FAILURE OF THE 3-COMPARTMENT MODEL TO DESCRIBE THE PHARMACOKINETICS IN BRAIN OF A HIGH-AFFINITY SUBSTITUTED BENZAMIDE

The applicability of using the standard 3-compartment model to describ e the neuropharmacokinetics of a high affinity substituted benzamide w as investigated. We performed the following experiments using the [F-1 8]-5-(3-fuoropropyl) analog of epidepride ([F-18]5-FPrEpid), a potent dopamine D2 receptor antagonist: constant left ventricular infusion, f irst-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 k(off) = 0.065 min(-1) , model prediction k(off) = 0.007 min(-1)) and the equilibrium dissoci ation constant (measured K-D = 0.14 nM, model prediction K-D = 2.2 nM) differ by an order of magnitude. Furthermore, the model cannot be use d to accurately estimate the receptor density. We postulate that the s ynapse geometry and physical relationship between receptors are necess ary components of a model that describes the pharmacokinetics of [F-18 ]5-FPrEPid. (c) 1993 Wiley-Liss, Inc.