Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT2A receptor occupancy as measured by positron emission tomography (PET)

Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D 2 receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT 2A receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine ( N -desmethyl cyamemazine) has similar affinity for 5-HT 2A receptors as cyamemazine, whereas its D 2 receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2–3):142–147, 2008 ). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT 2A receptors. Objectives The objective of this study is to measure steady-state plasma levels of N -desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D 2 and serotonin 5-HT 2A receptor occupancies (RO) assessed by positron emission tomography (PET). Methods Eight patients received Tercian® 37.5, 75, 150, or 300 mg/day according to their symptoms. Dopamine D 2 and serotonin 5-HT 2A RO were assessed at steady-state cyamemazine plasma levels using [ 11 C]raclopride and [ 11 C] N -methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant ( K i ) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. Results After 6 days of cyamemazine administration, plasma N -desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377–384, 2005 ). Plasma levels of N -desmethyl cyamemazine were closely related to striatal D 2 RO ( r 2 = 0.942) and extrastriatal 5-HT 2A RO ( r 2 = 0.901). The estimated K i(app) value of N -desmethyl cyamemazine for striatal D 2 receptors was about fivefold higher than that for extrastriatal 5-HT 2A receptors (48.7 vs. 10.6 nM). Striatal D 2 RO increased with the plasma levels of N -desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N -desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT 2A and D 2 receptor occupancy. Conclusions In patients orally given cyamemazine,