SYNTHESIS AND EVALUATION OF HALOARYL(VINYL) STEROIDS

这项研究项目的总体目标是开发新的 放射诊断试剂可以非侵入性地检测、定位和 类固醇激素(雌激素和/或黄体酮)反应的特征 人类乳腺肿瘤。这样的代理人将是有价值的，因为他们将 协助临床医生选择合适的治疗方案 提供了长期生存的预后指标，并且在 年对原发癌和转移癌的序贯评估 对治疗的反应。 本项目的作用是为选择 用于单光子或正电子发射标记的合适配体 放射性核素。雌激素和孕激素受体的相关因素 亲和力和选择性以及放射性核素都被考虑过。 具有高比活度并具有期望的排放物 特点。与之相关的化学物质 11β-取代-17α-炔基孕酮和雌激素，具有高 受体亲和力，可以与受体的亲和力 双(三烷基锡基)芳烃和乙烯生成的中间体 用氟、溴或碘代替，所有这些都具有 临床上有用的放射性核素。来自卤代芳基(乙烯基)系列 合成的类固醇、受体结合分析和体内研究 将指示哪些化合物将具有所需的性质 放射诊断应用。 具体目标包括：(1)合成一种常见的中间体 可制成几个系列的化合物；(2)特定部位 在甾体上引入试-烷基锡芳基或-乙烯基 细胞核；(3)转化为相应的卤代芳基(乙烯基)雌激素 和孕激素，在毫米级用于表征和在 用于潜在放射性标记的微摩尔标度；(4)评价 作为体内雌激素和孕激素受体配体的化合物； 以及(5)结构-活性-关系的发展以选择 用于后续放射性标记研究的最合适的化合物。 这项研究强调综合方法论的效率，以及 生物学评估，即最少数量的动物将被用于 生成结构-活动-关系。效率也是 通过拥有广泛专业知识的人员的经验而得到加强 项目的指定区域。因此，整个研究应该 在要求的时间内完成。

The overall objective of this research project is to develop new radiodiagnostic agents that can noninvasively detect, localize and characterize steroid hormone (estrogen and/or progesterone) responsive human mammary tumors. Such agents would be valuable in that they would assist clinicians in selecting the appropriate therapeutic regimen, in providing a prognostic indicator of long term survival, and in the sequential evaluation of the carcinoma, both primary and metastatic, in response to therapy. The role of this project is to provide a rational basis for selecting the appropriate ligand for labeling with a single photon or positron-emitting radionuclide. Factors related to estrogen and progesterone receptor affinity and selectivity have been considered as well as the radionuclides that are available in high specific activity and with desireable emission characteristics. The chemistry associated with the 11Beta-substituted-17Alpha-alkynyl progestins and estrogens, that have high receptor affinity, can be coupled with that of the bis(trialkylstannyl)arenes and ethylenes to produce intermediates that can be substituted with fluorine, bromine or iodine, all of which possess clinically useful radionuclides. From the series of haloaryl(vinyl) steroids that are synthesized, receptor binding assays and in vivo studies will indicate which compounds would possess the desireable properties for radiodiagnostic applications. The specific aims consist of: (1) The synthesis of a common intermediate from which several series of compounds can be made; (2) the site specific introduction of trial-kylstannylaryl or -vinyl groups on to the steroid nucleus; (3) the conversion to the corresponding haloaryl(vinyl) estrogens and progestins, both at millimolar scale for characterization and at the micromolar scale for potential radiolabeling; (4) the evaluation of the compounds as ligands for the estrogen and progesterone receptors in vivo; and (5) the development of structure-activity-relationships to select the most appropriate compounds for subsequent radiolabeling studies. The study emphasizes efficiency in the synthetic methodology, and in the biological evaluation, i.e., a minimal number of animals will be used to generate the structure-activity-relationships. The efficiency is also enhanced by the experience of the personnel who have extensive expertise in the designated areas of the project. As a result the entire study should be completed within the time period requested.