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

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.

Pathways for Small Molecule Delivery to the Central Nervous System across the Blood-Brain Barrier

“…A recent description of this approach is for the evaluation of a second-generation antipsychotic drug Lurasidone in non-human primates. 96 PET imaging pre-and post-drug administration confirms drug occupancy of D 2 and 5-HT 2 A receptors with 11 C-raclopride and 11 C-R-(+)-α-(2,3dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol, respectively.…”

Positron Emission Tomography in CNS Drug Discovery and Drug Monitoring

“…Thus, PET studies have taught drug developers to design D 2 antagonists that should show only a modest slope of dose/binding curves for striatal D 2 receptors and/or provide a extensive 5HT 2A binding at doses evoking 65–80% D 2/3 occupancy. For example, this approach served for evaluation of the recently launched AP lurasidone: Nakazawa and co-workers showed that this compound attained lesser 5-HT 2A occupancy than did olanzapine, as revealed with the highly selective radiotracer [ 11 C]volinanserin . Clinical dose findings for this compound was also performed with [ 11 C]raclopride PET, revealing that more than 40 mg is necessary to provide effective D 2/3 receptor occupancies .…”

“…For example, this approach served for evaluation of the recently launched AP lurasidone: Nakazawa and co-workers showed that this compound attained lesser 5-HT 2A occupancy than did olanzapine, as revealed with the highly selective radiotracer [ 11 C]volinanserin. 126 Clinical dose findings for this compound was also performed with [ 11 C]raclopride PET, revealing that more than 40 mg is necessary to provide effective D 2/3 receptor occupancies. 127 Another PET investigation of lurasidone in a large group of schizophrenia patients, however, showed that daily doses only modestly correlate with receptor occupancies, which were, however, predicted by plasma levels of the compound, along with its active metabolites.…”

Commentary on Boileau et al. (2013): Distinguishing D2/D3 dopaminergic contributions to addictions

“…In addition to allowing for detailed associations between neurotransmitter systems and behavior, dual radiotracer approaches may provide insight into receptor profiles of antipsychotic and antidepressant medications, yielding more detailed accounts of receptor occupancies in vivo . Thus, the use of more than one radiotracer in a single study to gain detailed information about neurotransmitter systems of known importance is a novel area of research for which the Boileau et al .…”