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

利用核医学成像进行胆碱能系统神经受体定位的基础研究

• 批准号: 03454280
• 负责人: HISADA Kinichi
• 金额: $ 3.52万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03454280/
• 关键词: Nuclear Medicine; Neurotransmitter; Receptor; Autoradiogram; Cholinergic system; Acetylcholine; DNA Probe; In Situ Hybridization; オ-トラジオグラム; DNAプロ-ブ; In Situハイブリダイゼ-ション

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

对脑胆碱能神经支配的核医学成像进行了基础性研究。在单侧基底前脑内损毁鹅膏酸，建立胆碱能去神经模型。为了从新反应的习得和长时记忆两个方面评估被动回避的表现，新研制了一种高精度的避暗装置。体外定量受体放射自显影被用来寻找一种有前景的配基，利用专用的图像处理系统来定位大脑中的胆碱能神经支配。大脑皮层M_1、M_2受体在同侧和对侧之间无显著差异。同时用~3H-2-(4-苯基哌啶)环己醇(AH5183)对突触前胆碱能神经进行标测。在t-…中，AH5183的结合平均减少了14%，具有统计学意义在模型中，与对侧相比，同侧部位的皮质更多。这些结果可能暗示AH5183是一个敏感的乙酰胆碱水平的突触前标志物。合成了N-异丙基-对碘苯丙胺(IMP)的类似物N-对碘苯乙基二氨基二硫醇(DADT-IPE)，并以氯化亚锡为还原剂，与~(99)T；~(99)T；Tc络合，合成了一种新的SPECT用配体。用高效液相色谱法从~(99)m&GT；~(99)T-DADT-IPE中分离出两个配合物(a和b)。竞争抑制实验表明，DADT-IPE的IC_(50)和IC值与IMP相似。其中一种络合物在大鼠体内的生物分布研究表明，静脉注射示踪剂后5min，示踪剂仍有0.65%的注射剂量留在脑内，60min时仍有0.53%的剂量留在脑内，而另一种配合物[^&lt；99m&gt；Tc-DADT-IPE(B)]在静脉注射后5min的脑内剂量为0.34%，60min后脑内的剂量为0.28%。~(99)m&GT；~(99)Tc-DADT-IPE(A)在大鼠脑内的清除半衰期大于5h。这些结果表明，99m&gt；TC-DADT-IPE(A)具有适合于脑血流灌注成像的特性。此外，在该模型中应用原位杂交技术，利用寡核苷酸DNA探针对M胆碱受体信使RNA的基因表达进行成像。较少

项目成果

Kazuhiro Shiba: "Technetium-99m p-iodophenethyl diaminodithiol (DADT-IPE): Potential brain perfusion imagin agent for SPECT" Nucl Med Biol. 19. 303-310 (1992)

Kazuhiro Shiba：“Technetium-99m 对碘苯乙基二氨基二硫醇 (DADT-IPE)：用于 SPECT 的潜在脑灌注成像剂”Nucl Med Biol。

Hiroshi Matsuda: "Acetazolamide effect on vascular response in areas with diashisis as measured by Tc-99m HMPAD brain SPECT." Clin Nucl Med. 17. 581-586 (1992)

Hiroshi Matsuda：“通过 Tc-99m HMPAD 脑部 SPECT 测量，乙酰唑胺对双动区域血管反应的影响。”

Hiroshi Matsuda: "Acetazolamide effect on vascular response in areas with diaschisis as measured by Tc-99m HMPAO brain SPECT." Clin Nucl Med. 17. 581-586 (1992)

Hiroshi Matsuda：“通过 Tc-99m HMPAO 脑部 SPECT 测量，乙酰唑胺对神经联系联系不全区域的血管反应有影响。”

Hiroshi Matsuda: "A quantitative approach to technetium-99m hexamethylpropylene amine oxime" Eur J Nucl Med. 19. 195-200 (1992)

Hiroshi Matsuda：“锝-99m 六甲基丙烯胺肟的定量方法”Eur J Nucl Med。

Hiroshi Matsuda: "Comparative SPECT study of stroke using Tc-99m ECD.I-123 IMP,and Tc-99m HMPAO" Clin Nucl Med.

Hiroshi Matsuda：“使用 Tc-99m ECD.I-123 IMP 和 Tc-99m HMPAO 进行中风的比较 SPECT 研究”Clin Nucl Med。