Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration - a positron emission tomography study

Rationale: Deramciclane fumarate is a new 5-HT2A and 5-HT2C receptor antago nist with putative anxiolytic effects. In the present study the binding of deramciclane to serotonin 5-HT2A receptors in frontal cortex of healthy mal e volunteers was studied using [C-11]-N-methyl spiperone ([C-11]-NMSP) and positron emission tomography. Methods: The receptor occupancy percentage wa s assessed by the means of inhibition of [C-11]-NMSP from the 5-HT2A recept ors in the frontal cortex. Single oral doses of 20, 50 and 150 mg deramcicl ane were given to three subjects at each dose level (total n = 9). The rece ptor occupancy was measured before deramciclane and at 3 and 6 h post-dosin g except at the 20 mg dose level where only the 3-h measurement was done. T he occupancy percentage was calculated with the ratio method using cerebell um as a reference area. Results: Deramciclane inhibited [C-11]-NMSP binding dose and concentration dependently. However, deramasciclane inhibited maxi mally only 52% of the [C-11]-NMSP binding in the frontal cortex, indicating a non-5-HT2A receptor binding component of this radioligand in frontal cor tex. On average, specific [C-11]-NMSP binding cerebellum ratios below 0.355 were not possible to achieve in this population. The 52% inhibition was re garded to represent near 100% 5-HT2A receptor occupancy. The 50 and 90% rec eptor occupancies were reached at deramciclane plasma concentrations of 21 ng/ml and 70 ng/ml, respectively. Conclusions: Deramciclane penetrates the blood-brain barrier in humans. Deramciclane binds to the 5-HT2A receptors i n the frontal cortex in a saturable manner in vivo. Consequently, the incre ase in deramciclane concentration in plasma above 70 ng/ml will not result in major increase in the 5-HT2A receptor occupancy in the brain.