MEDICINAL CHEMISTRY AND RADIOCHEMISTRY CORE ABSTRACT The Medicinal Chemistry and Radiochemistry (MCRC) Core is responsible for the development of radiotracers for Projects 1 and 2 and the Clinical Core. The MCRC Core is composed of three sites: University of Pennsylvania (Penn), Washington University in St. Louis (WUSTL), and the University of Pittsburgh (Pitt). The MCRC also benefits from a collaboration on structural biology through the NINDS U01/U19 Proteinopathy consortium. The studies conducted during our first 4 years of U19 support have provided 18 putative alpha- synuclein (Asyn) PET tracers and >10 putative 4R tau radiotracers. We will optimize candidate ligands to develop: 1) disease-specific radiotracers for imaging Asyn in Parkinson’s disease (PD) or Multiple System Atrophy (MSA), 2) pan-Asyn radiotracers for both PD and MSA, and 3) 4R tau selective radiotracers for Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and frontotemporal dementia (FTD). The MCRC Core will guide these efforts with a unique combination of 1) chemical biology approaches (photo- crosslinking MS proteomics and fluorescent probes); 2) structural biology approaches (both solid state NMR and cryo-electron microscopy); 3) computational modeling (ultra-high throughput screening, molecular dynamics, and machine learning); and 4) extensive radiochemistry expertise. Chemical biology studies will take place at Penn in conjunction with structural biology studies done through the U01/U19 Proteinopathy consortium to determine high resolution structures of the candidate molecules bound to Asyn or tau fibrils, as well as the selectivity determinants between binding sites. The resulting structural information will be used in computational modeling and ultra-high throughput screening at Penn to guide the design of new leads. The Asyn compound synthesis will take place at Penn and WUSTL. The tau lead compound synthesis will take place at Pitt in collaboration with Penn. These leads will be tested in radioligand competition binding assays, and where desirable, new radioligands will be synthesized for binding assays and animal experiments. The radiochemistry studies will be done at Penn to support the rodent imaging studies in Project 1, WUSTL to support the radioligand binding assays and nonhuman primate imaging studies in Project 1, and Pitt to support the radioligand binding and non-human primate imaging studies conducted in Project 2. The chemical biology studies of the MCRC Core, in combination with the structural biology done in collaboration with the U01/U19 Consortium, represents a comprehensive approach for determining the molecular interactions of U19 radiotracers with Asyn and 4R tau fibrils isolated from patient brain samples. This structural information will guide the in silico and SAR studies to generate a suite of high affinity radiotracers that are specific for the different subtypes of the synucleinopathies (PD and MSA) and 4R tauopathies (C...