Radiofluorination of 2-Arylquinolin-4-yl Oxypropanamide Derivatives for TSPO Imaging in Neuroinflammatory Murine, Nonhuman Primates, and Human Brain Autoradiography with Insensitivity to the rs6971 Polymorphism

The 18 kDa translocator protein (TSPO) is a critical target for PET imaging of neuroinflammation in central nervous system (CNS) disorders; however, many clinical TSPO PET tracers are limited by sensitivity to rs6971 polymorphism. In this study, three novel fluorine-containing oxypropanamide ligands were developed, with 11 (LW1, Ki = 0.07 nM) and 12 (LW2, Ki = 0.05 nM) showing high TSPO affinity. The radiolabeled [18F]12 demonstrated superior metabolic stability, specificity, and reduced polymorphism sensitivity compared to [18F]11 in autoradiography using Tg2576, PS19 mouse models, and human brain tissues. [18F]12 was further evaluated in APP/PS1 transgenic mice and ischemic stroke rats for neuroinflammatory imaging and in healthy rhesus monkeys to access pharmacokinetics via dynamic PET with arterial sampling. The combination of excellent brain penetration, high specificity, and rs6971 insensitivity supports [18F]12 as a promising TSPO PET tracer for clinical translation.