Amyloid Imaging Agents for Position Emission Tomography

描述（由申请人提供）：拟议的研究涉及开发正电子发射断层扫描（PET）放射性药物，该药物基于其与淀粉样蛋白（Ap）中发现的β -片原纤维的选择性结合而定位于人类受试者的大脑。脑内Ap沉积被认为在阿尔茨海默病（AD）的发病机制中起关键作用。我们的计划是合理设计、合成、开发和应用选择性和强效的A(3)结合氟-18标记的PET放射配体，这些配体能够穿透血脑屏障，并以高亲和力选择性地结合活人大脑中的Ap沉积物。许多这些放射性配体的结构是基于与众所周知的淀粉样蛋白选择性染料硫黄素t化学相关的先导化合物。预计，拟议的18f标记的AP放射性配体的应用将有可能直接评估大脑中的AP负担和治疗策略的反应，旨在阻止或逆转人类受试者大脑中的AP沉积。18f放射性核素标签的110分钟半衰期将使ap特异性PET放射性药物的区域分布变得可行，就像f- 18标记的FDG一样。我们的具体目标包括：1)合理设计、合成和评估选定的具有易于放射性标记位置的含氟ap结合剂阵列的体外性能；2)放射性标记最有希望的高比活性化合物，正电子发射放射性核素18F；3)评估这些放射性示踪剂在正常对照鼠类体内的特性；4)利用PET成像技术评估18f标记放射性示踪剂在正常对照狒狒体内的特性；5)在5名AD患者和5名年龄匹配的对照组中，采用3种18F标记的Ap药物进行人体PET成像中试研究，评估其相对于11c标记的Ap放射性示踪剂匹兹堡化合物- b （PIB）在同一受试者中的体内成像特性；6)选择一种18f标记的淀粉样蛋白剂，在10名对照受试者、10名轻度认知障碍（MCI）受试者和10名AD受试者中进行更广泛的人类PET成像研究，并将其成像特性与PIB进行比较。

DESCRIPTION (provided by applicant): The proposed research involves the development of positron emission tomography (PET) radiopharmaceuticals that localize in the brain of human subjects based upon their selective binding to beta- sheet fibrils found in amyloid-beta (Ap) protein. The deposition of Ap in brain is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Our plan is to rationally design, synthesize, develop, and apply selective and potent A(3-binding fluorine-18-labeled PET radioligands capable of penetrating the blood- brain barrier and selectively binding to Ap deposits in the brains of living human subjects with high affinity. The structure of many of these radioligands is based upon lead compounds related chemically to the well known amyloid-selective dye Thioflavin T. It is anticipated that the application of the proposed 18F-labeled AP radioligands will make possible direct assessment of cerebral Ap burden and response to therapeutic strategies aimed at halting or reversing Ap deposition in the brains of human subjects. The 110 min half-life of the 18F-radionuclide label will make regional distribution of the Ap-specific PET radiopharmaceuticals practical in the same manner as has been realized for F-18-labeled FDG. Our specific aims include: 1) rationally design, synthesize, and evaluate the in vitro properties of a selected array of Ap-binding agents containing fluorine in a position that can be readily radiolabeled; 2) radiolabel the most promising compounds with the high specific activity, positron-emitting radionuclide 18F; 3) assess the in vivo properties of these radiotracers in normal control rodents; 4) assess the in vivo properties of the 18F-labeled radiotracers in normal control baboons using PET imaging; 5) take three 18F- labeled Ap agents into pilot human PET imaging studies in 5 AD and 5 age-matched control subjects to assess their in vivo imaging properties relative to the 11C-labeled AP radiotracer Pittsburgh Compound-B (PIB) in the same subjects; and 6) select one 18F-labeled amyloid agent to perform more extensive human PET imaging studies in 10 control subjects, 10 subjects with mild cognitive impairment (MCI), and 10 AD subjects, and compare its imaging properties to those of PIB.