Failure of the three compartment model to describe the pharmacokinetics in brain of a high affinity substituted benzamide

Abstract

The applicability of using the standard 3-compartment model to describe the neuropharmacokinetics of a high affinity substituted benzamide was investigated. We performed the following experiments using the [18F]-5-(3-fluoropropyl) analog of epidepride ([18F]5-FPrEpid), a potent dopamine D2 receptor antagonist: constant left ventricular infusion, first-pass clearance, varying ligand specific activity, and displacing bound ligand with varying amounts of unlabelled ligand. Taken together, the information from these experiments rigorously tests the standard 3-compartment model. The obtained data and predictions from the model of the kinetic behavior of the ligand are inconsistent. The measured and model predicted dissociation rate (measured koff = 0.065 min-1, model prediction koff = 0.007 min-1) and the equilibrium dissociation constant (measured KD = 0.14 nM, model prediction KD = 2.2 nM) differ by an order of magnitude. Furthermore, the model cannot be used to accurately estimate the receptor density. We postulate that the synapse geometry and physical relationship between receptors are necessary components of a model that describes the pharmacokinetics of [18F]5-FPrEpid.

Measurement of Bmax and Kd with the Glycine Transporter 1 Radiotracer 18F-MK6577 using a Novel Multi-Infusion Paradigm

“…Note that this effect has been seen previously, where kinetics in the blocking state are accelerated compared with the tracer-only state. This can be explained by radioligand rebinding in a relatively isolated compartment referred to as the synaptic barrier, 29,30 that the k off parameter estimated from the tracer-only part of the data was unreliable, or that an extra nonspecific compartment was needed (i.e., k 5 ≠0, k 6 ≠0 in Delforge's model 31 ). We then compared the ratio of cold/hot concentrations during the equilibrium periods to that predicted by the ratio of the cold/ hot infusion rates.…”

Concentration and occupancy of dopamine transporters in cocaine abusers with [11C]cocaine and PET

“…Although these equations represent a simplification of the processes involved, they have generally been effective in describing PET data from receptor-ligand studies (e.g., Farde et al, 1989;Huang et al, 1986;Mintun et al, 1984;Wong et al, 1986), although some problems have appeared with the use of slowly dissociating ligands (Votaw et al, 1993). F and B in Equations 1 and 2 designate the ''free '' and ''bound'' ligand, respectively, Cp(t) refers to the plasma radioactivity due to [ 11 C]cocaine at time t, k on and k off are the receptor ligand binding constants (the dissociation equilibrium constant is Kd ϭ k off /k on ), and is the specific activity (SA).…”

Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands

“…Despite this apparent discrepancy between k 4 and k off , both k 3 (which posited as a function of three variables) and k 4 appear to be similarly decreased by a constant factor such that their ratio is proportional to the in vivo K D , which sometimes approximates that found in vitro. The cause of this apparent proportional scaling in k 3 and k 4 is unknown but has been ascribed to radioligand rebinding in a relatively isolated compartment referred to as the synaptic barrier (Delforge et al, 1996;Votaw et al, 1993).…”