Administration of the new COMT inhibitor OR-611 increases striatal uptake of fluorodopa

Authors

  • M. Guttman,

    1. McConneEll Brain Imaging Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • G. Léger,

    1. McConneEll Brain Imaging Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • A. Reches,

    1. Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel
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  • A. Evans,

    1. McConneEll Brain Imaging Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • H. Kuwabara,

    1. McConneEll Brain Imaging Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • J. M. Cedarbaum,

    1. Department of Neurology and Neuroscience, Cornell University, Burke Rehabilitation Center, White Plains, New York, U.S.A.
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  • Dr. A. Gjedde

    Corresponding author
    1. McConneEll Brain Imaging Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
    • Montreal Neurological Institute, 3801 University, Montreal, Quebec, Canada, H3A 2B4
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Abstract

L-Dopa is metabolized to 3–O-methyldopa (3OMD) by catechol-O- methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.

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