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 [¹¹C]<b>uPSEM792</b> shows poor brain penetration, and [¹⁸F]<b>ASEM</b> lacks receptor specificity. To address this, we developed novel chemogenetic ligands with improved brain permeability and radiolabeled them with fluorine-18. Two candidates, <b>PSG07</b> and <b>PSN09</b>, showed a high-affinity and potent agonist activity at PSAM⁴-GlyR and PSAM⁴-5-HT₃ receptors. Monkey PET imaging showed tracer localization at the PSAM⁴-GlyR expression site, with [¹⁸F]<b>PSN09</b> displaying a detectable signal. Functional imaging with [¹⁸F]FDG further confirmed neuronal inhibition following administration of <b>PSG07</b> and <b>PSN09</b>. These findings highlight <b>PSG07</b> and <b>PSN09</b> as promising chemogenetic actuators with the potential as radioligands for translational PET imaging in nonhuman primates.