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

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Kanerva H, Vilkman H, Nagren K, Kilkku O, Kuoppamaki M, Syvalahti E, Hietala J

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

Psychopharmacology (Berl). 1999 Jul;145(1):76-81.

PubMed ID

10445375 [ View in PubMed

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Abstract

RATIONALE: 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.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Deramciclane	5-hydroxytryptamine receptor 2A	Protein	Humans	Unknown	Antagonist	Details