性を評価するため、対照として糖代謝、アポトーシス、及び低酸素マーカーの腫瘍・炎症内分布をモデル動物において測定した。現在、上記(1)(2)に記載した標識化合物の腫瘍・炎症内分布を検討中である。
  • 文部科学省:科学研究費補助金(奨励研究(A))
    研究期間 : 2000年 -2001年 
    代表者 : 久下 裕司
     
    ^<18>F-FDGを用いるPET検査は、悪性腫瘍の鑑別診断、治療効果判定などにおいてきわめて有効性が高い。しかし、^<18>F-FDGは一部良性疾患にも集積することが明らかとなり、本検査による腫瘍鑑別診断の限界が指摘されている。これらの鑑別診断をより的確に行うには、悪性腫瘍や良性疾患への^<18>F-FDGの集積機序を明らかにすることが必須である。一方、最近、腫瘍・炎症へのFDG集積にはGlucose transporter(GLUT)が関与していることが明らかとなってきた。本研究では、腫瘍、感染性炎症、非特異的炎症モデルラットを用い、実験的腫瘍及び炎症組織におけるFDG集積とGLUT発現に及ぼすインシュリン及びグルコース負荷の影響を検討した。1.インシュリン負荷により腫瘍及び両炎症へのFDG集積は対照の約50%に低下したが、GLUT発現には大きな影響は与えなかった。2.グルコース負荷時のFDG集積は両炎症で対照の約50%、腫瘍で約85%であった。このとき、非特異的炎症ではGLUT1発現が有意に低下し、感染性炎症ではGLUT3発現が有意に低下した。GLUT1とGLUT3の発現は腫瘍では変化しなかった。したがって、グルコース負荷は腫瘍、炎症の鑑別診断の手がかりになる可能性がある。

教育活動情報

主要な担当授業

  • 医学研究概論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 医療機器開発特論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 医療機器、医学物理、画像診断、機能診断、放射線治療、粒子線治療 Medical device, Medical physics, Medical imaging, Functional Imaging, Radiation therapy, Particle beam therapy
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 医理工連携放射線防護学
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 放射線防護、国際的基準、国内法令、被ばく線量、リスク、安全取扱 Radiation Protection, International Standard, National Law, Exposed Dose, Risk, Safe Handling
  • 総合医理工学研究Ⅰ
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 分子プローブ、機能分子探索、プローブ合成・合成装置、病態分析、トランスレーション Molecular Probe, Bio-functional molecules, Synthesis and Synthetic Apparatus, Patho-Functional Bioanalysis, Translational Research
  • 総合医理工学研究Ⅱ
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 分子プローブ、機能分子探索、プローブ合成・合成装置、病態分析、トランスレーション Molecular Probe, Bio-functional molecules, Synthesis and Synthetic Apparatus, Patho-Functional Bioanalysis, Translational Research
  • 分子プローブ学
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 分子プローブ、核医学(PET、SPECT)分子プローブ、放射性同位元素の製造、標識反応、自動合成装置 Molecular Probe, Nuclear Medicine (PET, SPECT) Probe, Production of Radioisotope, Radiolabeling Reaction, Automated Synthetic Apparatus,
  • 基本医学総論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : トレーサー(分子プローブ)・生体機能/病態分析・マイクロドージング Tracer(Molecular Probe)/Patho-Functional Bioanalysis/Micro-dosing
  • 基本医学研究
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : ラジオアイソトープ,核医学,画像診断
  • 基本医学総論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 放射性同位元素,分子バイオイメージング,PET radioisotope, molecular imaging, PET
  • 基本医学総論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 分子イメージング,分子プローブ,トレーサー,分子・細胞機能 molecular imaging, molecular prove, tracer
  • 大学院共通授業科目(一般科目):自然科学・応用科学
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
  • 医理工学研究概論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments
  • 基本医学研究概論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments
  • 先端医理工学研究Ⅰ
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医理工学院
    キーワード : 分子プローブ、機能分子探索、プローブ合成・合成装置、病態分析、トランスレーション Molecular Probe, Bio-functional molecules, Synthesis and Synthetic Apparatus, Patho-Functional Bioanalysis, Translational Research
  • 先端医理工学研究Ⅱ
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医理工学院
    キーワード : 分子プローブ、機能分子探索、プローブ合成・合成装置、病態分析、トランスレーション Molecular Probe, Bio-functional molecules, Synthesis and Synthetic Apparatus, Patho-Functional Bioanalysis, Translational Research
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : トレーサー(分子プローブ)・生体機能/病態分析・マイクロドージング Tracer(Molecular Probe)/Patho-Functional Bioanalysis/Micro-dosing
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 放射性同位元素,分子バイオイメージング,PET,アイソトープ治療 radioisotope, PET
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 分子イメージング,分子プローブ,トレーサー,分子・細胞機能 molecular imaging, molecular prove, tracer
  • 基盤医学研究
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : ラジオアイソトープ,核医学,画像診断 radioisotope, nuclear medicine, diagnostic imaging
  • 臨床医学研究
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : ラジオアイソトープ,核医学,画像診断 radioisotope, nuclear medicine, diagnostic imaging
  • 医学総論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
  • 医学研究概論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments
  • 健康と社会
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 全学教育
    キーワード : アイソトープ・放射線の基礎, 社会生活に密接にかかわるアイソトープ・放射線, 先端医療におけるアイソトープ・放射線の利用,
  • 核医学
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 医学部
    キーワード : Radionuclide imaging,Emission tomography,Imaging,Radionuclide treatment
  • 科学・技術の世界
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 全学教育
    キーワード : 原子力技術、原子力発電、放射線、医療応用、宇宙探査、材料開発

大学運営

委員歴

  • 2016年 - 現在   日本核医学会   理事
  • 2015年 - 現在   The Society of Radiopharmaceutical Sciences (SRS)   理事
  • 2013年 - 現在   日本脳循環代謝学会   幹事
  • 2011年 - 現在   大学等放射線施設協議会   理事   日本脳循環代謝学会
  • 2010年 - 現在   日本放射線安全管理学会   理事   日本核医学会
  • 2013年 - 2016年   日本分子イメージング学会   理事


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