Savoxepine: striatal dopamine-D2 receptor occupancy in human volunteers measured using positron emission tomography (PET).
The extent and duration of striatal dopamine-D2 receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [11C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice. After 0.25 mg savoxepine, striatal D2 receptor occupancy peaked at 50-60% after 24-36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D2 receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3-7 h after administration and amounted to 40 to 75% at the peak time (20-29 h). This suggests that cumulative D2 receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D2 receptors with afford a good therapeutic ratio requires an alternative dosing regimen.
Leenders
K L
KL
PET Program, Paul-Scherrer Institut (PSI), Villigen, Switzerland.
Antonini
A
A
Thomann
R
R
Locher
J T
JT
Maître
L
L
Gerebtzoff
A
A
Beer
H F
HF
Ametamey
S
S
Weinreich
R
R
Gut
A
A
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003989:Dibenzoxazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D012457:Salicylamides; D013268:Stimulation, Chemical; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D003989:Dibenzoxazepines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; C052564:cipazoxapine