Radiopharmacological evaluation of [18F]F13640, a novel 5-HT1A receptor agonist

Objectives Brain serotonin 1A receptors (5-HT1A) exist in high- and low-affinity states. It is known that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT1A receptors, particularly in pathophysiological processes. Since all available fluorinated PET 5-HT1A radiopharmaceuticals are antagonists, it is of great interest to develop a fluorine-18 labelled agonist. The radiotracer candidates we proposed recently had a too low (2.24 nM) or a to high (0.3 nM) affinity for 5-HT1A receptors (Eur J Nucl Med 2010, 37(3): 594-605; J Nucl Med 2012, 53(6): 934-41). We propose now an agonist with an intermediate affinity for 5-HT1A receptors.

Methods F13640, 3-chloro-4-fluorophenyl-[4-fluoro-4-([(5-methylpyridin-2yl)methylamino]methyl)piperidin-1-yl]methanone is a novel ligand with high affinity (1nM) and high selectivity for 5-HT1A receptors. Its nitro-precursor was synthesized and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiographies in rat brain and PETscans on rats and cats. All results were compared with simultaneous studies using the antagonist [18F]MPPF, a validated 5-HT1A radiopharmaceutical.

Results The chemical and radiochemical purities of [18F]F13640 were > 99%. [18F]F13640 in vitro binding was consistent with the 5-HT1A receptors distribution. Ex vivo and in vivo studies revealed that the radiotracer readily entered the brain and displayed a specificity for 5-HT1A receptor rich regions. The formation of brain radioactive metabolites was excluded.

Conclusions [18F]F13640 has suitable characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT1A receptors. A quantification approach with kinetic modelling is needed to complete this work and prepare its translation to human studies.