担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bmc.2019.115189

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bmc.2019.04.030

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s11307-018-1253-4

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その他リンク： http://link.springer.com/article/10.1007/s11307-018-1253-4/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1088/1361-6463/aaff44

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その他リンク： http://iopscience.iop.org/article/10.1088/1361-6463/aaff44/pdf

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.7567/1347-4065/aae8e9

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その他リンク： http://stacks.iop.org/1347-4065/58/i=1/a=016002/pdf

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3987/com-18-s(f)66

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1248/bpb.b16-00945

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1039/c6cp06808a

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.crad.2016.04.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.abb.2016.03.023

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nucmedbio.2016.02.007

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 日本薬学会  

Molecular imaging is a newly emerging field aimed at advancing our understanding of biology and medicine through the noninvasive in vivo investigation of cellular molecular events involved in normal and pathologic processes. In this field, researchers and/or clinicians are combining modern tools of molecular and cell biology with state of the art technology in order to noninvasively image living subjects. Various imaging modalities such as optics (fluorescence and luminescence), nuclear magnetic resonance imaging, ultrasound, and radiation are being used to visually capture and study molecular and cellular events in living organisms. Among these modalities, nuclear medical molecular imaging uses radionuclides [i.e., positron emission tomography (PET) and single-photon emission computed tomography (SPECT)], and has characteristic properties that allow researchers and/or clinicians to obtain functional images of living subjects with high sensitivity. Translational molecular imaging, a research step between animal experiments and the clinical setting, has been successful when using nuclear medical molecular imaging. This approach leads to better methods for studying biological processes, as well as for diagnosing and managing diseases. In this review, two topics associated with our research on nuclear medical molecular imaging are summarized: (1) the development of a nuclear medical molecular imaging probe that targets cerebral nicotinic acetylcholine receptors (nAChRs), and the translational molecular imaging research conducted using this nAChR imaging probe; and (2) the development of oxygen-dependent degradable nuclear medical molecular imaging probes that target hypoxia-inducible factor-1-active tumor microenvironments.

DOI： 10.1248/yakushi.15-00279

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Various types of zinc (Zn) complexes have been developed as promising antidiabetic agents in recent years. However, the pharmacological action of Zn complex is not elucidated because the biodistribution of the complex in a living organism has not been studied. Nuclear medicine imaging is superior technology for the noninvasive analysis of the temporal distribution of drug candidates in living organisms. Gamma-ray emission imaging (GREI), which was developed by our laboratory as a novel molecular imaging modality, was adopted to visualize various γ-ray-emitting radionuclides that are not detected by conventional imaging techniques such as positron emission tomography and single-photon emission computed tomography. Therefore, we applied GREI to a biodistribution assay of Zn complexes. In the present study, 65Zn was produced in the natCu(p,n) reaction in an azimuthal varying field cyclotron for the GREI experiment. The distribution was then noninvasively visualized using GREI after the intravenous administration of a 65Zn-labeled di(1-oxy-2-pyridinethiolato)zinc [Zn(opt)2], ZnCl2, and di(l-histidinato)zinc. The GREI images were validated using conventional invasive assays. This novel study showed that GREI is a powerful tool for the biodistribution analysis of antidiabetic Zn complexes in a living organism. In addition, accumulation of 65Zn in the cardiac blood pool was observed for [Zn(opt)2], which exhibits potent antidiabetic activity. These results suggest that the slow elimination of Zn from the blood is correlated to the antidiabetic activity of [Zn(opt)2].

DOI： 10.1016/j.bbrep.2015.12.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Royal Society of Chemistry (RSC)  

<p>The stability of Cu²⁺–ATCUN complexes under physiologically relevant conditions is enhanced by inserting bulky and hydrophobic residues at positions 1 and 2 of the ATCUN peptide.</p>

DOI： 10.1039/c6dt01387b

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ppap.201500132

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その他リンク： http://onlinelibrary.wiley.com/wol1/doi/10.1002/ppap.201500132/fullpdf

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

The objective of this study is to examine the invasiveness of hemostasis by non-thermal plasma (NTP) compared with hemostasis by thermal coagulation (TC). The inflammation recovery process after hemostasis by TC and NTP was compared by using histological methods and nuclear medical molecular imaging. The necrotic areas in the NTP group disappeared after 5 days, whereas they remained 15 days after hemostasis in the TC group. The accumulation of 2-deoxy-2-[F-18] fluoro-D-glucopyranose (F-18-FDG), which reflects the existence of inflammatory cells, was higher in the TC group than in the NTP group on day 15. Thus, this study indicates that hemostasis by NTP is less inflammatory than TC. This report is the first to evaluate inflammation that occurred after hemostasis with medical devices noninvasively.

DOI： 10.1002/ppap.201500099

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Japan  

[Objective]Positron emission tomography (PET)/computed tomography (CT) using 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-D-Phe1-Tyr3-octreotide (DOTATOC) has been used to detect neuroendocrine tumors (NETs). The purpose of this study was to investigate the clinical efficacy of DOTATOC-PET/CT for detecting clinically suspected NETs when conventional imaging modalities were negative or inconclusive, in terms of additional value. [Methods]A total of 46 patients were analyzed retrospectively. Among them, 14 patients underwent a DOTATOC-PET/CT scan for detecting unknown primary tumors after histopathological confirmation of a NET at metastatic sites (group A): 7 patients for detecting metastasis or recurrence after surgery for NET because of their high hormone levels but with no recurrence detected by other imaging modalities (group B); the remaining 25 patients for detecting suspected NETs because their hormone levels were high with no history of histopathologically proven NET (group C). Additional information was assessed, according to each situation. [Results]In group A, unknown primary tumors were suspected by DOTATOC-PET/CT in 8 of 14 patients (gastrointestinal/pancreatic NET in 7 patients, prostatic cancer in 1 patient), but prostatic cancer was not confirmed by histopathology (i.e., false positive). In group B, DOTATOC-PET/CT depicted lesions in six of seven patients, including nodal metastasis (n = 5) and liver metastasis (n = 1). In group C, DOTATOC-PET/CT did not demonstrate any abnormal foci except in one case of pancreatic NET. Additional information was obtained in 50, 86, and 4 % of cases, in groups A, B, and C, respectively. [Conclusions]DOTATOC-PET/CT was useful for detecting NETs, especially when recurrence or metastases were suspected because of high hormone levels after surgery for a NET. It is unlikely, however, that additional information can be acquired in patients with no history of NET simply based on high hormone levels.

DOI： 10.1007/s12149-015-0973-7

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その他リンク： https://link.springer.com/article/10.1007/s12149-015-0973-7/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

Mechanochromic organic molecules (MOMs) that exhibit a large difference of fluorescence wavelength between two states have important potential applications, but few such compounds are known. Here, we report a new MOM, cis-ABPX01(0), which shows switchable near-IR and blue fluorescence responses. Detailed spectrophotometric and single-crystal X-ray analyses revealed that the near-IR fluorescence is attributable to fluorescence from slip-stacked dimeric structures in crystals, while the blue fluorescence is attributable to fluorescence from the monomer. Switching between the two is achieved by dynamic structural interconversion between the two molecular packing arrangements in response to mechanical grinding and solvent vapor-fuming.

DOI： 10.1021/jacs.5b00877

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer US  

First online: 22 July 2014【Purpose】We aimed to develop a gallium-68 (Ga-68)-labeled single-chain variable fragment (scFv) targeting the human epidermal growth factor receptor 2 (HER2) to rapidly and noninvasively evaluate the status of HER2 expression. 【Procedures】Anti-HER2 scFv was labeled with Ga-68 by using deferoxamine (Df) as a bifunctional chelate. Biodistribution of [(68)Ga]Df-anti-HER2 scFv was examined with tumor-bearing mice and positron emission tomography (PET) imaging was performed. The changes in HER2 expression after anti-HER2 therapy were monitored by PET imaging. 【Results】[(68)Ga]Df-anti-HER2 scFv was obtained with high radiochemical yield after only a 5-min reaction at room temperature. The probe showed high accumulation in HER2-positive xenografts and the intratumoral distribution of radioactivity coincided with HER2-positive regions. Furthermore, [(68)Ga]Df-anti-HER2 scFv helped visualize HER2-positive xenografts and monitor the changes in HER2 expression after anti-HER2 therapy.【Conclusion】[(68)Ga]Df-anti-HER2 scFv could be a promising probe to evaluate HER2 status by in vivoPET imaging, unless trastuzumab is prescribed as part of the therapy.

DOI： 10.1007/s11307-014-0769-5

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その他リンク： http://link.springer.com/article/10.1007/s11307-014-0769-5/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science (PLoS)  

DOI： 10.1371/journal.pone.0109866

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier Inc.  

[Introduction]Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related death. Since significant upregulation of αvβ6 integrin has been reported in PDAC, this integrin is a promising target for PDAC detection. In this study, we aimed to develop a radioiodinated probe for the imaging of αvβ6 integrin-positive PDAC with single-photon emission computed tomography (SPECT). [Methods]Four peptide probes were synthesized and screened by competitive and saturation binding assays using 2 PDAC cell lines (AsPC-1, αvβ6 integrin-positive; MIA PaCa-2, αvβ6 integrin-negative). The probe showing the best affinity was used to study the biodistribution assay, an in vivo blocking study, and SPECT imaging using tumor bearing mice. Autoradiography and immunohistochemical analysis were also performed. [Results]Among the 4 probes examined in this study, [125]I-IFMDV2 showed the highest affinity for αvβ6 integrin expressed in AsPC-1 cells and no affinity for MIA PaCa-2 cells. The accumulation of [125]I-IFMDV2 in the AsPC-1 xenograft was 3–5 times greater than that in the MIA PaCa-2 xenograft, consistent with the expression of αvβ6 integrin in each xenograft, and confirmed by immunohistochemistry. Pretreatment with excess amounts of A20FMDV2 significantly blocked the accumulation of [125]I-IFMDV2 in the AsPC-1 xenograft, but not in the MIA PaCa-2 xenograft. Furthermore, [123]I-IFMDV2 enabled clear visualization of the AsPC-1 xenograft. [Conclusion][123]I-IFMDV2 is a potential SPECT probe for the imaging of αvβ6 integrin in PDAC.

DOI： 10.1016/j.bbrc.2014.02.086

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

Because tumor cells grow rapidly and randomly, hypoxic regions arise from the lack of oxygen supply in solid tumors. Hypoxic regions in tumors are known to be resistant to chemotherapy and radiotherapy. Hypoxia-inducible factor-1 (HIF-1) expressed in hypoxic regions regulates the expression of genes related to tumor growth, angiogenesis, metastasis, and therapy resistance. Thus, imaging of HIF-1-active regions in tumors is of great interest. HIF-1 activity is regulated by the expression and degradation of its<italic>α</italic>subunit (HIF-1<italic>α</italic>), which is degraded in the proteasome under normoxic conditions, but escapes degradation under hypoxic conditions, allowing it to activate transcription of HIF-1-target genes. Therefore, to image HIF-1-active regions, HIF-1-dependent reporter systems and injectable probes that are degraded in a manner similar to HIF-1<italic>α</italic>have been recently developed and used in preclinical studies. However, no probe currently used in clinical practice directly assesses HIF-1 activity. Whether the accumulation of¹⁸F-FDG or¹⁸F-FMISO can be utilized as an index of HIF-1 activity has been investigated in clinical studies. In this review, the current status of HIF-1 imaging in preclinical and clinical studies is discussed.

DOI： 10.1155/2014/165461

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その他リンク： http://downloads.hindawi.com/journals/tswj/2014/165461.xml

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science  

99mTc-HYNIC-annexin A5 can be considered as a benchmark in the field of apoptosis imaging. However, 99mTc-HYNIC-annexin A5 has characteristics of high uptake and long retention in non-target tissues such as kidney and liver. To minimize this problem, we developed a novel 99mTc-labeled annexin A5 using a bis(hydroxamamide) derivative [C3(BHam)2] as a bifunctional chelating agent, and evaluated its usefulness as an imaging agent for detecting apoptosis. The amino group of C3(BHam)2 was converted to a maleimide group, and was coupled to thiol groups of annexin A5 pretreated with 2-iminothiolane. 99mTc labeling was performed by a ligand exchange reaction with 99mTc-glucoheptonate. Biodistribution experiments for both 99mTc-C3(BHam)2-annexin A5 and 99mTc-HYNIC-annexin A5 were performed in normal mice. In addition, in tumor-bearing mice, the relationship between the therapeutic effects of chemotherapy (5-FU) and the tumor accumulation of 99mTc-C 3(BHam)2-annexin A5 just after the first treatment of 5-FU was evaluated. 99mTc-C3(BHam)2-annexin A5 was prepared with a radiochemical purity of over 95%. In biodistribution experiments, 99mTc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than 99mTc-HYNIC- annexin A5. In the organs for metabolism, such as liver and kidney, radioactivity after the injection of 99mTc-HYNIC-annexin A5 was residual for a long time. On the other hand, radioactivity after the injection of 99mTc-C3(BHam)2-annexin A5 gradually decreased. In therapeutic experiments, tumor growth in the mice treated with 5-FU was significantly inhibited. Accumulation of 99mTc-C 3(BHam)2-annexin A5 in tumors significantly increased after 5-FU treatment. The accumulation of radioactivity in tumor correlated positively with the counts of TUNEL-positive cells. These findings suggest that 99mTc-C3(BHam)2-annexin A5 may contribute to the efficient detection of apoptotic tumor response after chemotherapy.

DOI： 10.1371/journal.pone.0081191

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer US  

[Purpose]We aimed to develop a radiolabeled peptide probe for the imaging of hypoxia-inducible factor-1 (HIF-1)-active tumors. [Procedures]We synthesized the peptide probes that contain or lack an essential sequence of the oxygen-dependent degradation of HIF-1α in proteasomes ([123/125]I-DKOP30 or [125]I-mDKOP, respectively). The degradation of probes was evaluated in vitro using cell lysates containing proteasomes. In vivo biodistribution study, planar imaging, autoradiography, and comparison between probe accumulation and HIF-1 transcriptional activity were also performed. [Results]The [125]I-DKOP30 underwent degradation in a proteasome-dependent manner, while [125]I-mDKOP was not degraded. Biodistribution analysis showed [125]I-DKOP30 accumulation in tumors. The tumors were clearly visualized by in vivo imaging, and intratumoral distribution of [125]I-DKOP30 coincided with the HIF-1α-positive hypoxic regions. Tumoral accumulation of 125I-DKOP30 was significantly correlated with HIF-1-dependent luciferase bioluminescence, while that of [125]I-mDKOP was not. [Conclusion] [123]I-DKOP30 is a useful peptide probe for the imaging of HIF-1-active tumors.

DOI： 10.1007/s11307-013-0647-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

DOI： 10.1021/jm300251n

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 日本薬学会  

In solid tumors, hypoxic regions arise because of an imbalance between oxygen supply and consumption. The transcription factor hypoxia-inducible factor-1 (HIF-1), which is overexpressed in hypoxic regions, was recently reported to be a master transcriptional activator of various genes (such as those involved in glucose metabolism, vascularization, invasion, and metastasis) related to malignant phenotypes. Therefore, the development of techniques for the noninvasive detection of HIF-1-active hypoxic tumor cells is of great interest. Although various modalities are used for molecular imaging in vivo, nuclear medical imaging, which can give information about organ functions, plays a central quantitative role in molecular imaging. However, because radioactive probes become attenuated due to the nuclide-specific half-life, an appropriate probe design and/or imaging method is required to obtain a high-contrasted image within a limited time. My colleagues and I have developed a probe and a method for the rapid detection of HIF-1-active hypoxic regions in tumors. Because the α subunit of HIF-1 (HIF-1α) controls the transcriptional activity of HIF-1 and is unique in that its degradation is regulated by the oxygen partial pressure, we first developed a fusion protein probe that is degraded similarly as HIF-1α. Then, to control the biodistribution of radioactivity, we utilized a "pretargeting method" that uses a combination of the fusion protein and a small-molecule radioactive probe that can bind to the protein and is rapidly cleared from the blood. Rapid and high-contrast imaging of HIF-1-active tumors can be achieved with this pretargeting method.<br>

DOI： 10.1248/yakushi.132.595

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jconrel.2012.01.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

DOI： 10.1021/jm201513c

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

DOI： 10.1021/ml200230e

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

<italic>Purpose</italic>. We aimed to clearly visualize heterogeneous distribution of hypoxia-inducible factor 1<italic>α</italic>(HIF) activity in tumor tissues<italic>in vivo</italic>.<italic>Methods</italic>. We synthesized of¹²⁵I-IPOS, a¹²⁵I labeled chimeric protein probe, that would visualize HIF activity. The biodistribution of¹²⁵I-IPOS in FM3A tumor-bearing mice was evaluated. Then, the intratumoral localization of this probe was observed by autoradiography, and it was compared with histopathological findings. The distribution of¹²⁵I-IPOS in tumors was imaged by a small animal SPECT/CT scanner. The obtained<italic>in vivo</italic>SPECT-CT fusion images were compared with<italic>ex vivo</italic>images of excised tumors. Fusion imaging with MRI was also examined.<italic>Results</italic>.¹²⁵I-IPOS well accumulated in FM3A tumors. The intratumoral distribution of¹²⁵I-IPOS by autoradiography was quite heterogeneous, and it partially overlapped with that of pimonidazole. High-resolution SPECT-CT fusion images successfully demonstrated the heterogeneity of¹²⁵I-IPOS distribution inside tumors. SPECT-MRI fusion images could give more detailed information about the intratumoral distribution of¹²⁵I-IPOS.<italic>Conclusion</italic>. High-resolution SPECT images successfully demonstrated heterogeneous intratumoral distribution of¹²⁵I-IPOS. SPECT-CT fusion images, more favorably SPECT-MRI fusion images, would be useful to understand the features of heterogeneous intratumoral expression of HIF activity<italic>in vivo</italic>.

DOI： 10.1155/2012/262741

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：wiley  

To image hypoxia-inducible factor-1 (HIF-1)-active tumors, we previously developed a chimeric protein probe ([(123/125) I]IPOS) that is degraded in the same manner as HIF-1α under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF-1. In vivo single-photon emission computed tomography (SPECT)/X-ray CT (CT) imaging, autoradiography, and double-fluorescent immunostaining for HIF-1α and pimonidazole (PIMO) were carried out 24 h after the injection of [(125) I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi-pinhole, high-resolution SPECT/CT imaging with [(125) I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [(125) I]IPOS in the tumors. Immunohistochemistry revealed that the HIF-1α-positive areas and PIMO-positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [(125) I]IPOS accumulation were positively and significantly correlated with the HIF-1α-positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [(125) I]IPOS-accumulated areas and HIF-1α-positive areas was significantly greater than that between the [(125) I]IPOS-accumulated areas and the PIMO-positive areas (P < 0.01). These findings indicate that [(125) I]IPOS accumulation reflects HIF-1 expression. Thus, [(123/125) I]IPOS can serve as a useful probe for the molecular imaging of HIF-1-active tumors.

DOI： 10.1111/j.1349-7006.2011.02057.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Verlag  

<Purpose> : 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. <Procedures> : We used POS, a genetically engineered form of streptavidin that selectively stabilizes in HIF-1-active cells, and (4-[18]F-fluorobenzoyl)norbiotinamide ([18]F-FBB), a radiolabeled biotin derivative, for performing a biodistribution study and for PET imaging. The tumoral [18]F-FBB accumulation was compared to the HIF-1-dependent luciferase bioluminescence and HIF-1α immunohistochemical signal. <Results> : [18]F-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 [18]F-FBB accumulation positively correlated with luciferase bioluminescence (R = 0.72, P < 0.05), and most of the area showing [18]F-FBB accumulation corresponded to HIF-1α-positive areas. <Conclusion> : Pretargeting with POS and [18]F-FBB is an effective approach for PET imaging of HIF-1-active areas in tumors.

DOI： 10.1007/s11307-010-0418-6

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その他リンク： http://link.springer.com/article/10.1007/s11307-010-0418-6/fulltext.html

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Blackwell  

We have recently clarified that nicotinic acetylcholine receptors (nAChRs) expressed in the thalamus play an important role in antiallodynic effects produced by the nAChR agonist, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA). This study aimed to reveal the in vivo relationship between thalamic nAChR occupancy rates and antiallodynic effects using 5IA and [¹²⁵I]5IA. We partially ligated the sciatic nerve of a rat to induce neuropathic pain. Antiallodynic effects were evaluated at 15, 30, 60, and 90 min after intracerebroventricular (i.c.v.) administration of multiple doses (1-100 nmol) of 5IA by the von Frey filament test. Receptor occupancy rates were measured by autoradiography at 15 and 90 min after administration. Antiallodynic effects of repetitive treatment of 5IA (5 and 50 nmol) were also examined. A significant and dose-dependent antiallodynic effect was observed 15 min after administration. It showed a good correlation with receptor occupancy rates (r = 0.97), indicating the binding of 5IA to nAChRs expressed in the thalamus involved in the antiallodynic effect. Five, 50, and 100 nmol of 5IA occupied the thalamic nAChRs until 90 min after administration, while the antiallodynic effect diminished. Five nanomoles of 5IA (which occupied 40% of thalamic nAChRs) showed a significant antiallodynic effect (percentage of the maximal possible effect (%MPE): 35 ± 7) after the second administration, while 50 nmol of 5IA (which occupied 80% of thalamic nAChRs) did not (%MPE: 7 ± 1). These findings suggest that not clearance of 5IA but desensitization of nAChRs caused by persistent binding of 5IA is responsible for the disappearance of antiallodynic effects.

DOI： 10.1002/syn.20819

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nima.2010.03.085

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Verlag  

PURPOSE: 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. METHODS: 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-1alpha immunohistochemistry. RESULTS: (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-1alpha-positive regions (R=0.58, p<0.0001). CONCLUSION: POS pretargeting with (123)I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours.

DOI： 10.1007/s00259-010-1467-4

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その他リンク： http://link.springer.com/article/10.1007/s00259-010-1467-4/fulltext.html

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Blackwell  

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 [(125)I]5IA.

DOI： 10.1111/j.1476-5381.2009.00613.x

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

We have developed an electron-tracking Compton camera (ETCC) for new medical imaging device. Conventional gamma camera, PET and SPECT, have the problem of energy limitation. This problem is one of the major problems for this study. However, our ETCC has a wide energy dynamic range (200-1300 keV). Also ETCC have the wide field of view because ETCC does not need a collimator and does not need to catch two gamma rays which produced by the annihilation process. In this paper, we show the results of imaging result of the 3-D which have imaged only one direction using one head camera. And we have developed the two-head ETCC. Two-head ETCC have a good efficiency and spatial resolution. © 2010 IEEE.

DOI： 10.1109/NSSMIC.2010.5874313

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

We have developed an electron-tracking Compton camera (ETCC) for new medical imaging device. Conventional gamma camera, PET and SPECT, have the problem of energy limitation. This problem is one of the major problems for this study. However, our ETCC has a wide energy dynamic range (200-1300 keV). Also ETCC have the wide field of view because ETCC does not need a collimator and does not need to catch two gamma rays which produced by the annihilation process.
In this paper, we show the results of imaging result of the 3-D which have imaged only one direction using one head camera. And we have developed the two-head ETCC. Two-head ETCC have a good efficiency and spatial resolution.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

We examined exendin(9-39), an antagonist of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), as a potential probe for imaging of pancreatic beta-cells. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Binding assay showed competitive inhibition of [(125)I]BH-exendin(9-39) binding by non-radioactive exendin(9-39). To assess in vivo selectivity, the biodistribution was evaluated by intravenous administration of [(125)I]BH-exendin(9-39) to mice. Radioactivity of harvested pancreas reached highest levels at 60 and 120min among organs examined except lung. Pre-administration of excess non-radioactive exendin(9-39) remarkably and specifically blocked the radioactivity of pancreas. After [(125)I]BH-exendin(9-39) injection into transgenic mice with pancreatic beta-cells expressing GFP, fluorescent and radioactive signals of sections of pancreas were evaluated with an image analyzer. Imaging analysis showed that the fluorescent GFP signals and the radioactive signals were correspondingly located. Thus, the GLP-1R antagonist exendin(9-39) may serve as a useful probe for pancreatic beta-cell imaging.

DOI： 10.1016/j.bbrc.2009.09.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2967/jnumed.108.061119

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nucmedbio.2008.11.007

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

We have developed the Electron tracking Compton Camera (ETCC) with reconstructing the 3-D tracks of the scattered electron in Compton process for both gamma-ray astronomy and medical imaging [1-3]. By measuring both the directions and energies of a recoil gamma ray and a scattered electron, the direction of the incident gamma ray is determined for an individual photon. Furthermore, a residual measured angle between the recoil electron and scattered gamma ray is powerful for the kinematical background-rejection. For the 3-D tracking of the electrons, the Micro Time Projection Chamber (mu-TPC) was developed, which consists of a new type of the micro pattern gas detector, or a Micro Pixel Gas Chamber (mu-PIC). The ETCC consists of this mu-TPC and the GSO crystal pixel arrays below the (mu) over bar TPC for detecting the recoil gamma rays. The ETCC provided the gamma ray images of point sources between 120keV and similar to 1 MeV with the angular resolution of 6 degree (FWHM) at 511 keV of F-18 ion, respectively. Also the angle of the scattered electron was measured with the resolution of similar to 80 degree.
Two mobile ETCCs with 10cm-cube TPC for small animal and 30cm-cube TPC for human body, are now being operated for Medical Imaging test. We have studied the imaging performances using both phantoms and small animals (rats and mice) for conventional radioisotopes of I-131 and F-18-FDG. In particular, new ETCC with LaBr3 pixel scintillator provides good images similar to SPECT for I-131 and human PET for 511keV, respectively, where a clear concentration to tumors in a mouse is observed The 30cm-cube ETCC can get an image for I m-size length objects in one measurement. Thus, we have carried out several comparisons of our images with those of SPECT and PET. Multi-tracer image using I-131 and FDG for small animal and the image for higher energy gamma ray above 511keV for plants using Mn-54 have been carried out successfully. Also several new biomarkers and new radio nuclides were examined to verify the merits of ETCC for medical imaging.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Society of Nuclear Medicine  

DOI： 10.2967/jnumed.107.050260

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

DOI： 10.1109/nssmic.2008.4774145

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.brainres.2007.10.107

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nucmedbio.2007.11.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Society of Nuclear Medicine  

DOI： 10.2967/jnumed.107.043471

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jns.2007.02.014

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

DOI： 10.1109/nssmic.2007.4436859

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

DOI： 10.1109/nssmic.2006.356499

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s00259-005-0017-y

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その他リンク： http://link.springer.com/article/10.1007/s00259-005-0017-y/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nucmedbio.2006.03.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nucmedbio.2005.06.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japanese Pharmacological Society  

In this study, we investigated the effect of vesicular zinc on ischemic neuronal injury. In cultured neurons, addition of a low concentration (under 100 μM) of zinc inhibited both glutamate-induced calcium influx and neuronal death. In contrast, a higher concentration (over 150 μM) of zinc decreased neuronal viability, although calcium influx was inhibited. These results indicate that zinc exhibits biphasic effects depending on its concentration. Furthermore, in cultured neurons, co-addition of glutamate and CaEDTA, which binds extra-cellular zinc, increased glutamate-induced calcium influx and aggravated the neurotoxicity of glutamate. In a rat transient middle cerebral artery occlusion (MCAO) model, the infarction volume, which is related to the neurotoxicity of glutamate, increased rapidly on the intracerebral ventricular injection of CaEDTA 30 min prior to occlusion. These results suggest that zinc released from synaptic vesicles may provide a protective effect against ischemic neuronal injury.<br>

DOI： 10.1254/jphs.fp0050805

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00273496883?from=CiNii

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

We have developed the Electron tracking Compton Camera (ETCC) with reconstructing the 3-D tracks of the scattered electron in Compton process in the range from sub-MeV to several MeV for both gamma-ray astronomy and medical imaging [1,2]. By measuring both the directions and energies of a recoil gamma ray and a scattered electron, the direction of the incident gamma ray is determined for each individual photon. Furthermore, a residual measured angle between the recoil electron and scattered gamma ray is powerful for the kinematical background-rejection. For the 3-D tracking of the electrons, the Micro Time Projection Chamber (mu-TPC) was developed, which consists of a new type of the micro pattern gas detector, or a Micro Pixel Gas Chamber (mu-PIC) [2,3,4]. The ETCC consists of this mu-TPC (10cm cube) and the 6x6x3mm GSO crystal pixel arrays with a flat panel photo-multiplier surrounding the base and side of the mu-TPC for detecting the recoil gamma rays. The ETCC provided the gamma ray images of point sources between 120keV and similar to 1 MeV with the angular resolution of 6 degree and 5 degree (FWHM) at 364keV of (131)Iodine and 511keV of F-18 ion, respectively. Also the angle of the scattered electron was measured with the resolution of similar to 80 degree, by which most backgrounds were removed by the kinematical constraint.A mobile ETCC for medical imaging, which is fabricated in a 1m cubic box, has been tested since October 2005. Here we present the imaging performances using both a phantom and a rat.

DOI： 10.1109/NSSMIC.2006.353834

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the human brain, especially the alpha(4)beta(2) subtype of nAChR. The cholinergic systems have roles in various neurophysiologic functions, such as learning, memory, and cognition, whereas normal aging and neurodegenerative diseases have been associated with changes in nAChRs. Recently, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA) has been synthesized as a radioligand for imaging nAChRs with SPECT. I-123-5IA shows higher affinity toward the nAChR alpha(4)beta(2) subtype, enhanced receptor subtype selectivity, good safety, and low nonspecific binding. Methods: In this study, a SPECT quantitative study of human nAChRs binding with I-123-5IA was conducted in healthy volunteers. An arterial input function was obtained for each subject and a 2-compartment model was used to determine the kinetic parameters of I-123-5IA using data from a 6-h scan. The distribution volume (V-T) (mL/mL), which is related to the number of unoccupied binding sites in the brain, was calculated and values were compared with results of a graphical analysis (Logan plot, V-LG). Results: Analysis of the unmetabolized compound showed a high parent fraction of I-123-5IA in plasma. The results from the 2-compartment model analysis showed high VT values for the thalamus; moderate values for the brain stem, cerebellum, and basal ganglia; and low values for the cortical regions. Good agreement was observed between VT values and results of autoradiographic experiments done in vitro for nAChR density in human brain. A high correlation index was observed between distribution volumes from model and graphical analyses. Conclusion: Our results indicated that I-123-5IA SPECT is suitable for the quantification of nAChRs in human brain.

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/bf02984473

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その他リンク： http://link.springer.com/article/10.1007/BF02984473/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

Central nicotinic acetylcholine receptors (nAChRs) represent major neurotransmitter receptors responsible for various brain functions, and changes in the density of nAChRs have recently been reported in several neurodegenerative diseases. Visualization of nAChRs in human brain has thus been of great interest, and the development of radiopharmaceuticals for the imaging and quantitative assessment of central nAChRs has been desired. In this study, we synthesized 5-(11)C-methyl-3-(2-(S)-azetidinylmethoxy)pyridine (5MA), a derivative of 3-(2-(S)-azetidinylmethoxy)pyridine (A-85380) (11)C-methylated at position 5 of the pyridyl fragment, and evaluated its potential for investigating central nAChRs by PET. Methods: (11)C-5MA was synthi by the incorporation of (11)C-methyl iodide into 5-butylstannyl A-85380, using a Pd-catalyzed coupling reaction. The affinity of 5MA for central nAChRs was measured by displacement of (-)-(3)H-cytisine from binding sites in rat cortical membranes. The biodistribution of (11)C-5MA was determined with mice. PET studies were performed on rhesus monkeys with a high-resolotion PET scanner for animals. Results: The overall synthesis time was 60 min from the end of radionudide production, and the radiochemical yield, after purification by high-performance liquid chromatography, was 30%. The radiochemical purity of the product was &gt;99%, with a specific radioactivity of &gt;36 GBq/mumol. In vitro receptor-binding assays demonstrated that 5MA has a high, selective binding affinity for nAChRs, being approximately 1.5-fold higher than that of A-85380, 3.5-fold higher than that of (-)-cytisine, and 10-fold higher than that of (-)-nicotine. The distribution studies in mice showed that the brain uptake of (11)C-5MA was profound. Regional cerebral distribution studies in mice demonstrated that the accumulation of (11)C-5MA was consistent with the density of nAChRs, with the highest uptake observed in the thalamus, a moderate uptake in the cortex and striatum, and the lowest uptake in the cerebellum. Furthermore, preinjection of nAChR-binding ligands, (-)nicotine and (-)-cytisine, reduced the uptake of (11)C-5MA in brain regions of high uptake in the untreated experiment. PET imaging studies with (11)C-5MA in rhesus monkeys demonstrated clear images consistent with the distribution of nAChRs in the brain. Conclusion: These results suggest that (11)C-5MA is a potential PET radiopharmaceutical for nuclear medical studies of nAChRs in the brain.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.ics.2003.12.067

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/bf02996300

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その他リンク： http://link.springer.com/article/10.1007/BF02996300/fulltext.html

総ページ数：xi, 303p   記述言語：日本語

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総ページ数：xvi, 427p, 図版 [14] p   記述言語：日本語

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出版者・発行元：Wiley  

DOI： 10.1002/ppap.201570043

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記述言語：英語   出版者・発行元：Hindawi Limited  

DOI： 10.1155/2015/365418

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その他リンク： http://orcid.org/0000-0002-1691-7302

担当区分：筆頭著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1155/2014/165461

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(公社)日本薬学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2014270749

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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記述言語：日本語   出版者・発行元：寺田国際事務所先端医療技術研究所  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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記述言語：英語   出版者・発行元：IEEE  

We have developed an electron-tracking Compton camera (ETCC) for new imaging reagents study. Energy limitation of gamma camera is major problem for this study. However, our ETCC has a wide energy dynamic range (200-1300 keV). In this paper, we show the results of imaging reagent stud) as follows: (1) F-18-FDG (511 keV) and 1-131-MIBG (364 keV) simultaneous imaging for double clinical tracer imaging, (2) Zn-65-porphyrin (1116 keV) imaging for high energy gamma-ray imaging and, (3) middle size animal imaging (rabbit). Also we studied the improvement for the camera system.

DOI： 10.1109/NSSMIC.2009.5401649

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

Web of Science

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-LISS  

Web of Science

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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担当区分：筆頭著者   記述言語：日本語   掲載種別：書評論文，書評，文献紹介等  

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Web of Science

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

Web of Science

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開催年月日： 2011年9月

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開催年月日： 2009年11月

記述言語：日本語  

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