title: 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone.
abstract: It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia.
authors.affiliation: Department of Psychiatry and Psychology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nyberg
authors.forename: L
authors.initials: L
authors.lastname: Farde
authors.forename: L
authors.initials: L
authors.lastname: Eriksson
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: B
authors.initials: B
authors.lastname: Eriksson
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D018967:Risperidone; D012457:Salicylamides / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007555:Isoxazoles; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012457:Salicylamides; D020891:Raclopride; D018967:Risperidone