Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics

There is great interest in positron emission tomography ( PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer ( a. k. a., its ` vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer- specific predictor, the PET Displacement Sensitivity ( PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine ( DA). The PDS predicts the change in binding potential ( DBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D-2/D-3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride ( highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride ( lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for DBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D-2/D-3 tracer. The values are in good agreement with the PDS- predicted rank order of sensitivity to displacement.