BIOLOGICALLY ACTIVE STEROID ANALOGS

用发射伽马的同位素标记的放射性类固醇 是荷尔蒙作用的不同寻常的探测器。当标签为 放射性碘，这种生物活性的类固醇激素是非常 用于类固醇受体研究的敏感配体，它们使 可能对含有类固醇的人类肿瘤进行外部成像 荷尔蒙受体。第一次生物活性伽马发射 合成了类固醇激素16α-[125I]碘-17β-雌二醇 在这个实验室里。它和我们的改良类似物，11β-甲氧基- 16α-[125I]碘-17β-雌二醇，已被广泛用于 雌激素受体的灵敏检测和定量。 我们正在合成16α-碘-17β-雌二醇的其他类似物 可能具有更好的雌激素受体特性，并将测试 它们在雌激素靶组织中的体内浓度。我们会 用[123I]标记这些类似物中最好的，用于活体成像 含有人类乳腺癌的雌激素受体。最近我们有 成功合成了一种寻找已久的类固醇探针， 伽马释放雄激素，E-17α-(2‘-碘-乙烯-4，9-雌二烯- 17β-醇-3-酮，E-MIVNT。我们合成了标记的E-MIVNT [125I]无载体形式(2,200Ci/mmo1)，并发现 与雄激素受体结合的亲和力很强，非特异性很低 有约束力的。E-[125i]MIVNT与其他 类固醇受体。我们正在测试E-MIVNT和其他17pha- 碘-乙烯基类化合物的雄激素活性、代谢和 体内集中在含有雄激素的组织中的能力 受体。这些雄激素中最合适的将被合成 [123I]用于男性前列腺癌的显像学研究 癌症。我们将合成[125I]雄激素和雌激素作为探针 在雄激素和雌激素作用的联合研究中 大脑。我们将合成一种[123I]标记的糖皮质激素 糖皮质激素受体的单光子发射计算机断层扫描 灵长类动物大脑的丰富区域。使用这个配体，我们将尝试 体内测定糖皮质激素与糖皮质激素相互作用的动力学 它的受体。这种[123I]糖皮质激素将为 研究大脑糖皮质激素受体的缺陷，这是 被认为与几种疾病有关，包括 抑郁和压力。在我们的伽马释放雌激素的合成中 我们已经搜索了类固醇核的区域，它们都是 易于发生化学反应，对受体透明 当较大的基团被取代时的相互作用。在这些研究中，我们 发现了一种独特的雌激素和抗雌激素化合物。在……里面 此外，我们还发现了活性雌激素的类似物，但 非常反复无常。我们正在合成这些化合物的其他衍生品 可能具有重要治疗作用的类固醇 更年期局部活性雌激素。

Radioactive steroids that are labelled with gamma-emitting isotopes are unusual probes of hormone action. When labelled with radioiodine, such biologically active steroid hormones are extremely sensitive ligands for the study of steroid receptors and they make possible the external imaging of human tumors that contain steroid hormone receptors. The first biologically active gamma-emitting steroid hormone 16alpha-[125I]iodo-17beta-estradiol was synthesized in this laboratory. It and our modified analog, 11beta-methoxy- 16alpha-[125I]iodo-17beta-estradiol, have been used extensively for the sensitive detection and quantification of the estrogen receptor. We are synthesizing other analogs of 16alpha-iodo-17beta-estradiol which may have superior estrogen receptor properties and will test them for in vivo concentration in estrogen target tissues. We will label the best of these analogs with [123I] for in vivo imaging of estrogen receptor containing human breast cancer. Recently we have succeeded in the synthesis of a long sought for steroidal probe, a gamma-emitting androgen, E-17alpha-(2'-iodovinyl-4,9-estradiene- 17beta-ol-3-one, E-MIVNT. We have synthesized E-MIVNT labelled with [125I] in carrier free form (2,200 Ci/mmol) and have found that is binds to the androgen receptor with very affinity and low nonspecific binding. E-[125I]MIVNT binds only poorly if it at all to other steroid receptors. We are testing E-MIVNT and other 17alpha- iodovinyl analogs for their androgenic potency, metabolism and ability to concentrate in vivo in tissues that contain the androgen receptor. The most suitable of these androgens will be synthesized with [123I] and used for imaging studies in males with prostatic cancer. We will synthesize the [125I]androgen and estrogen as probes in collaborative studies of androgen and estrogen action in the brain. We will synthesize an [123I]labelled glucocorticoid for Single Photon Emission Computed Tomography of glucocorticoid receptor rich regions of the primate brain. Using this ligand we will attempt to determine in vivo the kinetics of glucocorticoid interaction with its receptor. This [123I]glucocorticoid would provide a probe for investigating defects in the brain glucocorticoid receptor, which have been hypothesized to be involved in several disorders, including depression and stress. In our synthesis of gamma-emitting estrogens we have searched for regions of the steroid nucleus that are both accessible to chemical reactions and transparent to receptor interactions when bulky groups are substituted. In these studies we have found compounds that are unique estrogens and antiestrogens. In addition we have uncovered analogs that are active estrogens but extremely labile. We are synthesizing other derivatives of these steroids which may have important therapeutic actions for use as locally active estrogens in the menopause.