Mapping Neuroreceptors at work: on the Definition and Interpretation of Binding Potentials after 20 years of Progress

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This chapter summarizes some of the important maps of neuroreceptors that have been at work over the last 20 years. Positron-emitting radioligands and radiolabeled substrates of transmitter synthesizing enzymes were created for the in vivo imaging of brain tissue with positron emission tomography (PET). This class of tracers has advanced the search for mechanisms that regulate neurotransmission in the living human brain, but the methods of image analysis and interpretation are still controversial. The chapter discusses the main problems affecting the interpretations of the impressive maps of neuroreceptors including: (1) the discrepant meanings of the various measures called binding potential by different practitioners, (2) the uncertain definition of the Michaelis half-saturation constant and its consequent sensitivity to external influences, (3) the sensitivity of the steady-state measures of binding potential, maximum receptor number, and Michaelis half-saturation constant to the absence of a fully established steady state, and (4) the various interpretations of binding potential change reported by different practitioners of neuroreceptor mapping. The chapter also presents a number of solutions by the analysis of these issues and problems.

Section snippets

Twenty Years of Progress

Positron-emitting radioligands and radiolabeled substrates of transmitter synthesizing enzymes were created as early as 1983 for the in vivo imaging of brain tissue with positron emission tomography (PET) (Wagner et al., 1983) (Fig. 1). Although this class of tracers generally has advanced the search for mechanisms that regulate neurotransmission in the living human brain, the methods of image analysis and interpretation still arouse controversy. We discuss four specific issues in this chapter,

Definition of Binding Potential

The first problem is the uncertain definition of the binding potential, which tends to yield mutually incompatible results in the hands of different users. The term was introduced in one of the earliest models of neuroreceptor kinetics, presented by Mintun et al. (1984). The model demonstrated that the receptor quantity Bmax (i.e., the number of binding sites) and KD−1 (i.e., the binding affinity) were inseparable in vivo. Instead, they introduced the term binding potential for the ratio Bmax⧸KD

Solutions

The analysis of remaining issues and problems suggested a number of solutions. First, the discussion of the different definitions of the binding potential suggests that the most convenient definition is the familiar unitless ratio of the number of bound molecules for each molecule not so bound, commonly known as the B⧸F ratio when it is measured in vitro. Second, the discussion of the uncertain measurements of affinity constants suggests that the solvent to which it is referred must always be

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