Evaluation of dopamine D₂/D₃ and serotonin 5-HT₂A receptor occupancy for a novel antipsychotic, lurasidone, in conscious common marmosets using small-animal positron emission tomography.

RATIONALE: Lurasidone is a novel antipsychotic drug with potent binding affinity for dopamine D(2) and serotonin (5-hydroxytryptamine, 5-HT)(2A), 5-HT(7), and 5-HT(1A) 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(2)/D(3) and serotonin 5-HT(2A) 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 [(11)C]raclopride and [(11)C]R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907) for D(2)/D(3) and 5-HT(2A) receptors, respectively.

RESULTS

Increases in brain D(2)/D(3) 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(2A) receptor occupancy in the frontal cortex within the same dose range, while olanzapine showed broadly comparable 5-HT(2A) and D(2)/D(3) receptor occupancies.

CONCLUSIONS

Compared with olanzapine, lurasidone preferentially binds to D(2)/D(3) receptors rather than 5-HT(2A) receptors in common marmosets. These results suggest that the contribution of in vivo 5-HT(2A) 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.