Receptor occupancy studies are becoming commonplace for verifying drug mechanism of action and selecting early development candidates. Positron emission tomography (PET) has been applied to pharmacodynamic (PD) studies in several therapeutic areas including neurology, cardiology, and oncology. Prospective use of PET to define dosing requirements has been proposed particularly for central nervous system (CNS) Ytargeted drugs; however, correlations with clinical outcomes have been mostly anecdotal and not causally established.

THE PROMISE OF PET AND RECEPTOR OCCUPANCY THEORY PET, among other uses, enables the measurement of receptor occupancy; the percentage of target receptors occupied can be quantified as a function of the dose, and the time course of occupancy can be evaluated relative to a proposed regimen. Efficacy in the pharmacologic sense is assumed to be related to receptor occupancy, although this is a theoretical axiom. As a clinical research tool, PET can provide unique information about the distribution and properties of drug targets in vivo, disease-induced changes in biochemical and physiological processes, treatment response, and drug disposition. PET can also be used to assess directly the pharmacokinetics and PD of new drugs, both in laboratory animals and in humans. Its potential for biomarker identification and transporter mapping and kinetics also represents the new frontiers. 1 Ultimately, the insight PET brings into drug development must be interpreted in the context of a mechanistic rationale supported by exposureoutcome relationships. The scientific literature is unfortunately replete with examples of failures in drug development resulting from the lack of a similar mechanistic rationale. Linkage to drug activity can be pursued via any number of classic PD models; however, receptor occupancy itself and the myriad of other factors that may contribute to the desired pharmacodynamic or clinical effect (s) are typically more complex. The occupancy model was the first quantitative description put forward2 to explain the activity of drugs at receptors. It is based on mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. In particular, the magnitude of the response is directly proportional to the amount of drug bound to the receptor, with maximum response elicited once all receptors are occupied at equilibrium. Clark’s receptor occupancy model was proposed under the following assumptions: & Receptors must possess structural and steric specificity. & Receptors are saturable, and there is a finite number of binding sites. & Receptors must possess high affinity for endogenous ligand (s) at physiological concentrations. & Once the endogenous ligand binds to the receptor, some early recognizable chemical events must occur.