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

Lookup NU author(s): Bing Li, Dr Mark EldridgeORCiD

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Abstract

© 2026 American Chemical Society. 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.

Publication metadata

Author(s): Nerella SG, Liow J-S, Li B, Jenson AES, Pamie-George MT, Zoghbi SS, Gomez JL, Michaelides M, Magnus C, Sternson SM, Richmond BJ, Eldridge MAG, Telu S, Innis RB, Pike VW

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2026

Volume: 69

Issue: 3

Pages: 2773-2788

Print publication date: 12/02/2026

Online publication date: 19/01/2026

Acceptance date: 12/01/2026

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acs.jmedchem.5c02679

DOI: 10.1021/acs.jmedchem.5c02679

PubMed id: 41549782

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