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

TLDR

The study proposes an in vivo PET method using radiolabeled spiperone to quantitatively characterize neuroleptic binding sites and introduces the binding potential as a measure of tissue ligand‑binding capacity. The method uses a mathematical model of transport and nonspecific binding in the brain, applied to sequential PET scans of baboons injected with carrier‑added [18F]spiperone. The model reveals that Bmax and KD−1 cannot be separately determined with tracer PET, but estimates nonspecific binding at 94–95 % and striatal binding potential 17–22, matching in vitro values, demonstrating that PET can quantitatively assess drug binding sites and may aid disease investigation.

Abstract

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 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 max K 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 [ 18 F]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 cm 3 /(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.