Quantitative Imaging of Amyloid Deposits in AD and Aging

Case Western Reserve University, Cleveland OH

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Abstract

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.