[ 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.