In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428

Authors

  • Dr. Dean F. Wong M.D. Ph.D.,

    Corresponding author
    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    2. Department of Environmental Health Sciences, Division of Radiation Health Sciences, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    • Division of Nuclear Medicine Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205
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  • Babington Yung,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Robert F. Dannals,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    2. Department of Environmental Health Sciences, Division of Radiation Health Sciences, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Elias K. Shaya,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    2. NIDA-ARC, Baltimore, Maryland 21224
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  • Hayden T. Ravert,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Catherine A. Chen,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Boon Chan,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Traci Folio,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Ursula Scheffel,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    2. Department of Environmental Health Sciences, Division of Radiation Health Sciences, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • George A. Ricaurte,

    1. Department of Neurology, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • John L. Neumeyer,

    1. Research Biochemical Inc., Natick, Massachusetts 01760
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  • Henry N. Wagner Jr.,

    1. Department of Radiology, Division of Nuclear Medicine, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
    2. Department of Environmental Health Sciences, Division of Radiation Health Sciences, Johns Hopkins University and Medical Institution, Baltimore, Maryland 21205
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  • Michael J. Kuhar

    1. NIDA-ARC, Baltimore, Maryland 21224
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Abstract

[11C]WIN 35,428 was evaluated as a specific in vivo radioligand for the dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [11C]WIN 35,428 accumulated in brain regions containing dopamine transporters, i.e., the striata. This accumulation was Partially blocked by prior administration of (−)cocaine (4 mg/kg, i.v. ). Placement of a unilateral lesion of dopamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [11C]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D2 dopamine receptors with [11C]NMSP in the same MPTP-treated animals showed much less reduction in the postsynaptic D2 dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [11C]WIN 35,428.

A total of ten normal human volunteers (five males and five females) with ages ranging from 19 to 81 years were studied. The caudate/cerebellar and putamen/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma sampling resulted in an average binding potential (K3/K4) of 4.98 in the caudate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses of 6 mg mazindol. Subject 5 had significant reductions of 29% in the caudate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k3/k4 ratio from 6.7 to 3.7, and 46% in the putamen k3/k4 from 4.7 to 2.5. Subject 8 had significant reductions of 20% in both the caudate/cerebellar ratio and the putamen/cerebellar ratio at 90 min.

During the human PET studies, a number of neuropsychological tests and physiological measurements were performed. No significant changes were found after administration of the [11C]WIN 35,428 alone. Taken together, these data indicate that [11C]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site. © 1993 Wiley-Liss, Inc.

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