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 [C-11]N-methylspiperone ([C-11]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 [C-11]NMSP was inhibited dose-dependently. After administration of 6 mg of IMDL 100,907 the inhibition was 70%, corresponding to a 6-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.