2001 Fiscal Year Final Research Report Summary
Development of in vivo dynamic and noninvasive imaging methodology of neurotransmission system with optically active radioligand.
| Project/Area Number |
12557205
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Physical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SAJI Hideo Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (40115853)
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| Co-Investigator(Kenkyū-buntansha) |
OHMOMO Yoshiro Osaka University of Phamaceutical Sciences, Associate Professor, 助教授 (70183241)
FUKUYAMA Hidenao Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (90181297)
MAGATA Yasuhiro Hamamatsu University school of Medicine, Photon Medical Research Center, Professor, 光量子医学研究センター, 教授 (20209399)
AZUMA Makoto Nihon Medi-physics Co., Ltd, Research Center, Manager, 創薬研究所, 所長(研究職)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Brain / Nicotine receptor / Norepinephirine transporter / Opical isomer / Radioligand / In vivo imaging / In vivo mapping |
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| Research Abstract |
The method for in vivo dynamic and noninvasive investigation of neurotransmission system was developed using optically active radioligand and nuclear medical imaging system.
1. Changes in the density of nicotinic acethylcholine receptors (nAChRs) have recently been reported in the brains of patients with various disorders, including Alzheimer's disease. Thus, 5-Iodo-3-(2(S)-azetidinylmethoxy)Pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radioligand for investigating brain nAChRs by nuclear medical imaging methodology. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (-)-nicotine, and that 5IA bound selectively to the α4β2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [^<125>I]5IA was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [^<125>I]5IA was consistent wit
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h. the density of high affinity nAChRs. Administration of the nAChR agonists reduced the uptake of [^<125>I]5IA and resulted in similar levels of radioactivity throughout the brain. [^<125>I]5IA binding sites were shown to be saturable with unlabeled 5IA. Furthermore, SPECT studies with [^<123>I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR in vivo imaging radioligand.
2. Recent studies demonstrated changes of norepinephrine transpoter (NET) in several cerebral and cardiovascular diseases. Thus, (R)-N-metheyl-3-(2- idophenoxy)-3-phenylpropamine (MIPP) was developed based on the structure-activity relationship as a radioligand for investigating brain and myocardial NET by nuclear medical imaging methodology. showed The binding data revealed that the affinity of (R)-MIPP was twice and more than 100 higher than that of tomoxietine and (S)-enatiomer, and selectivity to NET was high. Biodistribution studies in rats also indicated high affinity and selectivity for NET. These results suggested that [^<123>I]5IA is a promising radioligand for nuclear medical studies of brain and myocardial NET in-human subjects. Less
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