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Dose-dependent effects of the CRF1 receptor antagonist R317573 on regional brain activity in healthy male subjects

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Abstract

Background

Corticotropin-releasing factor receptor type 1 (CRF1) antagonists have been proposed as therapeutic agents in the treatment of mood and anxiety disorders although clinical evidence supporting their development and understanding of a dose–response relationship has been lacking.

Methods

We tested two doses of the CRF1 antagonist R317573 for effects on regional cerebral glucose metabolism (rCMglu) using [18F] fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) following single-dose challenges in a double-blind, placebo-controlled, cross-over design, in 12 healthy male volunteers.

Results

Single 30- and 200-mg doses of R317573 resulted in dose-related changes in rCMglu. Relative increases in rCMglu were observed in frontal cortical regions while relative decreases occurred in the putamen and right amygdala after both doses. Relative decreases occurred in cerebellum and right parahippocampal gyrus following the higher dose.

Conclusions

R317573 appears to produce acute dose-dependent changes in rCMglu. Effects occurred in regions that may be behaviorally relevant to mood and anxiety disorders. In some regions, these effects may be related to the receptor (target) density. Measuring acute effects on rCMglu with FDG-PET may offer a method for defining pharmacologically active doses for central nervous system targets for which selective radiotracers are lacking.

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Acknowledgments

We would like to thank Taisho Pharmaceutical Co., Ltd. for their efforts in the identification and characterization of R317573 and their collaboration in clinical studies with the compound. We would like to thank Stijn Dirix, Michel Koole, Hendrikje Jeandarme, Dominique Vanderghinste, Tjibbe de Groot, and Marva Bex (University Hospital and K.U. Leuven) and Anne Van Hecken and Jo Van Effen (Center for Clinical Pharmacology, University Hospital Gasthuisberg, K.U. Leuven) for their skillful help during tracer production, project management, and data acquisition. This study was sponsored by Johnson & Johnson Pharmaceutical Research and Development (J&JPRD), Beerse, Belgium. Study number: R317573DEP1005.

Disclosure/Conflict of interest

MES, PvdA, EM, and TS are employees of J&JPRD. RA, TB, JdH, and KVL have provided professional services to J&JPRD based on service provider contracts.

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Authors and Affiliations

  1. Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Mark E. Schmidt, Peter van der Ark, Erik Mannaert & Thomas Steckler

  2. Abiant, Inc., Deerfield, IL, USA

    Randolph D. Andrews & Terry Brown

  3. Center for Clinical Pharmacology, University Hospital Gasthuisberg (K.U. Leuven), Leuven, Belgium

    Jan de Hoon

  4. Division of Nuclear Medicine, University Hospital and K.U. Leuven, Leuven, Belgium

    Koen Van Laere

Authors
  1. Mark E. Schmidt
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  2. Randolph D. Andrews
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  3. Peter van der Ark
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  4. Terry Brown
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  5. Erik Mannaert
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  6. Thomas Steckler
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  7. Jan de Hoon
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  8. Koen Van Laere
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Corresponding author

Correspondence to Mark E. Schmidt.

Additional information

Clinical trial identification: Study number: R317573DEP1005; title: A randomized, double-blind, placebo-controlled, crossover study in healthy young male subjects to explore acute effects of R317573 on regional brain glucose metabolism using [18F] fluoro-deoxyglucose (FDG) positron emission tomography (PET); Eudract: 2006-002220-42.

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Schmidt, M.E., Andrews, R.D., van der Ark, P. et al. Dose-dependent effects of the CRF1 receptor antagonist R317573 on regional brain activity in healthy male subjects. Psychopharmacology 208, 109–119 (2010). https://doi.org/10.1007/s00213-009-1714-1

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  • DOI: https://doi.org/10.1007/s00213-009-1714-1

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