First-in-human evaluation of 18F-mefway, a PET radioligand specific to serotonin-1A receptors

The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A-specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-(18)F-fluoromethylcyclohexane)carboxamide ((18)F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of (18)F-mefway in humans.

Dynamic (18)F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22-38 y). Scans were initiated with the injection of 192-204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of (18)F-mefway. To examine the test-retest variability of (18)F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone.

(18)F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4-0.9 at 120 min. Rapid metabolism of (18)F-mefway was observed, with no detected (18)F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7-1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test-retest variability was 8%. No evidence of radioactivity uptake in bone was observed.

(18)F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make (18)F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.