SYNTHESIS OF GLUCOCORTICOID RECEPTOR LIGANDS

这项提议寻求继续研究类固醇激素卤代类似物的设计和合成。将开发合成程序，允许将放射性碘(125I和123I)和氟(18F)结合到雄激素和糖皮质激素中，从而保持其激素活性。放射性标记雄激素可用于前列腺癌等雄激素反应性肿瘤的灵敏检测和体外雄激素受体的定量。它们也将在组织的放射自显影研究中有很大的用处，例如大脑，其中存在雄激素受体，但定位于特定的细胞或区域。这类研究对于阐明雄激素在胎儿发育中大脑性别分化等过程中的作用具有重要价值。具有糖皮质激素活性的标记化合物将在脑内糖皮质激素受体丰富区域的测绘和成像中具有价值。由于皮质类固醇影响神经功能的具体神经生理机制尚不完全清楚，因此这类研究对于确定和理解它们在大脑中的作用和功能具有越来越重要的意义。在早期的工作中，该实验室成功地强调了放射性标记孕激素和雄激素的开发，后来对糖皮质激素的开发感兴趣。这一提议代表了我们工作的下一个进化步骤，它将完成我们对雄激素的研究，并更加重视糖皮质激素受体高亲和力配体的开发。几种可能的雄激素和糖皮质激素受体的碘化或氟化配体将被合成，然后在这项合作研究中测试它们竞争与整个类固醇受体阵列结合的能力。这些非放射性卤化类固醇类似物的相同前体将用于合成这些类似物的放射性卤化版本，这些类似物具有良好的发现特性。这些放射性类固醇将在一系列体外和体内激素分析中进行研究，以确定它们以受体介导的方式在组织中浓缩的能力。该提案特别要求为非放射性配体及其前体的化学合成提供资金。

This proposal seeks to continue investigations into the design and synthesis of halogenated analogs of steroid hormones. Synthetic procedures will be developed which will permit the incorporation of radioactive iodine (125I and 123I) and fluorine (18F) into androgens and glucocorticoids which will subsequently retain their hormonal activity. Radiolabeled androgens will be useful for the sensitive detection of androgen responsive tumors such as prostate cancer and for quantifying the androgen receptor in vitro. They will also have great utility for autoradiographic studies of tissues, such as brain, in which the androgen receptor is present, but localized in specific cells or regions. Such studies have great value in elucidating the role of androgens in processes such as the sexual differentiation of the brain in fetal development. Labeled compounds with glucocorticoid activity will be valuable in mapping and imaging of glucocorticoid receptor rich regions of the brain. Since the specific neurophysiological mechanisms by which corticosteroids influence neuronal function are not fully understood, such studies are of increasing importance in defining and understanding their role and function in the brain. In earlier work this laboratory has successfully emphasized the development of radiolabeled progestins and androgens with later interest developing in glucocorticoids. This proposal represents the next evolutionary step in our work, which will complete our studies of androgens and more heavily emphasize the development of high affinity ligands for the glucocorticoid receptor. Several potential iodinated or fluorinated ligands for this androgen and glucocorticoid receptors will be synthesized and then tested in this collaborative study for their ability to compete for binding to the entire array of steroid receptors. The same precursors of these non-radioactive halogenated steroid analogs will be used to synthesize the radio-halogenated versions of these analogs which show favorable finding characteristics. These radioactive steroids will be studied in a battery of in vitro and in vivo hormonal assays to ascertain their ability to concentrate in tissues in a receptor mediated fashion. This proposal specifically requests funding for the chemical synthesis of the non-radioactive ligands and their precursors.