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]uPSEM792 shows poor brain penetration,
and [18F]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 PSAM4-GlyR and PSAM4-5-HT3 receptors. Monkey PET imaging showed tracer localization
at the PSAM4-GlyR expression site, with [18F]PSN09 displaying a detectable signal. Functional imaging with
[18F]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.