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Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

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Abstract

Rationale

Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Objectives

The objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine.

Methods

We examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose.

Results

We found that cariprazine occupied D2/D3 receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.

Conclusions

We conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.

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Acknowledgments

We thank the members of the Karolinska PET group for their assistance. This research was supported in part by the Intramural Program of the National Institute of Mental Health, Bethesda, Maryland, USA.

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Authors and Affiliations

  1. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, 171 76, Sweden

    Nicholas Seneca, Sjoerd J. Finnema, Christer Halldin & Balázs Gulyás

  2. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Nicholas Seneca & Robert B. Innis

  3. Gedeon Richter Ltd., Budapest, 1103, Hungary

    István Laszlovszky, Béla Kiss, Attila Horváth, Gabriella Pásztor, Margó Kapás, István Gyertyán & Sándor Farkas

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  1. Nicholas Seneca
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  2. Sjoerd J. Finnema
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  3. István Laszlovszky
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  4. Béla Kiss
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  5. Attila Horváth
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  8. István Gyertyán
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  9. Sándor Farkas
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  10. Robert B. Innis
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  11. Christer Halldin
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  12. Balázs Gulyás
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Correspondence to Balázs Gulyás.

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Christer Halldin and Balázs Gulyás have contributed equally to this work.

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Seneca, N., Finnema, S.J., Laszlovszky, I. et al. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography. Psychopharmacology 218, 579–587 (2011). https://doi.org/10.1007/s00213-011-2343-z

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