Hoyte R M, MacLusky N J, Hochberg R B
Department of Chemistry, College at Old Westbury, State University of New York 11568.
J Steroid Biochem. 1990 Jun;36(1-2):125-32. doi: 10.1016/0022-4731(90)90122-9.
Two iodinated steroids, E-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone and Z-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone were synthesized in a search for a gamma-emitting androgen that binds with high affinity to the androgen receptor. Such compounds would be extremely useful research tools for studies of androgen responsive tissues and as in vivo probes of androgen responsive tumors such as prostate cancer. These 17 alpha-iodovinyl steroids were synthesized because many 17 alpha-substituents do not interfere markedly with binding to the androgen receptor and because similar analogs of other steroids, estrogens and progestins, have been shown to have the requisite properties for ligands to those receptors. Both of these potential ligands were tested for their ability to compete with [3H]R1881 for binding to the androgen receptor in cytosols from prostate, hypothalamus and pituitary. The relative binding affinities ranged between 5 and 20%, depending upon the tissue and steroid. In order to test the two ligands directly, they were both synthesized labelled with 125I and tested for binding to the androgen receptor in prostatic cytosol and in vivo for specific concentration in androgen responsive tissues. While there was considerable binding in the prostatic cytosol, it was not specific because 5 alpha-dihydrotestosterone did not compete. Likewise in the in vivo experiment there was no evidence for androgen receptor mediated concentration of the tracers. While on the basis of relative binding affinity, these 2 steroids appeared to be good candidates for androgen receptor ligands, neither were useful for this purpose. These results contribute new information which will be valuable in the design of other gamma-emitting androgens and emphasises that, in this process, other factors such as metabolism and nonspecific binding must be considered.
为了寻找一种能与雄激素受体高亲和力结合的发射γ射线的雄激素，合成了两种碘化甾体，即E-17α-(2-碘乙烯基)-5α-二氢睾酮和Z-17α-(2-碘乙烯基)-5α-二氢睾酮。这类化合物对于雄激素反应性组织的研究以及作为雄激素反应性肿瘤（如前列腺癌）的体内探针将是极其有用的研究工具。合成这些17α-碘乙烯基甾体是因为许多17α-取代基不会显著干扰与雄激素受体的结合，而且其他甾体、雌激素和孕激素的类似物已显示具有作为那些受体配体的必要特性。测试了这两种潜在配体与[3H]R1881竞争结合前列腺、下丘脑和垂体胞质溶胶中雄激素受体的能力。相对结合亲和力在5%至20%之间，具体取决于组织和甾体。为了直接测试这两种配体，将它们都用125I标记后进行合成，并测试它们与前列腺胞质溶胶中雄激素受体的结合以及在体内雄激素反应性组织中的特异性浓度。虽然在前列腺胞质溶胶中有相当多的结合，但不具有特异性，因为5α-二氢睾酮不能竞争。同样，在体内实验中，没有证据表明示踪剂是由雄激素受体介导富集的。虽然基于相对结合亲和力，这两种甾体似乎是雄激素受体配体的良好候选物，但两者都不适用于此目的。这些结果提供了新的信息，这对于设计其他发射γ射线的雄激素将是有价值的，并强调在这个过程中，必须考虑其他因素，如代谢和非特异性结合。
