PMID- 1322988 OWN - NLM STAT- MEDLINE DCOM- 19920904 LR - 20190709 IS - 0022-2623 (Print) IS - 0022-2623 (Linking) VI - 35 IP - 15 DP - 1992 Jul 24 TI - Probes for narcotic receptor mediated phenomena. 18. Epimeric 6 alpha- and 6 beta-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinans as potential ligands for opioid receptor single photon emission computed tomography: synthesis, evaluation, and radiochemistry of [125I]-6 beta-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinan. PG - 2826-35 AB - The epimeric 6 beta- and 6 alpha-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinans (1, ioxy) and (2, epioxy), respectively, were each synthesized in five steps starting with naltrexone. The configuration of the 6-iodo group of 1 was unequivocally determined to be beta-based on single crystal X-ray analysis of its precursor 3-acetoxy-6 beta-iodo-14-hydroxy-17-(cyclopropylmethyl)-4,5 alpha-epoxymorphinan (10). Both 1 and 2 as well as their corresponding 3-O-acetates 10 and 11 were found to readily cross the blood-brain barrier and completely reverse the analgesic effects of a 10 mg/kg intraperitoneal dose of morphine sulfate as determined by the paw withdrawal latency test. Compounds 1 and 2 were found to bind with high affinity to mu, delta, and kappa receptors in vitro. In general, 1 and 2 exhibited higher affinity for mu and kappa receptors than naltrexone while the 6 beta-iodo epimer 1 (ioxy) was more potent than its epimer 2. In a comparison of the 6 beta-halogen substituent on binding affinity across opioid receptor subtypes, it was generally found that I greater than Br greater than F. On the basis of the results of in vitro and in vivo testing, 1 was selected as a target for radioiodination and evaluation as a potential single photon emission computed tomography imaging agent for opioid receptors. Carrier-free [125I]-1 was synthesized in near quantitative yield by the sequence of reaction of excess 3-acetoxy-6 alpha-[[(trifluoromethyl)sulfonyl]oxy]-14-hydroxy-17- (cyclopropylmethyl)-4,5 alpha-epoxymorphinan (8) with anhydrous Na125I in dry acetonitrile for 90 min at 76 degrees C followed by deacetylation of the product with 1:1 aqueous ammonia/acetonitrile at 25 degrees C. The potential of [125I]-1 as an in vivo imaging agent for opioid receptors is evaluated and discussed. FAU - de Costa, B R AU - de Costa BR AD - Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892. FAU - Iadarola, M J AU - Iadarola MJ FAU - Rothman, R B AU - Rothman RB FAU - Berman, K F AU - Berman KF FAU - George, C AU - George C FAU - Newman, A H AU - Newman AH FAU - Mahboubi, A AU - Mahboubi A FAU - Jacobson, A E AU - Jacobson AE FAU - Rice, K C AU - Rice KC LA - eng PT - Journal Article PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Indicators and Reagents) RN - 0 (Iodine Radioisotopes) RN - 0 (Morphinans) RN - 0 (Receptors, Opioid) RN - 141392-30-5 (6-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5-epoxymorphinan) SB - IM MH - Animals MH - Binding Sites MH - Blood-Brain Barrier MH - Brain/diagnostic imaging/metabolism MH - Chromatography, High Pressure Liquid MH - Guinea Pigs MH - Indicators and Reagents MH - Iodine Radioisotopes MH - Male MH - Molecular Structure MH - Morphinans/chemical synthesis/*metabolism/pharmacology MH - Rats MH - Rats, Inbred Strains MH - Receptors, Opioid/*metabolism MH - Tomography, Emission-Computed, Single-Photon MH - X-Ray Diffraction EDAT- 1992/07/24 00:00 MHDA- 1992/07/24 00:01 CRDT- 1992/07/24 00:00 PHST- 1992/07/24 00:00 [pubmed] PHST- 1992/07/24 00:01 [medline] PHST- 1992/07/24 00:00 [entrez] AID - 10.1021/jm00093a016 [doi] PST - ppublish SO - J Med Chem. 1992 Jul 24;35(15):2826-35. doi: 10.1021/jm00093a016.