Quantitative Imaging of Amyloid Deposits in AD and Aging

描述(由申请人提供)：在这份量化研究职业发展指导奖(K25)的申请书中，描述了候选人的研究和职业发展计划。该项目旨在为考生定制教育和研究活动，以实现两大目标。目前的目标是候选人继续他在阿尔茨海默氏症和衰老方面的淀粉样成像研究。候选人的长期目标是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领域的独立研究人员。为了实现这些目标，应聘者将接受神经科学、生物统计学、药理学和药物动力学方面的进一步培训，以及负责生物医学和临床研究的培训。他还将通过期刊俱乐部、研究研讨会、讲座和会议，以及通过与其他研究人员和受训人员的互动来获得相关知识。生物医学成像的实用技能将主要通过在匹兹堡大学马西斯和克伦克博士的指导下拟议的微型PET研究来获得。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的转基因小鼠模型中的淀粉样显像剂。这将使我们能够第一次在模仿未来人类研究的中枢神经系统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，本项目将满足以下特定目标：1)合理设计和合成一系列精选的淀粉样结合剂；2)评估新化合物对淀粉样蛋白沉积的体外结合亲和力和专一性；3)在体外脑进入、分泌和代谢方面的研究中评估选定的化合物；4)使用microPET技术评估选定化合物在含有淀粉样蛋白的转基因小鼠模型中的体内性质，以确定体内结合的特异性和详细的药动学特征。我们研究的总体目标是确定有效的、选择性的和脑透性的淀粉样蛋白探针，适用于活体人类研究。

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.