Amyloid Imaging Agents for Positron Emission Tomography

用于正电子发射断层扫描的淀粉样蛋白成像剂

• 批准号: 6327357
• 负责人: CHESTER A MATHIS
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327357
• 关键词: Alzheimer's disease; amyloid proteins; atherosclerotic plaque; baboons; bioimaging /biomedical imaging; blood brain barrier; brain metabolism; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; fluorescence microscopy; genetically modified animals; human tissue; laboratory mouse; neuritic plaques; pathologic process; pharmacokinetics; positron emission tomography; protein binding; protein structure function; radionuclides; radiotracer; tissue /cell culture

The proposed research involves the development of radiopharmaceuticals that localize in the brain of Alzheimer's disease (AD) subjects bases upon their selective binding to beta- sheet fibrils such as those found in amyloid-beta protein (Abeta). The deposition of amyloid protein in brain is believed to play a key role in the pathogenesis of AD. At present, no method is capable of directly assessing the amount of amyloid deposited in the brains of living human subjects. Our plan is to rationally design and synthesize selective and potent amyloid- binding radioliglands capable of penetrating the blood-brain barrier and selectively binding to amyloid deposits with high affinity. The structure of these radioligands is based upon lead compounds distantly-related chemically to the classic amyloid stains Congo red and Thioflavin-T. It is anticipated that the application of the proposed amyloid radioligands will make possible the first direct assessment of cerebral amyloid burden and response to therapeutic strategies aimed at halting or reversing amyloid deposition in the brains of human subjects. Our specific aims include: 1) rationally design, synthesize, and evaluate the in vitro properties of a selected array of amyloid- binding agents; 2) radiolabel the most promising compounds with the positron-emitting radionuclides 11C or 18F; 3) assess the in vivo properties of these radiotracers in transgenic mouse models of amyloid plaque deposition to determine the absolute brain uptake of the agents, radiotracer clearance, and specific retention of the radiotracer in rodent brain containing high densities of amyloid plaques; and 4) assess the in vivo properties of the radiotracers in normal control baboons using positron emission tomography (PET) imaging to determine the peripheral metabolism and pharmacokinetics of the compounds in non-human primate brain prior to initiating studies in human subjects.

拟议的研究涉及开发定位于阿尔茨海默病（AD）受试者大脑中的放射性药物，其基础是它们与β-折叠原纤维（例如淀粉样β蛋白（Abeta）中发现的纤维）的选择性结合。淀粉样蛋白在大脑中的沉积被认为在AD的发病机制中发挥着关键作用。 目前，还没有方法能够直接评估活体人类受试者大脑中沉积的淀粉样蛋白的量。 我们的计划是合理设计和合成选择性和有效的淀粉样蛋白结合放射性配体，其能够穿透血脑屏障并以高亲和力选择性地结合淀粉样蛋白沉积物。 这些放射性配体的结构基于与经典淀粉样蛋白染色剂刚果红和硫磺素-T 化学上远亲相关的先导化合物。 预计所提出的淀粉样蛋白放射性配体的应用将使得首次直接评估大脑淀粉样蛋白负荷和对旨在阻止或逆转人类受试者大脑中淀粉样蛋白沉积的治疗策略的反应成为可能。我们的具体目标包括：1）合理设计、合成和评估一系列选定的淀粉样蛋白结合剂的体外特性； 2) 用正电子发射放射性核素 11C 或 18F 对最有希望的化合物进行放射性标记； 3) 评估这些放射性示踪剂在淀粉样斑块沉积转基因小鼠模型中的体内特性，以确定药物的绝对大脑摄取、放射性示踪剂清除率以及放射性示踪剂在含有高密度淀粉样斑块的啮齿动物大脑中的特异性保留； 4) 在开始对人类受试者进行研究之前，使用正电子发射断层扫描 (PET) 成像评估正常对照狒狒中放射性示踪剂的体内特性，以确定化合物在非人类灵长类动物大脑中的外周代谢和药代动力学。