PROJECT 1: Development of Alpha Synuclein PET Radioligands for Imaging Synucleinopathies The goal of Project 1 is to conduct a series of in vitro binding studies, in vivo brain uptake and PET imaging studies in the process of evaluating radiotracers for imaging aggregated alpha synuclein (Asyn) in the synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The compounds evaluated in this project will be identified via in silico ultrahigh throughput screening and traditional structure-activity relationship (SAR) studies conducted in the Medicinal Chemistry and Radiochemistry (MCRC) Core. The in vitro binding assays described in this project will consist of three different types: 1) screening of ?in silico hits? in Asyn fibrils using radioligands for the different binding sites with the goal of identifying ?fibril confirmed hits?; 2) in vitro binding assays of the fibril confirmed hits to identify new lead compounds having an affinity for ASyn in PD and MSA tissue of <50 nM; and, 3) indirect and direct binding assays of compounds developed as part of the SAR studies in the MCRC Core targeting or more of the binding sites in Asyn fibrils. Compounds having a high affinity for Asyn and good selectivity versus other proteinopathies (Abeta, tau and TDP43) will be advanced to a series of in vitro autoradiography and in vivo studies as a means of identifying a suitable candidate(s) for translational imaging studies in humans. Another function of Project 1 is to cross-validate potential PET radiotracers having a high affinity for 4R tau developed by the MCRC Core and evaluated in Project 2. The successful accomplishment of the research objectives of this U19 Center will require the frequent communication between the members of the MCRC Core, Project 1 and Project 2. This will be accomplished by through the series of bi-weekly teleconference calls and meetings of the Center Steering Committee, External Liaison Committee, and NINDS program staff as outlined in the administrative Core. The ultimate goal of the research described in Project 1 is to identify radiotracers for the different synucleinopathies that will be conducted in translational imaging studies described in the Clinical Core.