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: 3410989
• 负责人: DONALD M WIELAND
• 金额: $ 25.86万
• 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 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3410989
• 关键词: Alzheimer's disease; GABA receptor; Huntington's disease; Macaca mulatta; brain mapping; dogs; dopamine receptor; drug metabolism; laboratory rat; neurons; neurotransmitter metabolism; neurotransmitters; positron emission tomography; radiopharmacology; stereochemistry

This proposal is a two-part study aimed at developing radiotracers that map the specific neurons in mammalian brain. The primary goal is to develop an {I-123} labeled tracer that will allow external detection of regional cholinergic neuron density of the human brain by single photon emission tomography. Such as agent would have potential widespread use in Nuclear Medicine for assessing the extent of cholinergic neuron involvement in Alzheimer's disease, olivopontocerebellar atrophy, progressive supranuclear palsy, and in demented patients with Parkinson's disease. We have adopted vesamicol, a potent inhibitor of vesicular acetylcholamine storage, as the design basis for a presynaptic cholinergic nerve marker. Work in our laboratory with a derivative of vesamicol, 5-[I-125] iodobenzovesamicol, has shown it to be a highly specific in vivo marker for the cholinergic neuron of murine brain. A systematic structure-activity study of [I-125] labeled vesamicol analogs will be pursued to determine optimum brain uptake, neuronal specificity, and tracer kinetics. Regions of bulk tolerance will be determined so incorporation of radioiodine will cause minimal perturbation of binding to the vesamicol receptor. A spectrum of hydrophilic groups will be evaluated to modulate lipophilicity within the optimum log P window for brain uptake. Evaluation of promising tracers will include gross regional brain distribution, quantitative autoradiography, pharmacological blocking/receptor saturation studies, and tracer kinetic analyses in rat and monkey, the latter with [I-123] labeled tracer using a newly developed small animal imaging device. The second goal is to develop tracers that map neuron-specific reuptake systems in brain. Initial efforts will focus on dopaminergic neurons using [I-125] analogs of the GBR series of inhibitors. Synthetic efforts will also be directed at radioiodinated inhibitors of the GABA uptake system. The major challenge to successful design of radiolabeled presynaptic uptake inhibitors is to maximize brain uptake without sacrificing neuronal selectivity. Major structural changes of the inhibitor will be made to hopefully counter the lipophilic-enhancing properties of iodine. Bioevaluation of these radiotracers will be essentially as described above for the cholinergic markers.

该建议是一项分为两部分的研究，旨在开发映射的放射性示例 哺乳动物大脑中的特定神经元。主要目标是开发 {i-123}标记为示踪剂，将允许外部检测区域 人脑的胆碱能神经元密度通过单光子发射 断层扫描。例如代理商将在核中可能广泛使用 评估胆碱能神经元参与程度的医学 阿尔茨海默氏病，橄榄球脑萎缩，进行性上核 麻痹，以及患有帕金森氏病的痴呆患者。我们已经采用了 Vesamicol是囊泡乙酰胆碱储存的有效抑制剂，作为 突触前胆碱能神经标记的设计基础。在我们的工作中工作 实验室具有vesamicol的衍生物，5- [I-125]碘苯并菜木木糖， 已经证明它是胆碱能的高度特异性体内标记 鼠大脑的神经元。 [I-125]的系统结构活性研究 将追求标记的vesamicol类似物以确定最佳大脑 摄取，神经元特异性和示踪剂动力学。批量区域 将确定耐受性，因此放射碘的合并将导致 与vesamicol受体结合的最小扰动。一部分 将评估亲水性基团以调节亲脂性 最佳日志P窗口用于脑部吸收。对有前途的示踪剂的评估将 包括总区域大脑分布，定量自显影术， 药理阻断/受体饱和研究和示踪剂动力学 在大鼠和猴子中进行分析，后者使用[I-123]标记示踪剂使用 新开发的小动物成像装置。 第二个目标是开发绘制神经元特异性再摄取的示踪剂 大脑中的系统。最初的努力将使用使用多巴胺能神经元 [I-125] GBR系列抑制剂的类似物。合成的努力将 也可以针对GABA摄取系统的放射性施用抑制剂。 成功设计放射性标记的突触前摄取的主要挑战 抑制剂是在不牺牲神经元的情况下最大化脑摄取 选择性。抑制剂的重大结构变化将进行 希望能够应对碘的亲脂增强特性。 这些放射性示例的生物评估本质上是如上所述 对于胆碱能标记。