title: 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.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Gifford
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000000981:diagnostic imaging*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D013997:Time Factors; D014055:Tomography, Emission-Computed / Q000379:methods*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014316:Tritium
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D014316:Tritium