Amyloid Imaging Agents for Positron Emission Tomography

这项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，这些药物基于它们与β-折叠纤维的选择性结合，例如在淀粉样β蛋白(Abeta)中发现的那些。淀粉样蛋白在脑内的沉积被认为在AD的发病机制中起着关键作用。目前，还没有一种方法能够直接评估活体受试者大脑中沉积的淀粉样蛋白的数量。我们的计划是合理地设计和合成选择性和有效的淀粉样蛋白结合放射性配基，能够穿透血脑屏障，并以高亲和力选择性结合淀粉样蛋白沉积。这些放射性配体的结构是基于先导化合物，这些化合物在化学上与经典的淀粉样蛋白刚果红和硫代黄素-T有很大关系。预计，拟议的淀粉样放射性配基的应用将使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、合成和评估一系列淀粉样蛋白结合剂的体外性能；2)用发射正电子的放射性核素11C或18F标记最有希望的化合物；3)在淀粉样斑块沉积的转基因小鼠模型中评估这些放射性示踪剂的体内特性，以确定这些试剂的绝对脑摄取、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块的啮齿类动物脑中的特异性保留；以及4)在启动人类研究之前，使用正电子发射断层扫描(PET)成像来评估放射性示踪剂在正常对照狒狒体内的性质，以确定化合物在非人类灵长类动物脑中的外周代谢和药代动力学。

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.