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.