2. Academic Validation
  3. Discovery of Fluorinated Ultrapotent Chemogenetic Ligands for PET Imaging and Neural Modulation in Nonhuman Primates

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

  • J Med Chem. 2026 Feb 12;69(3):2773-2788. doi: 10.1021/acs.jmedchem.5c02679.
Sridhar Goud Nerella 1,  Jeih-San Liow 1,  Bing Li 2,  Adrian E S Jenson 1,  Matilah T Pamie-George 1,  Sami S Zoghbi 1,  Juan L Gomez 3,  Michael Michaelides 3,  Chris Magnus 4,  Scott M Sternson 4,  Barry J Richmond 2,  Mark A G Eldridge 2 5,  Sanjay Telu 1,  Robert B Innis 1,  Victor W Pike 1
Affiliations

Affiliations

  • 1 Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 2 Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 3 Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, United States.
  • 4 Department of Neurosciences, University of California, San Diego, California 92093, United States.
  • 5 Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.
PMID: 41549782 DOI: 10.1021/acs.jmedchem.5c02679
Abstract

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.

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