title: Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine.
abstract: The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Kodaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Harumasa
authors.initials: H
authors.lastname: Takano
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Takahashi
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Arakawa
authors.forename: Michie
authors.initials: M
authors.lastname: Miyoshi
authors.forename: Masaki
authors.initials: M
authors.lastname: Okumura
authors.forename: Tatsui
authors.initials: T
authors.lastname: Otsuka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000328:Adult; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D018967:Risperidone / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D020891:Raclopride; C009074:N-n-propylnorapomorphine; D018967:Risperidone; D001058:Apomorphine