BLOOD-BRAIN-BARRIER PERMEABILITY AND BIOAVAILABILITY OF A HIGHLY POTENT AND MU-SELECTIVE OPIOID RECEPTOR ANTAGONIST, CTAP - COMPARISON WITHMORPHINE

D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) is a cyclic, penicillam ine-containing octapeptide that is structurally similar to somatostati n and displays greater antagonist potency and selectivity for mu-opioi d receptors, compared with the classical mu-selective antagonist D-Phe -Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2. The aim of this study was to deter mine whether CTAP can enter the central nervous system (CNS) by crossi ng either the blood-brain barrier or the blood-cerebrospinal fluid bar rier (CSF) and to characterize the mechanism of CNS entry. CNS entry o f [H-3]CTAP was compared with that of the vascular space marker [C-14] inulin and the mu-agonist [H-3]morphine. By using an in situ brain per fusion technique coupled to high-performance liquid chromatographic an alysis, greater amounts of radioactivity were detected in the brain or CSF at most time points for [H-3]CTAP, compared with [C-14]inulin. [H -3]CTAP was found to remain predominantly intact in the brain after a 20-min rat brain perfusion (62.8%). CTAP was also stable in the blood and serum of rats (T-1/2 > 500 min), showing that the structure of thi s peptide offers enzymatic resistance. Additionally, [H-3]CTAP was fou nd to be extensively protein-bound to albumin in the perfusion medium (68.2%) and to proteins in rat serum (84.2%). Entry into the brain and CSF was not inhibited by the addition of unlabeled CTAP to the perfus ion medium, suggesting that passage into the CNS is most likely throug h diffusion across the membranes that comprise the blood-brain barrier , rather than by saturable transport. Also, greater amounts of [H-3]mo rphine entered both the brain and CSF after a 20-min brain perfusion, compared with [H-3]CTAP. The increased CNS penetration observed for [H -3]morphine, compared with [H-3]CTAP, is likely due to the increased l ipophilicity of morphine, as shown by its higher octanol/saline partit ion coefficient. Based on the pharmacokinetic profile, CTAP may be a p romising mu-selective antagonist that can be used as a treatment for o piate overdose or addiction and also as a pharmacological tool to furt her understand opioid neurobiology.