Kinetic analysis of the opiate antagonist cyclofoxy in rat brain: simultaneous infusion of active and inactive enantiomers.

The opiate antagonist (-)-cyclofoxy [(-)-CF] and the receptor inert enantiomer (+)-CF were radiolabeled with 18F or 3H and administered to conscious Sprague-Dawley rats; an isotope effect was not observed. Constant i.v. infusion of both 18F-(-)-CF and 3H-(+)-CF in tracer amounts showed a marked difference in the tissue level of 18F-(-)-CF among various brain structures, whereas the values for 3H-(+)-CF were lower and much less variable. Co-infusion of unlabeled (-)-CF (1 mg/rat) did not change the tissue binding of 3H-(+)-CF in any brain structure, but reduced that of 18F-(-)-CF to the same level as 3H-(+)-CF. These results demonstrate an identical nonspecific tissue binding for (+)- and (-)-CF in vivo, and suggest that (+)-CF can be used to measure the "nonspecific" component of (-)-CF binding in brain. A nonlinear analysis of the 3H-(+)-CF data indicated the presence of both "instantaneous" and time-dependent components in nonspecific tissue binding and that nonspecific binding varied 1.5-fold in different brain structures. The combined 3H-(+)-CF and 18F-(-)-CF data were fitted to a four-compartment model, which includes parameters for capillary transport, "instantaneous" and time-dependent nonspecific tissue binding, as well as receptor association and dissociation. The receptor-association rate constant varied considerably in various structures of cerebrum (2.0-8.7 min-1), whereas receptor dissociation was estimated within a narrow range (0.12-0.17 min-1). The receptor binding potential (receptor association/dissociation) ranged between 12.7 and 56.2 and was in good agreement with previous estimates in vitro.