Assessment of Dynamic Neurotransmitter Changes with Bolus or Infusion Delivery of Neuroreceptor Ligands

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Abstract
To describe the effect of endogenous dopamine on [11C]raclopride binding, we previously extended the conventional receptor ligand model to include dynamic changes in neurotransmitter concentration. Here, we apply the extended model in simulations of neurotransmitter competition studies using either bolus or bolus-plus-infusion (B/I) tracer delivery. The purpose of this study was (1) to develop an interpretation of the measured change in tracer binding in terms of underlying neurotransmitter changes, and (2) to determine tracer characteristics that maximize sensitivity to neurotransmitter release. A wide range of kinetic parameters was tested based on existing reversible positron emission tomography tracers. In simulations of bolus studies, the percent reduction in distribution volume (Δ V) caused by a neurotransmitter pulse was calculated. For B/I simulations, equilibrium was assumed, and the maximum percent reduction in tissue concentration (Δ C) after neurotransmitter release was calculated. Both Δ V and Δ C were strongly correlated with the integral of the neurotransmitter pulse. The values of Δ V and Δ C were highly dependent on the kinetic properties of the tracer in tissue, and Δ V could be characterized in terms of the tissue free tracer concentration. The value of Δ V was typically maximized for binding potentials of ~3 to 10, with Δ C being maximized at binding potentials of ~1 to 2. Both measures increased with faster tissue-to-blood clearance of tracer and lower nonspecific binding. These simulations provide a guideline for interpreting the results of neurotransmitter release studies and for selecting radiotracers and experimental design.

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