Discovery and Evaluation of Imidazo[2,1-][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging.

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1-][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [I], with moderate binding affinity (IC = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [I], we developed a potential PET tracer, [F] (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC = 245 nM), good brain uptake (SUV = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [F] appears to be a promising candidate for α-syn PET imaging and merits further development.