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

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 B_max (i.e., the number of binding sites) and K_D⁻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 B_maxK_D⁻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.