Introduction: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [18F]2FNQ1P, a new PET radiotracer of 5-HT6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target.
Methods: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat.
Results: In all species, autoradiography data revealed high binding levels of [18F]2FNQ1P in cerebral regions with high 5-HT6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided KD and Bmax values of respectively 1.34 nM and 0.03 pmol·mg-1 in rat, 0.60 nM and 0.04 pmol·mg-1 in pig, 1.38 nM and 0.07 pmol·mg-1 in non-human primate, and 1.39 nM and 0.15 pmol·mg-1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [18F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection).
Conclusion: These radiopharmacological data confirm that [18F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT6 receptors and suggest that it could be used as a radiopharmaceutical in humans.
Keywords: 5-HT(6) receptor; PET radiotracer development; Serotonin.
Copyright © 2020 Elsevier Inc. All rights reserved.