RADIOIODINATED TRACERS FOR MAPPING BRAIN NEURONS

用于绘制脑神经元图的放射性碘示踪剂

• 批准号: 2265627
• 负责人: DONALD M WIELAND
• 金额: $ 27.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2265627
• 关键词: Macaca nemestrina; analog; autoradiography; brain mapping; brain metabolism; choline acetyltransferase; cholinergic receptors; copper; depolarizing neuromuscular blocking agent; dogs; drug design /synthesis /production; drug metabolism; human subject; hydropathy; iodine; laboratory mouse; laboratory rat; nuclear medicine; radiopharmacology; radiotracer; single photon emission computed tomography; stereochemistry; technetium

This proposal is aimed at the development of radiotracer that map the density of cholinergic neurons in mammalian brain. The specific objective is to develop an iodine-123 or technetium-99m labeled tracer that will allow external detection of regional cholinergic neuron density of the human brain by single photon emission tomography (SPECT). Such an agent would have potential widespread use in Nuclear Medicine for assessing the extent of cholinergic neuron involvement in Alzheimer's disease, Parkinson's disease with dementia, olivopontocerebellar atrophy, and progressive supranuclear palsy. We have adopted benzovesamicol and vesamicol, potent inhibitors of the vesicular acetylcholine transporter, as the design bases for development of a presynaptic cholinergic nerve marker. Work in our laboratory under the current grant produced (-)-5- [123I]iodobenzovesamicol which underwent successful preclinical testing and is presently under evaluation in humans. This tracer would be greatly improved if the brain uptake was enhanced by lowering the lipophilicity (log P=3.43) of the tracer to the optimum range of log P=1- 2. This has been difficult to accomplish in the benzovesamicol series because of low synthetic yields and isomeric mixtures. Hence, a new structural class of benzovesamicols, the benzovesamicols, the benzo(a) series, will be synthesized, which favors regiospecific incorporation of radioiodine ortho to log P-lowering substituents such as hydroxy and amino groups. Two additional radioiodine-based approaches, quinoline analogs of benzovesamicol and 4-iodo-vinylvesamicol, should possess improved lipophilicitities while maintaining high affinity for the vesamicol receptor. Three types of [99mTc]-N2S2 derivatives of vesamicol will be synthesized which should possess log P values, molecular volumes, and molecular weights that make them likely choices to cross the blood-brain barrier and map the cholinergic nerve terminals. A thiosemicarbazone vesamicol analogue will also be prepared for both Tc-99m and Cu-62 labeling. Evaluation of promising tracers will include gross regional brain distribution, quantitative autoradiography, in vivo pharmacological blocking/receptor saturation studies, in vitro competitive binding to the vesamicol receptor in rat cortical homogenates, tracer kinetic analysis in rat and monkey, the latter by SPECT, and correlation with other cholinergic markers such as choline acetyltransferase.

该建议旨在开发映射的放射性示意剂 哺乳动物大脑中胆碱能神经元的密度。 具体 目的是开发碘-123或Technetium-99m标记的示踪剂 这将允许外部检测区域胆碱能神经元密度 单光子发射断层扫描（SPECT）的人脑的脑大脑。 这样的 代理商可能在核医学中广泛使用 评估胆碱能神经元参与阿尔茨海默氏症的程度 疾病，帕金森氏病，患有痴呆症，橄榄球脑萎缩， 和进行性上核麻痹。 我们已经采用了苯并木糖和 囊泡，囊泡乙酰胆碱转运蛋白的有效抑制剂， 作为开发突触前胆碱能神经的设计基础 标记。 根据目前生产的赠款（ - 5-）在我们的实验室工作 [123i]碘苯并菜木糖进行了成功的临床前测试 目前正在人类评估。 这个示踪剂将是 如果通过降低大脑的摄取来增强大脑的摄取，可以大大改善 示踪剂的亲脂性（log p = 3.43）至log p = 1-的最佳范围 2。这在苯并木糖系列中很难完成 由于合成产量低和异构混合物。 因此，一个新的 苯并木糖的结构类别，苯佐糖，苯并（a） 系列将合成，有利于重新融合 放射性碘矫正器到降低P降低P的取代基，例如羟基和 氨基群。 另外两种基于放射性碘的方法，喹啉 苯佐奶酪和4-碘 - 乙烯基氨基氨基酚的类似物应拥有 提高亲脂性的同时，保持了高亲和力 vesamicol受体。 将合成三种类型的[99mtc] -n2s2衍生物 应该具有log P值，分子体积和分子 使他们可能选择越过血脑屏障的重量 并绘制胆碱能神经末端。 硫代乳果泡 TC-99M和CU-62标签也将准备模拟。 有前途的示踪剂的评估将包括区域大脑 分布，定量放射自显影，体内药理 阻止/受体饱和研究，体外竞争性结合与 大鼠皮质匀浆中的vesamicol受体，示踪剂动力学分析 在大鼠和猴子中，后者通过SPECT，与其他 胆碱能标记，例如胆碱乙酰转移酶。