Quantitative Imaging of Amyloid Deposits in AD and Aging

描述（由申请人提供）：在本申请的指导定量研究职业发展奖（K25），候选人的研究和职业发展计划进行了说明。该项目旨在为候选人定制教育和研究活动，以实现两个主要目标。目前的目标是候选人继续他的研究在淀粉样蛋白成像在阿尔茨海默氏症和衰老。长期目标是让候选人获得先进的生物医学研究技能，并发展成为与衰老相关的生物医学成像的独立研究人员。为了实现这些目标，候选人将获得神经科学，生物统计学，药理学和药代动力学以及负责任的生物医学和临床研究的进一步培训。他还将通过期刊俱乐部，研究研讨会，讲座和会议，并通过与其他研究人员和学员的互动获得相关知识。生物医学成像的实践技能将主要通过在匹兹堡大学的马西斯和Klunk博士的指导下拟议的microPET研究获得。在这项拟议的研究中，候选人计划使用microPET来评估淀粉样蛋白沉积转基因小鼠模型中的淀粉样蛋白成像剂。这将使我们第一次在模拟未来人体研究的CNS模型中评估先导化合物的体内结合特异性和药代动力学特征。因此，本项目将满足以下具体目标：1）合理设计和合成一系列选定的淀粉样蛋白结合剂; 2）评价新化合物对淀粉样蛋白沉积物的体外结合亲和力和特异性; 3）评价选定化合物在脑内无淀粉样蛋白沉积的正常对照小鼠的脑进入、脑内代谢和脑内代谢的离体研究中的作用; 4）使用microPET评估所选化合物在含淀粉样蛋白的转基因小鼠模型中的体内性质，以确定体内结合特异性和详细的药代动力学特征。我们的研究的总体目标是确定有效的，选择性的，脑渗透性淀粉样蛋白探针适合在人体内的研究。

DESCRIPTION (provided by applicant): In this application for a Mentored Quantitative Research Career Development Award (K25), the candidate's research and career development plans are described. The project is designed to customize the educational and research activities for the candidate to achieve two major goals. The immediate goal is for the candidate to continue his research in amyloid imaging in Alzheimer's disease and aging. The long-term goal is for the candidate to acquire advanced biomedical research skills and develop as an independent researcher in aging-related biomedical imaging. To achieve these goals, the candidate will obtain further trainings in neuroscience, biostatistics, pharmacology, and pharmacokinetics as well as in responsible conduct of biomedical and clinical research. He will also acquire related knowledge through journal clubs, research seminars, lectures, and conferences, and through interaction with other investigators and trainees. The practical skills in biomedical imaging will primarily be obtained through the proposed microPET studies under the guidance of Drs. Mathis and Klunk at the University of Pittsburgh. In this proposed research, the candidate plans to use microPET to evaluate amyloid-imaging agents in transgenic mice models of amyloid deposition. This will allow us for the first time to evaluate the in vivo binding specificity and pharmacokinetic profiles of lead compounds in a CNS model that mimics the future human studies. Therefore, this project will satisfy the following specific aims: 1) rationally design and synthesize a selected array of amyloid-binding agents; 2) evaluate the new compounds for in vitro binding affinity and specificity for amyloid deposits; 3) evaluate selected compounds in ex vivo studies of brain entry, crearance; and metabolism in normal control mice with no amyloid deposits in the brain; 4) use microPET to assess the in vivo properties of selected compounds in amyloid-containing transgenic mouse models to determine in vivo binding specificity and detailed pharmacokinetic profiles. The overall goal of our research is to identify potent, selective, and brain permeable amyloid probes suitable for in vivo human studies.