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Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369

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Abstract

Rationale

The serotonin 5-HT1B receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B receptor antagonist with potential antidepressant properties.

Objectives

To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT1B receptors using PET and the radioligand [11C]AZ10419369.

Methods

PET studies with [11C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1–40 mg).

Results

After administration in non-human primates and human subjects, AZD3783 reduced regional [11C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K i,plasma) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively.

Conclusions

The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT1B receptors with a similar in vivo affinity for human and monkey receptors. [11C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT1B receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT1B receptor compounds.

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Acknowledgments

The authors thank all members of the PET group at the Karolinska Institutet, Christina M. Resuello, and the Bioanalytical section of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Wilmington, DE for the excellent technical assistance during this study. The work at Karolinska Institutet was supported by a grant from AstraZeneca and the Swedish Science Council (VR 09114).

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Authors and Affiliations

  1. Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska University Hospital, R5:02, 17176, Stockholm, Sweden

    Katarina Varnäs, Per Karlsson, Zsolt Cselényi, Christer Halldin & Lars Farde

  2. AstraZeneca Pharmaceuticals Clinical Neuroscience, 151 85, Södertälje, Sweden

    Svante Nyberg, Matts Kågedal, Zsolt Cselényi & Lars Farde

  3. AstraZeneca Pharmaceuticals CNS Discovery, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    M. Edward Pierson

  4. AstraZeneca Pharmaceuticals Clinical Pharmacology, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    Dennis McCarthy, Alan Xiao & Minli Zhang

Authors
  1. Katarina Varnäs
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  2. Svante Nyberg
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  3. Per Karlsson
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  4. M. Edward Pierson
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  5. Matts Kågedal
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  6. Zsolt Cselényi
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  7. Dennis McCarthy
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  8. Alan Xiao
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  9. Minli Zhang
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  10. Christer Halldin
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  11. Lars Farde
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Correspondence to Katarina Varnäs.

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Varnäs, K., Nyberg, S., Karlsson, P. et al. Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369. Psychopharmacology 213, 533–545 (2011). https://doi.org/10.1007/s00213-011-2165-z

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  • DOI: https://doi.org/10.1007/s00213-011-2165-z

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