Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study.
BACKGROUND
Deramciclane fumarate is a new 5-HT2A and 5-HT2C receptor antagonist with putative anxiolytic effects. In the present study the binding of deramciclane to serotonin 5-HT2A receptors in frontal cortex of healthy male volunteers was studied using [11C]-N-methyl spiperone ([11C]-NMSP) and positron emission tomography.


METHODS
The receptor occupancy percentage was assessed by the means of inhibition of [11C]-NMSP from the 5-HT2A receptors in the frontal cortex. Single oral doses of 20, 50 and 150 mg deramciclane were given to three subjects at each dose level (total n = 9). The receptor occupancy was measured before deramciclane and at 3 and 6 h post-dosing except at the 20 mg dose level where only the 3-h measurement was done. The occupancy percentage was calculated with the ratio method using cerebellum as a reference area.


RESULTS
Deramciclane inhibited [11C]-NMSP binding dose and concentration dependently. However, deramasciclane inhibited maximally only 52% of the [11C]-NMSP binding in the frontal cortex, indicating a non-5-HT2A receptor binding component of this radioligand in frontal cortex. On average, specific [11C]-NMSP binding cerebellum ratios below 0.355 were not possible to achieve in this population. The 52% inhibition was regarded to represent near 100% 5-HT2A receptor occupancy. The 50 and 90% receptor 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 in the frontal cortex in a saturable manner in vivo. Consequently, the increase in deramciclane concentration in plasma above 70 ng/ml will not result in major increase in the 5-HT2A receptor occupancy in the brain.
Kanerva
H
H
Orion Corporation, Orion Pharma, Espoo, Finland.
Vilkman
H
H
Någren
K
K
Kilkku
O
O
Kuoppamäki
M
M
Syvälahti
E
E
Hietala
J
J
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001892:Camphanes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry*; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D018967:Risperidone / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D001892:Camphanes; D018492:Dopamine Antagonists; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D018967:Risperidone; C060555:deramciclane