Project 1: Development of Alpha Synuclein PET Radioligands for Imaging Synucleinopathies
Project Leads: Robert H. Mach PhD, Kelvin Luk, PhD, Virginia M.-Y. Lee PhD, Paul T. Kotzbauer MD, PhD, Zhude Tu, PhD
This Project will 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 MCRC Core. Compounds with 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. 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.
Project 2: Development of 4R-Tau PET Radioligands for Imaging Tauopathies
Project Leads: Chester A. Mathis, PhD, William E. Klunk MD, PhD
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 have 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.
This research will pursue parallel tracks of lead compound identification and optimization, working closely with the MCRC Core 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 candidate agents’ sensitivity and specificity for 4R-tau, identifying the most promising leads to advance to in vivo studies in rodents and non-human primates. 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.