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EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study

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Abstract

While serotonin 5HT2-receptors have been implicated in the etiology and pharmacological treatment of a number of neuropsychiatric conditions, there are few potent and specific agents available for use in human clinical studies. EMD 281014 is a highly specific 5HT2-receptor antagonist that is currently under development. To find optimal doses for early clinical studies, we conducted a PET study using [18F]setoperone in nine healthy subjects scanned at baseline and following the administration of 1, 3, and 7 mg EMD 281014. The study drug was well tolerated by all study participants, and all doses resulted in ≥70% occupancy at frontal 5HT2-receptors 3 h after drug administration. The data suggest that daily dosing of ≥3 mg EMD 281014 should be sufficient to provide sustained high levels of 5HT2-receptor occupancy in future clinical trials.

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Acknowledgments

The authors gratefully acknowledge the volunteers for their participation; Doug Hussey, Penny Barsoum, Tabasum Hussain, Ruiping Guo and Armando Garcia for technical assistance; and Dr. Alan Wilson for supervising the radiochemical syntheses. The study was funded by Merck KGaA, Germany.

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Authors and Affiliations

  1. Department of Psychiatry, University of Toronto, Toronto, Canada

    David Mamo, Edward M. Sellers, Myroslava K. Romach & Shitij Kapur

  2. The Centre for Addiction and Mental Health, Clarke Site, Schizophrenia Program and PET Centre, 250 College Street, Toronto, ON, Canada, M5T 1R8

    David Mamo & Shitij Kapur

  3. Merck KGaA, Darmstadt, Germany

    Ewen Sedman & Joachim Tillner

  4. Ventana Clinical Research Corporation, Toronto, Canada

    Edward M. Sellers & Myroslava K. Romach

Authors
  1. David Mamo
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  2. Ewen Sedman
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  3. Joachim Tillner
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  4. Edward M. Sellers
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  5. Myroslava K. Romach
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  6. Shitij Kapur
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Correspondence to Shitij Kapur.

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Mamo, D., Sedman, E., Tillner, J. et al. EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study. Psychopharmacology 175, 382–388 (2004). https://doi.org/10.1007/s00213-004-1817-7

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  • DOI: https://doi.org/10.1007/s00213-004-1817-7

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