title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakazawa
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yokoyama
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishimura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horisawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuma
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002144:Callithrix; D003342:Corpus Striatum / Q000378:metabolism; D054833:Isoindoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069056:Lurasidone Hydrochloride; D008297:Male; D000077152:Olanzapine; D049268:Positron-Emission Tomography; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D054833:Isoindoles; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D001569:Benzodiazepines; D000077152:Olanzapine; D000069056:Lurasidone Hydrochloride