[18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans

Abstract Purpose:F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here we characterize brain labeling of 5-HT1A receptors by [18F]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) and test-retest protocol. 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:[18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed excellent correlation with kinetic models using AIF. Considering test-retest parameters and the prolonged binding kinetics of [18F]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 [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640’s kinetic properties allow injection out of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry.Trial Registration EudraCT 2017-002722-21