A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography

Authors

  • Mark A. Mintun MD,

    1. Edward Mallinckrodt Institue of Radiology Washington University School of Medicine, St Louis, MO 63110
    2. Department of Neurology and Neurosurgery (Neurology), Washington University School of Medicine, St Louis, MO 63110
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  • Marcus E. Raichle MD,

    Corresponding author
    1. Edward Mallinckrodt Institue of Radiology Washington University School of Medicine, St Louis, MO 63110
    2. McDonnel Center for Studies of Higher Brain Function Washington University School of Medicine, St Louis, MO 63110
    3. Department of Neurology and Neurosurgery (Neurology), Washington University School of Medicine, St Louis, MO 63110
    • Washington University School of Medicine, Box 8131, St Louis, MO 63110
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  • Michael R. Kilbourn PhD,

    1. Edward Mallinckrodt Institue of Radiology Washington University School of Medicine, St Louis, MO 63110
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  • G. Frederick Wooten MD,

    1. Department of Neurology and Neurosurgery (Neurology), Washington University School of Medicine, St Louis, MO 63110
    Current affiliation:
    1. Department of Neurology, University of Virginia Medical Center, Charlottesville, VA 22908
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  • Michael J. Welch PhD

    1. Edward Mallinckrodt Institue of Radiology Washington University School of Medicine, St Louis, MO 63110
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Abstract

We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD−1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD−1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added [18F]spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability–surface area product) to be in the range of 0.025 to 0.036 cm3/(s·ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favourably to in vitro values in the literature. To our knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.

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