The goal of Project 2 is to develop a positron emission tomography (PET) radiopharmaceutical useful for imaging 4-repeat (4R) tauopathies, which include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and familial frontal temporal dementias (fFTDs). Several useful PET agents for imaging mixed 3R+4R- tau aggregates in Alzheimer's disease (AD) have been reported, although none of these agents has proven useful for imaging 4R-tau in non-AD 4R-tauopathies. Novel disease modifying therapies that target tau offer new treatment possibilities for patients with different tauopathies. Key to a successful therapeutic strategy will be the ability to discriminate patients with different tauopathies and to assess the efficacy of anti-tau treatments. The proposed research in this project will pursue parallel tracks of lead compound identification and optimization, working closely with the Medicinal Chemistry and Radiochemistry Core (MCRC) to identify new 4R-tau candidate radioligands for subsequent evaluation in Project 2. Binding studies in tissue specimens of 4R-tauopathies and other proteinopathies will characterize the sensitivity and specificity of candidate ligands for aggregated 4R-tau, identifying the most promising leads to advance to in vivo studies in rodents and non-human primates. Initially, Project 2 will obtain human tissue binding data using two compounds with favorable 4R-tau binding properties, PM-PBB3 and CBD-2115, and will fully define their binding characteristics in a variety of human post-mortem tissues. Subsequently, the MCRC will prepare a series of analogs of PM-PBB3 and CBD-2115 for in vitro binding assays in Project 2 to help define the structure-activity relationship (SAR) of the analogs. The MCRC will employ its computational chemistry resources to help guide the selection of PM-PBB3 and CBD-2115 analogs for synthesis and subsequent evaluation and will also generate new lead compounds for testing in Project 2. In vitro binding assays conducted in Project 2 will test the predictive power of the in silico studies conducted by the MCRC and help refine binding site features that most influence radioligand-4R-tau interactions. These refinements will assist future in silico screening studies conducted by the MCRC aimed at providing new 4R-tau ligands for testing in Project 2. Project 2 will employ a staged approach using both in vitro and in vivo assay methods to characterize and evaluate candidate 4R-tau PET imaging agents provided by the MCRC, identifying the most promising 4R-tau agents for subsequent evaluation in first-in-human studies of PSP and fFTD subjects in the Clinical Core.
