Project 2: 4R-Tau

Development of 4R-Tau PET Radioligands for Imaging Tauopathies

Project Lead: Chester A. Mathis, 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.