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: 6642708
• 负责人: CHESTER A MATHIS
• 金额: $ 34.79万
• 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/6642708
• 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.

所提出的研究涉及开发定位于阿尔茨海默病（AD）受试者的脑中的放射性药物，其基于它们与β-折叠原纤维（例如在淀粉样β蛋白（Abeta）中发现的那些）的选择性结合。淀粉样蛋白在脑内的沉积被认为在AD的发病机制中起关键作用。 目前，没有方法能够直接评估淀粉样蛋白沉积在活体人类受试者大脑中的量。 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，能够穿透血脑屏障，并选择性地结合淀粉样蛋白沉积与高亲和力。 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黄-T化学上远相关的铅化合物。 预计所提出的淀粉样蛋白放射性配体的应用将使首次直接评估脑淀粉样蛋白负荷和对旨在停止或逆转人类受试者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）合理地设计、合成和评价所选淀粉样蛋白结合剂阵列的体外性质; 2）用正电子发射放射性核素11 C或18F放射性标记最有希望的化合物; 3）在淀粉样蛋白斑沉积的转基因小鼠模型中评估这些放射性示踪剂的体内性质，以确定试剂的绝对脑摄取，放射性示踪剂清除，和放射性示踪剂在含有高密度淀粉样蛋白斑的啮齿动物脑中的特异性保留;和4）在人类受试者中开始研究之前，使用正电子发射断层摄影术（PET）成像评估放射性示踪剂在正常对照狒狒中的体内性质，以确定化合物在非人灵长类动物脑中的外周代谢和药代动力学。