Evaluation of the importance of rebinding to receptors in slowing the approach to equilibrium of high-affinity PET and SPECT radiotracers

Abstract

The importance of rebinding to receptors in influencing the kinetics of in vivo binding of PET and SPECT radiotracers was evaluated by examining the binding of a high-affinity D1 receptor radiotracer, [3H]SCH 23390, in tissue homogenates, living brain slices, and in vivo. In rat striatal homogenates, [3H]SCH 23390 binding reached equilibrium with a half-time of 6 min. By contrast, in striatal brain slices incubated in [3H] SCH 23390, the radioactivity levels in the slice increased in a linear fashion over the 4-h incubation, with no indication of an approach to equilibrium at the termination of the experiment. In in vivo experiments, [3H]SCH 23390 was given as a slow intravenous infusion to mice, using a paradigm that kept the plasma concentration at a constant level. Under these conditions, striatal [3H] SCH 23390 levels increased in a linear fashion over the 4-h infusion period, similar to what was observed in the brain slices, and as in the slices there was no indication of approach to a steady state. However, when given instead as a single-bolus intravenous dose, the striatal [3H]SCH 23390 levels reached a peak only 15 min after injection. Calculations based on the slice experiments, in which the blood-brain barrier is absent, suggested that the rate-limiting step accounting for the failure of [3H]SCH 23390 levels to reach equilibrium was its hindered diffusion as a result of repeated rebinding to receptors. This phenomenon may also be important in vivo and should be considered as a factor in determining the time-course of binding of radiotracers in PET and SPECT experiments where either the receptor density or radiotracer affinity is high.

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

“…This is especially the case in situations where the receptor density in the tissue is high, as is the situation for D 1 and D 2 receptors in the striatum for example. In such receptorrich brain regions high affinity radiotracers tend to accumulate in a non-reversible manner and consequently fail to approach a situation, at least within the time course of the experiment, in which equilibrium binding conditions exist (Gifford et al 1998). As a result their total accumulation in the target region will depend strongly on their rate of delivery via the blood stream, in addition to the receptor availability in this region.…”

Dopamine Depletion and In Vivo Binding of PET D1 Receptor Radioligands: Implications for Imaging Studies in Schizophrenia

“…Elevations in synaptic DA levels promote internalization (Dumartin et al, 1998;Vickery and von Zastrow, 1999), whereas decreases in synaptic DA levels promote externalization (Dumartin et al, 2000). Externalization of D 1 receptors upon acute DA depletion might result in decreased in vivo affinity of [ rate in homogenates' preparation compared to intact slides (Gifford et al, 1998 (Butkerait and Friedman, 1993 Table 3. Additional research, including in vitro measurement of the expression and cellular localization of D1 receptors following DA depletion, is required to test this hypothesis.…”

Significant dissociation of brain and plasma kinetics with antipsychotics

“…1,2 To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and Novel antipsychotics are currently used to treat diverse medical conditions such as schizophrenia, mania, depression, and dementia.…”

“…9 We measured the time course of drug plasma levels and brain D 2 receptor occupancy in healthy volunteers after a single dose of 3-4 mg risperidone (n = 4) or 15 mg olanzapine (n = 4). We used [ 11 C]raclopride as a PET-ligand to estimate central D 2 receptor occupancy in the striatum, 1 and [ 11 C]FLB457 for quantification of extra-striatal D 2 blockade in the thalamus. 10 Additionally, we investigated the time course of plasma levels and striatal D 2 occupancy in five stable patients suffering from schizophrenia.…”

“…5 In addition, a relatively low dissociation rate at brain receptors may lead to both drugs being attached for a relatively long time to their binding sites, even after plasma levels have declined. 2 Furthermore, the tissue concentration of lipophilic compounds such as olanzapine or risperidone is known to be 4-to 46-fold higher than the plasma concentration in the rat. 16 Therefore, the effective concentration at their molecular target in the human brain is likely much higher than their plasma concentration.…”