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: 2037284
• 负责人: DONALD M WIELAND
• 金额: $ 25.48万
• 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 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2037284
• 关键词: 6 hydroxydopamine; autoradiography; baboons; biomaterial development /preparation; blood lipoprotein metabolism; brain mapping; brain metabolism; chemical binding; chromaffin cells; high performance liquid chromatography; hydropathy; iodine; laboratory mouse; laboratory rat; membrane transport proteins; molecular site; neurons; radionuclide emission tomography; radiotracer; reserpine; substantia nigra; synaptic vesicles; tetrabenazine

DESCRIPTION: (Adapted from the applicant's abstract) This is a proposal to continue the development of radioiodinated tracers for mapping presynaptic nerve terminal density in mammalian brain. Parkinson s disease is characterized by massive degeneration of nigrostriatal dopamine neurons. Radiotracer imaging methods tend to underestimate actual nerve terminal loss possibly because of compensatory responses of surviving nerve terminals. A radiotracer that binds to surviving nerve terminals at a site minimally involved in homeostasis may provide a more precise assessment of nerve terminal loss. This capability would be especially important in tracking the long term efficacy of neuroprotective drug strategies initiated in patients with mild Parkinson s disease. Kilbourn and co-workers have developed a method for determining the regional brain density of the type 2 monoamine vesicular transporter (VMAT2) using [C-11]dihydrotetrabenazine (DTBZ). Studies with DTBZ have shown that striatal VMAT2 density is linearly correlated to the integrity of substantia nigra dopamine neurons and not subject to drug- or lesion-induced compensatory regulation. This proposal will focus on developing radioiodine labeled derivatives of DTBZ that selectively bind to VMAT2. A successful ligand will require simultaneous modification of two areas of the DTBZ molecule - one for iodine attachment and a second for polar group incorporation to counteract the lipophilicity-enhancing effect of iodine. Candidate iodo-DTBZ derivatives will be screened in vitro by radioligand binding assays using rat brain and bovine chromaffin vesicle ghosts. Ex vivo studies in rodents with [I-125]tracer will include determination of regional brain distribution by direct sampling/counting and by autoradiography. Tracer kinetic analysis with determination of brain and blood metabolites will be performed in rats. Validation of VMAT2 binding specificity will include testing for saturability, blockade by DTBZ and reserpine, stereoselectivity, and response to graded 6-hydroxydopamine striatal lesions. The most promising tracers will be labeled with iodine-123 and studied in baboons by emission tomography to test safety, imaging characteristics, and striatal washout time.

描述：（改编自申请人的摘要）这是一项提案 继续开发用于绘制突触前图的放射性碘示踪剂 哺乳动物大脑中的神经末梢密度。 帕金森病是 其特征是黑质纹状体多巴胺神经元的大规模变性。 放射性示踪成像方法往往会低估实际的神经末梢损失 可能是因为幸存的神经末梢的代偿反应。 一个 放射性示踪剂与某个部位幸存的神经末梢结合最少 参与体内平衡可以提供更精确的神经评估 终端损失。 此功能对于跟踪尤其重要 神经保护药物策略的长期疗效始于 患有轻度帕金森病的患者。 基尔伯恩和他的同事们 开发了一种确定 2 型区域脑密度的方法 使用 [C-11]二氢丁苯那嗪的单胺囊泡转运蛋白 (VMAT2) （DTBZ）。 DTBZ 研究表明纹状体 VMAT2 密度 与黑质多巴胺神经元的完整性线性相关 且不受药物或病变引起的补偿调节。 这 提案将重点开发放射性碘标记的 DTBZ 衍生物 选择性结合 VMAT2。 成功的配体需要 同时修饰 DTBZ 分子的两个区域 - 一个区域用于碘 附件和第二个用于极性基团合并以抵消 碘的亲脂性增强作用。 候选碘-DTBZ衍生物 将使用大鼠脑通过放射性配体结合测定进行体外筛选 牛嗜铬小泡鬼。 啮齿类动物的离体研究 [I-125]示踪剂将包括通过以下方式确定区域大脑分布 直接采样/计数和放射自显影。 示踪动力学分析 将在大鼠中进行大脑和血液代谢物的测定。 VMAT2 结合特异性的验证将包括测试 饱和度、DTBZ 和利血平的阻断、立体选择性和 对分级 6-羟基多巴胺纹状体损伤的反应。 最有前途的 示踪剂将用碘 123 标记并通过发射在狒狒身上进行研究 用于测试安全性、成像特征和纹状体冲刷的断层扫描 时间。