[(18)F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT(1A) receptors in humans

PURPOSE: F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT(1A) receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [(18)F]F13640 binds preferentially to functional 5-HT(1A) receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT(1A) receptors by [(18)F]F13640 in humans and describe a simplified model for its quantification. METHODS: PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). RESULTS: [(18)F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [(18)F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. CONCLUSION: The favorable brain labeling and kinetic profile of [(18)F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT(1A) receptors, unlike previous radiopharmaceuticals that act as antagonists. [(18)F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. TRIAL REGISTRATION. Trial Registration EudraCT 2017–002,722-21. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-06103-1.