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- Title
Evaluation of dopamine D/D and serotonin 5-HT receptor occupancy for a novel antipsychotic, lurasidone, in conscious common marmosets using small-animal positron emission tomography.
- Authors
Nakazawa, Shunsuke; Yokoyama, Chihiro; Nishimura, Naohiro; Horisawa, Tomoko; Kawasaki, Akihiro; Mizuma, Hiroshi; Doi, Hisashi; Onoe, Hirotaka
- Abstract
Rationale: Lurasidone is a novel antipsychotic drug with potent binding affinity for dopamine D and serotonin (5-hydroxytryptamine, 5-HT), 5-HT, and 5-HT receptors. Previous pharmacological studies have revealed that lurasidone exhibits a preferable profile (potent antipsychotic activity and lower incidence of catalepsy) to other antipsychotic drugs, although the contribution of receptor subtypes to this profile remains unclear. Objectives: To compare target engagements of lurasidone with those of an atypical antipsychotic, olanzapine, we performed evaluation of dopamine D/D and serotonin 5-HT receptor occupancy in vivo by positron emission tomography (PET) with conscious common marmosets. Methods: We measured brain receptor occupancies in conscious common marmosets after oral administrations of lurasidone or olanzapine by PET with [C]raclopride and [C]R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907) for D/D and 5-HT receptors, respectively. Results: Increases in brain D/D receptor occupancies of both lurasidone and olanzapine, which reached >80 % at maximum, were observed in the striatum with significant correlations to plasma drug levels. However, lurasidone showed lower 5-HT receptor occupancy in the frontal cortex within the same dose range, while olanzapine showed broadly comparable 5-HT and D/D receptor occupancies. Conclusions: Compared with olanzapine, lurasidone preferentially binds to D/D receptors rather than 5-HT receptors in common marmosets. These results suggest that the contribution of in vivo 5-HT receptor blocking activity to the pharmacological profile of lurasidone might differ from olanzapine in terms of the low risk of extrapyramidal syndrome and efficacy against negative symptoms.
- Subjects
DOPAMINE receptors; ANTIPSYCHOTIC agents; SEROTONIN receptors; POSITRON emission tomography; DRUG synergism; PHARMACOLOGY; DISEASE incidence
- Publication
Psychopharmacology, 2013, Vol 225, Issue 2, p329
- ISSN
0033-3158
- Publication type
Article
- DOI
10.1007/s00213-012-2815-9