OVERALL ABSTRACT This grant application was submitted in response to RFA-NS-24-011, “Center without Walls for PET Ligand Development for ADRDs”. It describes a request for continued support for the Center without Walls for Imaging Proteinopathies with PET (U19 NS110456), a project that was funded through RFA- NS-19-014. The competing renewal describes our continued development of Positron Emission Tomography (PET) ligands for imaging two proteinopathies: 1) alpha synuclein (Asyn) for imaging the synucleinopathies Parkinson’s disease and multiple system atrophy; and 2) 4R tau for imaging the 4R tauopathies frontotemporal degeneration and progressive supranuclear palsy. The Proteinopathy Imaging Center (short title) consists of a synergistic, collaborative effort between the University of Pennsylvania (Penn), Washington University-St. Louis (WUSTL), University of Pittsburgh (Pitt), University of California-San Francisco (UCSF), and Yale University. The organization of the Proteinopathy Imaging Center is both innovative and unique for the following reasons: 1) it partners faculty members with an international reputation in the neurobiology (V. Lee, K. Luk, P Kotzbauer) and structural biology (E.J. Petersson) of the proteinopathies with experts in radiotracer development at Penn (RH Mach), Pitt (C. Mathis), and WUSTL (Z. Tu) in developing radiotracers for Asyn and 4R tau; 2) it involves the multi-site collaboration of clinical investigators who are experts in the use of PET to study CNS disorders (J. Perlmutter, WUSTL; R. Carson, Yale; G. Rabinovici, UCSF; A. Siderowf and I. Nasrallah, Penn; V. Villemagne;Pitt); and 3) it involves the utilization of state-of-the-art PET imaging devices for whole body distribution (PennPET Explorer) and high resolution brain studies (NeuroeXplorer, Yale) of our Asyn and 4R tau radiotracers. The Proteinopathy Imaging Center also consists of a series of cross-validation studies at both the basic science (i.e., radiotracer characterization) and clinical research (i.e., consensus diagnosis) levels that can only be accomplished through the U19 funding mechanism. The PI of the Center is Robert H. Mach, the Britton Chance Professor of Radiology at Penn. The Center consists of three Cores (Administrative, Medicinal Chemistry and Radiochemistry, Clinical) and two projects (Asyn, 4R tau). The cores are organized so that there is an overall Core Director or Co- Director, and a site Director at each site participating in the Core activities. The radiotracers developed by the Center without Walls for Imaging Proteinopathies with PET are expected to lead to generation of imaging strategies that are of interest to the scientific mission of the NINDS. They are also expected to provide novel imaging strategies to advance our knowledge on the role of Asyn and 4R tau in neurodegenerative disorders.