Clozapine can induce high dopamine D(2) receptor occupancy in vivo.
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.
Suhara
Tetsuya
T
Brain Imaging Project, National Institute of Radiological Sciences, Chiba, Japan. suhara@nirs.go.jp
Okauchi
Takashi
T
Sudo
Yasuhiko
Y
Takano
Akihiro
A
Kawabe
Koichi
K
Maeda
Jun
J
Kapur
Shitij
S
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
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D020891:Raclopride; D003024:Clozapine