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

• Published in: Psychopharmacologia 1999-07, Vol.145 (1), p.76-81
• Main Authors: KANERVA, H, VILKMAN, H, NAGREN, K, KILKKU, O, KUOPPAMÄKI, M, SYVÄLAHTI, E, HIETALA, J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Animals; Biological and medical sciences; Blood-brain barrier; Bornanes - administration & dosage; Bornanes - blood; Bornanes - metabolism; Cerebellum; Cerebral Cortex - chemistry; Cortex (frontal); Dopamine Antagonists - metabolism; Dosage; Dose-Response Relationship, Drug; Humans; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oral administration; Pharmacology. Drug treatments; Positron emission tomography; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Risperidone - metabolism; Serotonin Antagonists - administration & dosage; Serotonin Antagonists - blood; Serotonin Antagonists - metabolism; Serotonin S2 receptors; Serotoninergic system; Spiperone; Tomography; Tomography, Emission-Computed
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s002130051034

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. 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. 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. 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.