Pharmacokinetics of [3H]-buprenorphine in the rat

The present study was undertaken to evaluate the potential usefulness of 11C-buprenorphine (bup) as a ligand for investigating opioid receptors in living primates, including humans, using positron-emission transaxial tomography (PETT). Because PETT studies of receptor function are best carried out under conditions of low receptor occupancy, the pharmacokinetics, uptake into brain, and specific binding to opioid receptors within brain of 3H-bup were examined in rats under conditions in which occupancy of opioid receptors by 3H-bup never exceeded 2% of sites in the brain at any time point examined. Male Sprague Dawley rats (weight range 140-220 grams) were injected s.c. with either naloxone (10 mg/kg) or saline. Five min later, a saline solution containing [15, 16-3H] bup (39 Ci/mmole) was injected into tail veins at a dose of 0.4 microgram/kg body weight. At least 90-95% of radioactivity was cleared from the blood in the first 5 min. In saline pretreated rats, total brain uptake 15 min after injection of 3H-bup was about 0.4% of the administered dose. Ligand specifically bound to receptors may be estimated by comparing the amount of radioactivity in the brain following injection of labeled ligand alone to that obtained when a high concentration of an unlabeled competitor is pre- or co-administered. In the present study, average levels obtained in brain (excluding cerebellum) were higher in saline pretreated rats than in naloxone pretreated rats at all time points and the difference increased with time indicating specific binding to opioid receptors. Specific binding may also be estimated by comparing radioactivity accumulated in brain areas rich in opioid receptors with "background" levels achieved in areas known to be low in opioid receptors, e.g., the cerebellum in rats. In the present study, ratios of the amount of radioactivity in brain (excluding cerebellum) to the amount in the cerebellum increased with time (to about 4 after 60 min) in saline pretreated rats, but remained close to 1 in naloxone pretreated rats. The effects of biological variation were less when specific binding was estimated by the latter method since each animal served as its own control. Tissue distribution of radioactivity to other tissues (blood, skin, muscle, fat, liver, kidney) was similar in naloxone and saline pretreated rats. The results presented here suggest that 11C-bup or an 18F-labeled fluorinated derivative would be a useful ligand for PETT studies.