Active cyamemazine metabolites in patients treated with cyamemazine

Rationale Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine [D.sub.2] receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin [5-HT.sub.2A] receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for [5-HT.sub.2A] receptors as cyamemazine, whereas its [D.sub.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.sub.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.sub.2] and serotonin [5-HT.sub.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.sub.2] and serotonin [5-HT.sub.2A] RO were assessed at steady-state cyamemazine plasma levels using [[sup.11]C]raclopride and [[sup.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.sub.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.sub.2] RO ([r.sup.2] = 0.942) and extrastriatal [5-HT.sub.2A] RO ([r.sup.2] = 0.901). The estimated [K.sub.i(app)] value of N-desmethyl cyamemazine for striatal [D.sub.2] receptors was about fivefold higher than that for extrastriatal [5-HT.sub.2A] receptors (48.7 vs. 10.6 nM). Striatal [D.sub.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 significant