Radiosynthesis and preclinical evaluation of 18F-F13714 as a fluorinated 5-HT1A receptor agonist radioligand for PET neuroimaging.

Unlabelled: PET brain imaging of the serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) receptor has been widely used in clinical studies. Currently, only a few well-validated radiolabeled antagonist tracers are available for in vivo imaging of this central receptor. 5-HT(1A) receptors exist in high- and low-affinity states, depending on their coupling to G proteins. Agonists bind preferentially to receptors in the high-affinity state and thereby could provide a measure of functional 5-HT(1A) receptors. Therefore, it is of great interest to develop an (18)F-labeled full agonist 5-HT(1A) receptor radiotracer. In this study, we radiolabeled the high-affinity 5-HT(1A) receptor agonist (18)F-F13714 and investigated its potential as a PET tracer.

Methods: F13714 nitro precursor was synthesized and radiolabeled via a fluoronucleophilic substitution. In vitro binding assays were performed using established protocols. Radiopharmacologic evaluations included in vitro autoradiography in rat brain and PET scans on anesthetized cats.

Results: The chemical and radiochemical purities of (18)F-F13714 were greater than 98%. F13714 has a high affinity (0.1 nM) and selectivity for 5-HT(1A) receptors. In vitro (18)F-F13714 binding in rats was consistent with the known 5-HT(1A) receptors distribution (hippocampus and cortical areas) and was particularly high in the dorsal raphe. In vitro binding of (18)F-F13714 was blocked in a dose-dependent fashion by WAY100635, the prototypical 5-HT(1A) antagonist, and by the endogenous agonist, serotonin (5-HT). Addition of Gpp(NH)p also inhibited in vitro (18)F-F13714 binding, consistent with a preferential binding of the compound to G-protein-coupled receptors. Ex vivo tissue measurements in rat revealed an absence of brain radioactive metabolites. In vivo studies showed that the radiotracer entered the cat brain readily and displayed a preferential labeling of 5-HT(1A) receptors located in cingulate cortex. In vivo labeling was prevented by preinjection of WAY100635.

Conclusion: (18)F-F13714 is a radiofluorinated agonist that presents suitable characteristics for probing the high-affinity states of the 5-HT(1A) receptors in vitro and in vivo. Thus, it is a promising tool for investigation of 5-HT(1A) agonist binding in the living human brain.