Amyloid Imaging Agents for Position Emission Tomography

描述（由申请方提供）：拟定研究涉及开发正电子发射断层扫描（PET）放射性药物，基于其与淀粉样β（Ap）蛋白中发现的β折叠原纤维的选择性结合，定位于人类受试者的大脑中。Ap在脑内的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、开发和应用选择性且有效的A（3-结合氟-18标记的PET放射性配体，能够穿透血脑屏障并以高亲和力选择性结合活体人类受试者大脑中的Ap沉积物。这些放射性配体中的许多的结构基于与众所周知的淀粉样蛋白选择性染料硫磺素T化学相关的先导化合物。预期所提出的18F标记的AP放射性配体的应用将使得能够直接评估脑Ap负荷和对旨在停止或逆转人类受试者脑中Ap沉积的治疗策略的响应。18F-放射性核素标记物的110分钟半衰期将使AP-特异性PET放射性药物的区域分布以与F-18-标记的FDG相同的方式实用。我们的具体目标包括：1）合理设计、合成和评价在可容易地放射性标记的位置上含有氟的所选AP结合剂阵列的体外性质; 2）放射性标记具有高比活度、正电子发射放射性核素18F的最有希望的化合物; 3）评价这些放射性示踪剂在正常对照啮齿动物中的体内性质; 4）使用PET成像评估18F标记的放射性示踪剂在正常对照狒狒中的体内性质; 5）将三种18F标记的AP试剂用于在5名AD和5名年龄匹配的对照受试者中的初步人类PET成像研究，以评估它们相对于11 C标记的AP放射性示踪剂匹兹堡化合物-B（PIB）; 6）选择一种18F标记的淀粉样蛋白试剂在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体PET成像研究，并将其成像特性与PIB的成像特性进行比较。

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.