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.

提出的研究涉及在阿尔茨海默氏病（AD）受试者的大脑中的放射性药物的发展，其选择性结合与β纤维纤维（例如在淀粉样蛋白β蛋白（Abeta）中发现的）。据信，淀粉样蛋白在大脑中的沉积在AD的发病机理中起关键作用。 目前，尚无能力直接评估沉积在活人受试者大脑中的淀粉样蛋白的数量。 我们的计划是合理设计并合成能够穿透血脑屏障并选择性地结合具有高亲和力的淀粉样蛋白沉积物的选择性和有效的淀粉样蛋白结合放射性岩。 这些放射线的结构基于铅化合物在化学上与经典淀粉样蛋白污渍刚果红色和硫牛素-T的化学相关。 预计所提出的淀粉样放射线的应用将使您可以首次直接评估脑淀粉样蛋白负担，并对旨在停止或逆转人类受试者淀粉样蛋白沉积的治疗策略的反应。我们的具体目的包括：1）合理设计，合成和评估所选淀粉样蛋白结合剂阵列的体外特性； 2）放射性标记最有前途的化合物，发射正电子核素11c或18f； 3）评估这些放射性示意剂在淀粉样菌斑沉积的转基因小鼠模型中的体内特性，以确定剂量的脑脑摄取的绝对脑摄取，放射性示意剂清除率以及放射性杆子在啮齿动物脑中含有高密度的淀粉样plaques的啮齿动物脑中的特定保留。 4）使用正常对照狒狒中的放射性示踪性（PET）成像评估放射性示意剂的体内特性，以确定非人类灵长类动物大脑在人类受试者启动研究之前，在非人类灵长类动物大脑中的化合物的外围代谢和药代动力学。