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Change in Binding Potential as a Quantitative Index of Neurotransmitter Release Is Highly Sensitive to Relative Timing and Kinetics of the Tracer and the Endogenous Ligand

¹ Division of Research, Section of Imaging Science, Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana
² Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indiana University—Purdue University, Indianapolis, Indiana

Change in binding potential (BP) is often used to indicate alterations in neurotransmitter concentration in response to stimuli. Increasingly, it is being used in bolus studies as a quantitative index of dopamine (DA) release. In bolus studies, however, BP is an average quantity over time that is influenced by the dynamics of both the tracer and the neurotransmitter. We sought to characterize the sensitivity of BP to changes in endogenous DA concentration and to elucidate possible biases in BP with respect to timing of task-induced or drug-induced increases in DA. Methods: Noiseless simulations of ¹¹C-raclopride PET curves were performed in a specific binding region with concomitant increases in endogenous DA. DA changes were modeled as -functions, -variates, or as realistic drug-induced increases in DA over time, based on published results. Graphical estimation of BP with a reference region as the input function was used, with a multilinear formulation of the operational equation. Results: Simulations demonstrated that BP (a) is linear over a narrow range of integrated DA release, (b) has an inherent sensitivity to timing of DA perturbations, and (c) could incorrectly infer the relative amounts of DA released between subject populations or experimental conditions. These results are explained by what we term the effective weighted availability, which describes the interaction of a DA function and free raclopride concentration over time and follows directly from earlier work. Conclusion: We illustrate how, under quite plausible circumstances, BP may lead to erroneous conclusions about relative amounts of DA released after dopaminergic perturbations. Our findings caution against using BP as a quantitative or rank index of DA release when comparing different dopaminergic stimuli.

Key Words: binding potential • kinetics • sensitivity • bias • neurotransmitter release