Discovery of Fluorinated Ultrapotent Chemogenetic Ligands for PET Imaging and Neural Modulation in Nonhuman Primates

Chemogenetic technologies offer a powerful approach to modulating neural circuits with high precision and hold promise for therapeutic applications in neuropsychiatric disorders. However, translating these tools for noninvasive monitoring in the primate brain has been limited by a lack of suitable positron emission tomography (PET) radioligands. Existing ultrapotent ligands activate PSAM receptors, but the PET ligand [ 11 C] uPSEM792 shows poor brain penetration, and [ 18 F] ASEM lacks receptor specificity. To address this, we developed novel chemogenetic ligands with improved brain permeability and radiolabeled them with fluorine-18. Two candidates, PSG07 and PSN09, showed a high-affinity and potent agonist activity at PSAM 4 -GlyR and PSAM 4 -5-HT 3 receptors. Monkey PET imaging showed tracer localization at the PSAM 4 -GlyR expression site, with [ 18 F] PSN09 displaying a detectable signal. Functional imaging with [ 18 F]FDG further confirmed neuronal inhibition following administration of PSG07 and PSN09 . These findings highlight PSG07 and PSN09 as promising chemogenetic actuators with the potential as radioligands for translational PET imaging in nonhuman primates.