1992 Fiscal Year Final Research Report Summary
Basic research on neuroreceptor mapping of cholinergic system using nuclear medicine imaging
| Project/Area Number |
03454280
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Radiation science
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| Research Institution | Kanazawa University |
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Principal Investigator |
HISADA Kinichi Kanazawa University, School of Medicine, Professor, 医学部, 教授 (50019882)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Hiroshi Kanazawa University, School of Medicine, Assistant, 医学部付属病院, 助手 (90173848)
SHIBA Kazuhiro Kanazawa University, Radioisotope Center, Assistant, アイソトープ総合センター, 助手 (40143929)
AMANO Ryohei Kanazawa University, School of Allied Medical Professions, Associate Professor, 医療技術短期大学部, 助教授 (30111769)
MORI Hirofumi Kanazawa University, Radioisotope Center, Professor, アイソトープ総合センター, 教授 (90019604)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Nuclear Medicine / Neurotransmitter / Receptor / Autoradiogram / Cholinergic system / Acetylcholine / DNA Probe / In Situ Hybridization |
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| Research Abstract |
A fundamental study was performed on the nuclear medicine imaging of cholinergic innervation in the brain. A cholinergic denervation model was experimentally prepared by producing an ibotenic acid lesion in the unilateral basal forebrain. To assess the passive avoidance performance in terms of acquisition of new responses and long term retention, a step-through apparatus with high precision was newly developed. In-vitro quantitative receptor autoradiography was performed to look for a promising ligand for mapping cholinergic innervation in the brain using a dedicated image processing system. No significant differences were observed in total,M_1, and M_2 muscarinic acetylcholine receptors in the cortices between the ipsilateral and contralateral sites in the model. Simultaneously mapping of presynaptic cholinergic innervation was carried out using ^3H-2-(4-phenylpiperidino)cyclohexanol (AH5183). Statistically significant 14% decrease of AH5183 binding on an average was demonstrated in t
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he cortices of the ipsilateral site, relative to the contralateral site in models. These results may imply that AH5183 is a sensitive presynaptic marker of acetylcholine levels. To develop a new useful ligand for SPECT, an N-p-iodophenethyl diaminodithiol (DADT-IPE), an analog of N-isopropyl-p-iodoamphetamine(IMP), was synthesized and subsequently complexioned with ^<99m>Tc,using stannous chloride as a reducing agent. Two complexes (a and b) were separated from ^<99m>Tc-DADT-IPE by HPLC. Competitive inhibition studies showed that the IC_<50> value of DADT-IPE was similar to that of IMP. Biodistribution studies of one of the complexes [^<99m>Tc-DADT-IPE(a)] in rats show that 0.65% of the injected dose of the tracer remained in the brain at 5 min after intravenous injection, with 0.53% of the dose remaining in the brain at 60 min post-injection, whereas the corresponding values for the other complex [^<99m>Tc-DADT-IPE(b)] were 0.34% dose in the brain at 5 min and 0.28% dose in the brain 60 min post-injection. The half-life for clearance of ^<99m>Tc-DADT-IPE(a) from rat brain was found to be more than 5h. These results suggest that ^<99m>Tc-DADT-IPE(a) has characteristics which are suitable for cerebral perfusion imaging. Moreover in-situ hybridization technique was applied to this model for imaging of gene expression of messenger RNA for muscarinic acetylcholine receptors using oligonucleotide DNA probes. Less
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