DOSE-DEPENDENT OCCUPANCY OF CENTRAL DOPAMINE-D(2) RECEPTORS BY THE NOVEL NEUROLEPTIC CP-88,059-01 - A STUDY USING POSITRON EMISSION TOMOGRAPHY AND C-11 RACLOPRIDE

Positron emission tomography (PET) and C-11-raclopride were used to me asure the occupancy of central dopamine D2 receptors by a new neurolep tic, CP-88,059-1. In a double blind dose escalation study, seven healt hy male subjects received a predose of between 2 mg and 60 mg CP-88,05 9-1, 5 h before PET scanning. One additional subject was assigned to p lacebo predose. Receptor occupancy was defined as the percentage reduc tion in binding potential compared with that seen in the subject predo sed with placebo and with that seen in seven unmedicated normal volunt eers previously studied. Binding of C-11-raclopride decreased in a dos e dependent manner, and 85% dopamine D2 receptor occupancy was achieve d with the highest dose of CP-88,059-1. The findings confirm that brai n dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The stu dy highlights the potential of positron emission tomography in the pre clinical evaluation of new drugs.