OPIOID RECEPTOR IMAGING AND DISPLACEMENT STUDIES WITH [6-O-[C-11]METHYL]BUPRENORPHINE IN BABOON BRAIN

Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an an algesic and in the treatment of opiate addiction. We have used [6-O-[C -11]methyl]buprenorphine ([C-11]BPN) to measure the regional distribut ion in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in v ivo, and the tissue distribution in mice, The regional distribution of radioactivity in baboon brain determined with PET was striatum > thal amus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum, This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in a dult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HP LC analysis of baboon plasma showed the presence of labeled metabolite s with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining a t 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [C-11]BPN binding in thalamus, striatum, cingulate gyrus , and frontal cortex to values 0.25 to 0.60 of that with no interventi on. There were minimal (<15%) effects on cerebellum, Naloxone treatmen t significantly reduced the slope of the Patlak plot in receptor-conta ining regions. These results demonstrate that [C-11]BPN can be displac ed by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies wi th PET. Mouse tissue distribution data were used to estimate the radia tion dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.