Basic research on neuroreceptor mapping of cholinergic system using nuclear medicine imaging

对脑内胆碱能神经支配的核医学显像进行了基础性研究。通过在一侧基底前脑中产生鹅膏蕈氨酸损伤，实验制备胆碱能去神经模型。为了评估被动回避行为在获得新反应和长期保持方面的表现，新开发了一种高精度的步进装置。体外定量受体放射自显影进行寻找一个有前途的配体映射胆碱能神经支配的大脑中使用一个专用的图像处理系统。结果表明，大鼠同侧和对侧皮质M_1和M_2受体总数无显著性差异。同时用^-3 H-2-（4-苯基哌啶基）环己醇（AH 5183）绘制突触前胆碱能神经分布。AH 5183结合率平均降低14%，具有统计学显著性。 ...更多信息 模型中同侧部位的皮质相对于对侧部位。这些结果可能意味着AH 5183是一个敏感的突触前乙酰胆碱水平的标志物。为了开发一种新的SPECT配体，合成了N-异丙基-p-碘苯丙胺（IMP）的类似物N-p-碘苯乙基二氨基二硫醇（DADT-IPE），并<99m>以氯化亚锡为还原剂，与~（14）Tc形成络合物。通过HPLC从^ Tc-DADT-IPE中分离出两种复合物（a和B）<99m>。竞争性抑制研究表明，<50>DADT-IPE的IC值与IMP相似。其中一种复合物[^<99m>Tc-DADT-IPE（a）]在大鼠体内的生物分布研究表明，静脉注射后5 min，脑中残留的示踪剂剂量为0.65%，注射后60 min，脑中残留的示踪剂剂量为0.53%，而另一种复合物[^<99m>Tc-DADT-IPE（B）]在注射后5 min和60 min的相应值分别为脑中残留的示踪剂剂量的0.34%和0.28%。发现^<99m>Tc-DADT-IPE（a）从大鼠脑中清除的半衰期大于5 h。这些结果表明，^<99m>Tc-DADT-IPE（a）具有适合脑灌注显像的特性。此外，原位杂交技术应用于该模型的毒蕈碱乙酰胆碱受体的基因表达成像的信使RNA的寡核苷酸DNA探针。少

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 … More 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