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Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and11C-raclopride

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Abstract

Positron emission tomography (PET) and11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.

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Authors and Affiliations

  1. MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, W12 OHS, London, UK

    C. J. Bench, A. A. Lammertsma, R. J. Dolan, P. M. Grasby, D. J. Turton, S. Osman & R. S. J. Frackowiak

  2. Royal Free Hospital and School of Medicine, Rowland Hill Street, NW3 2QG, London, UK

    C. J. Bench, R. J. Dolan & P. M. Grasby

  3. Charterhouse Clinical Research Unit, The Royal Masonic Hospital, Ravenscourt Park, W6 OTN, London, UK

    S. J. Warrington

  4. Pfizer Central Research, CT13 9NJ, Sandwich, Kent, UK

    K. Gunn & M. Cuddigan

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  1. C. J. Bench
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  2. A. A. Lammertsma
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  3. R. J. Dolan
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  4. P. M. Grasby
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  5. S. J. Warrington
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  6. K. Gunn
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  7. M. Cuddigan
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  8. D. J. Turton
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  9. S. Osman
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  10. R. S. J. Frackowiak
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Bench, C.J., Lammertsma, A.A., Dolan, R.J. et al. Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and11C-raclopride. Psychopharmacology 112, 308–314 (1993). https://doi.org/10.1007/BF02244926

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  • DOI: https://doi.org/10.1007/BF02244926

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