title: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride.
abstract: Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: Fuji
authors.initials: F
authors.lastname: Yokoi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.forename: Kathleen
authors.initials: K
authors.lastname: Biziere
authors.forename: Massoud
authors.initials: M
authors.lastname: Stephane
authors.forename: Ahmet S
authors.initials: AS
authors.lastname: Dogan
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Hayden
authors.initials: H
authors.lastname: Ravert
authors.forename: Ajit
authors.initials: A
authors.lastname: Suri
authors.forename: Steven
authors.initials: S
authors.lastname: Bramer
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics*; D020891:Raclopride; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D020891:Raclopride; D000068180:Aripiprazole