title: Clozapine can induce high dopamine D(2) receptor occupancy in vivo.
abstract: BACKGROUND
  Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D(2) receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited.
  
  
  OBJECTIVE
  In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D(2) receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy.
  
  
  METHODS
  PET examination with [(11)C]raclopride was performed to measure the dopamine D(2) receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [(11)C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection.
  
  
  RESULTS
  Dopamine D(2) receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine.
  
  
  CONCLUSIONS
  Clozapine could occupy a high proportion of dopamine D(2) receptors. The time course of occupancy was relatively fast, with a half-life of several hours.
authors.affiliation: Brain Imaging Project, National Institute of Radiological Sciences, Chiba, Japan. suhara@nirs.go.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sudo
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawabe
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000465:Algorithms; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000187:drug effects; D003024:Clozapine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D008253:Macaca mulatta; D008297:Male; D020891:Raclopride / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D020891:Raclopride; D003024:Clozapine