Discovery and Evaluation of Imidazo[2,1-<i>b</i>][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging
Qi Zeng, Xiaojun Zhang, Yuying Li, Qi‐Lei Zhang, Jiapei Dai, Xiao‐Xin Yan, Yu Liu, Jinming Zhang, Sen Liu, Mengchao Cui
Abstract
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- b ][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [ 125 I] ITA-3, with moderate binding affinity (IC 50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [ 125 I] ITA-3, we developed a potential PET tracer, [ 18 F] FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC 50 = 245 nM), good brain uptake (SUV peak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [ 18 F] FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.