Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain.
Selective 5-hydroxytryptamine-2A (5-HT2A) antagonism has been proposed as a mechanism of atypical antipsychotic drug action. MDL 100,907, a new selective 5-HT2A receptor antagonist, has high affinity in vitro for 5-HT2A receptors and is being developed as a potential antipsychotic drug. In this study, neocortical 5-HT2A receptor occupancy was measured in six healthy male volunteers after placebo and escalating single doses (1-72 mg) of MDL 100,907 using positron emission tomography and the nonspecific radioligand [11C]N-methylspiperone ([11C]NMSP). Receptor occupancy was calculated using a ratio-equilibrium analysis, assuming that maximal radioligand binding inhibition represents 100% 5-HT2A receptor occupancy. Plasma concentrations of MDL 100,907 were measured with high-pressure liquid chromatography. The pharmacokinetic parameters area under the curve and peak plasma concentration increased linearly with dose, with rapid absorption and a 6- to 9-hour elimination half-life. The neocortical binding of [11C]NMSP was inhibited dose-dependently. After administration of 6 mg of MDL 100,907 the inhibition was 70%, corresponding to a 5-HT2A receptor occupancy of 90%. The calculated maximal inhibition was 77%. These observations indicate that MDL 100,907 passes the blood-brain barrier and binds to 5-HT2A receptors in a saturable manner in the living human brain. Repeated doses of MDL 100,907, 10 mg/day or more, should induce a sustained 5-HT2A receptor occupancy in most patients. Thus, MDL 100,907 provides a suitable tool to evaluate the potential of selective 5-HT2A receptor antagonism in the treatment of schizophrenia.
Andrée
B
B
Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden. bengt.andree@neuro.ks.se
Nyberg
S
S
Ito
H
H
Ginovart
N
N
Brunner
F
F
Jaquet
F
F
Halldin
C
C
Farde
L
L
D001667:Binding, Competitive / Q000502:physiology; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000000981:diagnostic imaging*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D012016:Reference Values; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed
D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C079049:volinanserin