Positron emission tomography (PET) and single photon emission tomography (SPET) can be used to measure the distribution of radioactively labelled tracers in the brain. When the tracer is a ligand for a specific neuroreceptor, the distribution of the labelled tracer provides a quantitative measure of the spatial distribution of accessible receptors. However, not only are there many technical difficulties in preparing a labelled tracer that binds with high specificity to the receptor of interest, and in executing the imaging procedure, but there are intrinsic uncertainties regarding the behaviour of ligands in vivo that complicate the interpretation of the observed binding of the administered ligand. In particular, the administered ligand must compete with any endogenous ligand that is present. A decrease in the amount of tracer that binds to receptors in a particular condition may reflect either a decrease in receptor number or an increase in the concentration of endogenous ligand occupying the receptors, thus making fewer available.
The situation is made even more complex by the fact that competition between endogenous ligand and administered ligand does not appear to obey the laws of equilibrium binding that are observed in vitro. If the administered radio-ligand is present at trace concentrations that occupy only a minute proportion of the available receptors, the number of available receptors should be determined by the total number of receptors and the concentration of endogenous ligand. The relative affinities of the endogenous ligand and the administered ligand for the receptor should have a negligible effect on the observed density of available receptors. The number of available receptors should be the total density of receptors minus the proportion occupied by the endogenous ligand, irrespective of the presence of trace amounts of the radio-ligand. However, that is not what is observed. The binding of administered ligands that bind very strongly to the
receptor appears to be unaffected by the presence of endogenous ligand, whereas ligands that bind weakly are sensitive to the presence of endogenous ligand.
For example, the dopamine D2 ligand N-methylspiperone, which binds very tightly to the D2 receptor, is apparently insensitive to the presence of endogenous ligand, whereas raclopride, which binds relatively weakly, is affected by endogenous ligand, although less strongly than would be predicted. This has led to apparently contradictory findings regarding D2 receptor density in the basal ganglia in schizophrenia, measured by different investigators using different tracers. Wong et al (1986), using N-methylspiperone, found an apparent increase in D2 receptor
density in previously unmedicated schizophrenic patients relative to healthy subjects, while Farde et al (1988), who employed raclopride, found no generalised increase, although they did find an increase in the left putamen relative to the right.
The situation is made even more complex by the fact that competition between endogenous ligand and administered ligand does not appear to obey the laws of equilibrium binding that are observed in vitro. If the administered radio-ligand is present at trace concentrations that occupy only a minute proportion of the available receptors, the number of available receptors should be determined by the total number of receptors and the concentration of endogenous ligand. The relative affinities of the endogenous ligand and the administered ligand for the receptor should have a negligible effect on the observed density of available receptors. The number of available receptors should be the total density of receptors minus the proportion occupied by the endogenous ligand, irrespective of the presence of trace amounts of the radio-ligand. However, that is not what is observed. The binding of administered ligands that bind very strongly to the
receptor appears to be unaffected by the presence of endogenous ligand, whereas ligands that bind weakly are sensitive to the presence of endogenous ligand.
For example, the dopamine D2 ligand N-methylspiperone, which binds very tightly to the D2 receptor, is apparently insensitive to the presence of endogenous ligand, whereas raclopride, which binds relatively weakly, is affected by endogenous ligand, although less strongly than would be predicted. This has led to apparently contradictory findings regarding D2 receptor density in the basal ganglia in schizophrenia, measured by different investigators using different tracers. Wong et al (1986), using N-methylspiperone, found an apparent increase in D2 receptor
density in previously unmedicated schizophrenic patients relative to healthy subjects, while Farde et al (1988), who employed raclopride, found no generalised increase, although they did find an increase in the left putamen relative to the right.
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