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.

该提案是一项由两部分组成的研究，旨在开发可绘制地图的放射性示踪剂 哺乳动物大脑中的特定神经元。主要目标是开发一个 {I-123}标记的示踪剂将允许外部检测区域 单光子发射的人脑胆碱能神经元密度 断层扫描。这种试剂在核领域有可能广泛使用 用于评估胆碱能神经元参与程度的药物 阿尔茨海默病、橄榄脑桥小脑萎缩、进行性核上性萎缩 麻痹，以及患有帕金森病的痴呆患者。我们已经采用了 vesamicol 是一种有效的囊泡乙酰胆胺储存抑制剂 突触前胆碱能神经标记物的设计基础。在我们的工作 实验室用维沙考衍生物，5-[I-125]碘苯并维沙考， 已表明它是胆碱能的高度特异性体内标记物 小鼠大脑的神经元。 [I-125] 的系统结构-活性研究 将寻找标记的维沙考类似物来确定最佳大脑 摄取、神经元特异性和示踪动力学。散装区域 将确定耐受性，因此放射性碘的掺入将导致 与维萨米考受体结合的最小干扰。一系列 将评估亲水基团以调节亲脂性 大脑摄取的最佳 log P 窗口。对有前途的示踪剂的评估将 包括大脑总体区域分布、定量放射自显影、 药理学阻断/受体饱和研究和示踪动力学 在大鼠和猴子中进行分析，后者使用 [I-123] 标记的示踪剂使用 新开发的小动物成像设备。 第二个目标是开发绘制神经元特异性重摄取图的示踪剂 大脑中的系统。最初的努力将集中在多巴胺能神经元上 [I-125] GBR 系列抑制剂的类似物。综合努力将 也可针对 GABA 摄取系统的放射性碘抑制剂。 成功设计放射性标记突触前摄取的主要挑战 抑制剂的目的是在不牺牲神经元的情况下最大化大脑的摄取 选择性。抑制剂的主要结构变化将是 希望能够抵消碘的亲脂性增强特性。 这些放射性示踪剂的生物评价基本上如上所述 用于胆碱能标记物。