We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen 7α-9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780; Faslodexâ¢). The latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu(I)-promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the 17-hydoxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key intermediates for the 18F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me4NF, followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16α-fluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with 18F by substituting Me4NF for 18Fâ in acetonitrile.
我们以强效抗
雌激素 7δ-9-[(4,4,5,5,5-五
氟戊基)亚磺酰基]壬基}-
雌甾-1,3,5(10)-
三烯-3,17δ²
-二醇(ICI 182,780;Faslodexâ¢)为基础,制备了一系列新的 7δ-取代的 16δ-
氟雌二醇衍
生物。后者由
雌二醇组成,在 7δ-位有一条侧链,具有有趣的药物特性,可用于
雌激素受体(ER)阳性乳腺癌的内分泌治疗。ICI 182,780 与其他已用于激素治疗的选择性
雌激素受体调节剂(
SERMs)相比具有相当大的优势,这促使我们开发了三种新的 16δ±-
氟衍
生物,它们有望用于正电子发射断层扫描(PET),对乳腺肿瘤中的
雌激素受体密度进行成像。6-脱氢-19-去
甲睾酮在
格氏试剂的Cu(I)促进下进行共轭加成,从而在7δ-位引入长侧链。随后,17-羟基氧化和 A 环芳香化得到了 7δ±-取代的
雌酮衍
生物。进一步加成以完成侧链,就得到了 ICI 182,780 嵌合物,并将其转化为活性 16δ²、17δ²-环
硫酸盐,即 18F 标记反应的关键中间体。用 Me4NF 通过亲核
氟化打开环
硫酸盐,然后在酸性
乙醇中快速
水解保护醚和
硫酸酯基团,就得到了 ICI 182,780 所需的 16δ±-
氟 PET 衍
生物。通过在
乙腈中用 Me4NF 代替 18Fâ,后一种方法很容易进行 18F 放射性标记。