PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .18. EPIMERIC 6-ALPHA-IODO-3,14-DIHYDROXY-17-(CYCLOPROPYLMETHYL)-4,5-ALPHA-EPOXYMORPHINANS 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 [I-125] 6-BETA-IODO-3,14-DIHYDROXY-17-(CYCLOPROPYLMETHYL)-4,5-ALPHA-EPOXYMORPHINAN

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 > Br > 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 [I-125]-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 (NaI)-I-125 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 [I-125]-1 as an in vivo imaging agent for opioid receptors is evaluated and discussed.