Equilibrium Methods

Another single-scan technique has been developed for quantification of receptors by using infusion to produce true equilibrium [84,134,135]. By administering tracer as a combination of bolus plus continuous infusion (B/I), constant radioactivity levels can be reached in blood and in all regions of interest. The total tissue volume of distribution can be determined from the ratio of tissue activity to metabolite-corrected plasma activity. This value will include free, non-specifically bound, and specifically bound tracer. Estimates of the nonspecific component, e.g., from a region with low receptor binding, from measurements with an inactive enantiomer, or from data acquired after displacement with excess cold ligand, can be subtracted to estimate the binding potential, Bmax/KD [136] (Kd is the dissociation equilibrium constant). Multiple infusions at different specific activities can be used to determine Bmax [137,138].

This infusion approach can be extended to provide receptor-binding data in two states: at baseline and post-stimulus (e.g., drug-induced neurotransmitter changes), with a single administration of tracer. Without infusion, such data are conventionally acquired with paired studies, each with a bolus injection. In the first study, control levels of binding are measured, for example, by determining V by compartment modeling [56] or graphical analysis [111]. Then, following the pharmacological intervention, a second measurement of binding is made with a second injection of tracer. This approach has been used successfully with the D2 ligand [11C]raclopride [95, 139] as well as with a number of other tracers. For example, Dewey et al. have demonstrated the effects of changes in synap-tic dopamine by direct effects on the dopamine system itself [140] and by indirect pharmacological interventions [141,142]. In humans, this paired-study approach has been used to measure drug occupancy [143-146].

The alternative study design is to administer the tracer as a combined bolus plus continuous infusion (B/I) to measure short-term changes in free receptor concentration [101,147,148]. First, the B/I administration of tracer is performed to achieve constant radioactivity levels in blood and all brain regions. Once equilibrium is achieved, control binding levels can be determined. For example, the volume of distribution V can be measured directly from the tissue-to-plasma concentration ratio. Then, a stimulus is administered while the infusion of radiotracer continues, and the change in specific binding of the tracer can be monitored. An example of B/I data is shown in Fig. 6.10 assessing the effects of amphetamine-induced dopamine release with [11C]raclopride. By comparing the pre-and post-amphetamine levels of specific binding determined directly from the tissue concentration values (Basal Ganglia/Cerebellum -1), the change in specific

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Figure 6.10. ROI data from basal ganglia (•) and cerebellum (■) following combined bolus plus infusion administration of the D2 dopamine ligand [11C]raclopride. At 40 min (arrow), 0.4 mg/kg of amphetamine was administered intravenously, producing displacement of raclopride due to competition with increased synaptic dopamine.

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Figure 6.10. ROI data from basal ganglia (•) and cerebellum (■) following combined bolus plus infusion administration of the D2 dopamine ligand [11C]raclopride. At 40 min (arrow), 0.4 mg/kg of amphetamine was administered intravenously, producing displacement of raclopride due to competition with increased synaptic dopamine.

binding from amphetamine can be measured. This B/I study design permits the measurement of pre- and post-intervention binding levels from a single administration of tracer. It is particularly well adapted to tracers with longer half-lives.

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