de Costa B R, Iadarola M J, Rothman R B, Berman K F, George C, Newman A H, Mahboubi A, Jacobson A E, Rice K C
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1992 Jul 24;35(15):2826-35. doi: 10.1021/jm00093a016.
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.
差向异构的6β-碘代-3,14-二羟基-17-(环丙基甲基)-4,5α-环氧吗啡喃（1，ioxy）和6α-碘代-3,14-二羟基-17-(环丙基甲基)-4,5α-环氧吗啡喃（2，epioxy）分别从纳曲酮开始经五步合成。基于其前体3-乙酰氧基-6β-碘代-14-羟基-17-(环丙基甲基)-4,5α-环氧吗啡喃（10）的单晶X射线分析，明确确定1的6-碘代基团构型为β型。通过爪部撤离潜伏期试验确定，1和2及其相应的3-O-乙酸酯10和11都能很容易地穿过血脑屏障，并完全逆转腹腔注射10mg/kg硫酸吗啡的镇痛作用。发现化合物1和2在体外与μ、δ和κ受体具有高亲和力结合。一般来说，1和2对μ和κ受体的亲和力高于纳曲酮，而6β-碘代差向异构体1（ioxy）比其差向异构体2更有效。在比较阿片受体亚型上6β-卤素取代基对结合亲和力的影响时，通常发现碘大于溴大于氟。基于体外和体内测试结果，选择1作为放射性碘化的目标，并评估其作为阿片受体潜在单光子发射计算机断层扫描成像剂的可能性。通过在76℃下将过量的3-乙酰氧基-6α-[[(三氟甲基)磺酰基]氧基]-14-羟基-17-(环丙基甲基)-4,5α-环氧吗啡喃（8）与无水Na125I在干燥乙腈中反应90分钟，然后在25℃下用1:1氨水/乙腈对产物进行脱乙酰化反应，以近乎定量的产率合成了无载体的[125I]-1。评估并讨论了[125I]-1作为阿片受体体内成像剂的可能性。
