Androgen and Glucocorticoid Receptor Ligands

雄激素和糖皮质激素受体配体

• 批准号: 6727301
• 负责人: ROBERT M HOYTE
• 金额: $ 21.54万
• 依托单位: COLLEGE AT OLD WESTBURY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-10-01 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727301
• 关键词: androgen analog; androgen receptor; corticosteroid receptors; deuterium; drug design /synthesis /production; fluoride ion; glucocorticoids; halogenation; iodine; positron emission tomography; radionuclide emission tomography; radiotracer; receptor binding; single photon emission computed tomography; steroid hormone analog

This proposal seeks support to continue our progress in the design and synthesis of halogenated derivatives and analogs of steroid hormones that retain affinity for their cellular receptors and that can be prepared by procedures that permit the incorporation of radioactive iodine ([123]I) and fluorine ([18]F). Target compounds are androgens and glucocorticoids. The radiohalogenated androgens will have great utility for ln-vivo imaging of androgen receptor (AR) containing tissues where iodine-123 labeled compounds can be used in single photon emission computed tomography (SPECT) and fluorine-18 labeled androgens will be important because of their applications in positron emission tomography (PET). These sensitive methods are important for the detection of androgen responsive tumors such as prostate cancer as well as the metastases that may follow. Thus the labeled compounds are expected to be useful in monitoring the progress of cancer patients in therapy. Labeled compounds with glucocorticoid activity will be valuable in mapping and imaging of glucocorticoid receptor (GR) rich regions of the brain using SPECT ([123]1labeled compounds) and PET ([18]F-labeled compounds). Such studies are of increasing importance in defining and understanding the role and function of corticosteroids in the brain where they are reputed to be involved in psychiatric disorders such as depression and in the management of stress. This laboratory has successfully pursued the development of radiolabeled progestins, androgens and, more recently, glucocorticoids. This proposal seeks to optimize our synthetic work on androgens as well as to develop ester derivatives and deuterated analogs designed to improve tissue uptake and metabolic stability, thus leading to more effective imaging agents. Similarly we seek to expand upon and extend our success in the development of high affinity ligands for the glucocorticoid receptor by optimizing synthetic procedures, exploring new ligands and incorporating features designed to improve tissue uptake. Thus, the synthesis of several potential iodinated or fluorinated ligands for the androgen and glucocorticoid receptors, as well as derivatives thereof, will be pursued and optimized. These compounds will be tested in this collaborative study for their ability to compete for binding to the entire array of steroid receptors. The same precursors of these nonradioactive halogenated steroid analogs will be used to synthesize the radiohalogenated versions of those analogs and derivatives which show favorable binding 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 synthesis and other chemical studies of the nonradioactive ligands and their precursors.

这项提议寻求支持，以继续我们在设计和合成类固醇激素的卤代衍生物和类似物方面的进展，这些卤代衍生物和类固醇激素保持与其细胞受体的亲和力，并可以通过允许掺入 放射性碘([123]I)和氟([18]F)。目标化合物是雄激素和糖皮质激素。放射性卤代雄激素将在体内对含有雄激素受体(AR)的组织进行成像，其中碘-123标记化合物可以 将其应用于单光子发射计算机断层扫描(SPECT)和氟-18标记雄激素将因其在正电子发射断层扫描(PET)中的应用而具有重要意义。这些灵敏的方法对于检测前列腺癌等雄激素反应性肿瘤以及随之而来的转移是很重要的。因此，这些标记的化合物有望用于监测癌症患者的治疗进展。具有糖皮质激素活性的标记化合物在使用SPECT([123]1标记化合物)和正电子发射计算机断层扫描(PET)绘制和成像大脑中糖皮质激素受体(GR)丰富区域将是有价值的 ([18]F标记化合物)。这类研究在确定和理解皮质类固醇在大脑中的作用和功能方面越来越重要，因为它们被认为与抑郁症等精神疾病有关，并参与压力的管理。这个实验室已经成功地开发了放射性标记的孕激素、雄激素和最近的糖皮质激素。这项建议旨在优化我们在雄激素方面的合成工作，并开发旨在提高组织摄取和代谢稳定性的酯类和氚类似物，从而导致更有效的显像剂。同样，我们寻求通过优化合成程序、探索新的配体并结合旨在改善组织摄取的功能，来扩大和扩大我们在开发糖皮质激素受体高亲和力配体方面的成功。因此，几种潜在的雄激素和糖皮质激素受体的碘化或氟化配体的合成，如 以及其衍生产品，将被追求和优化。这些化合物将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及其衍生物的放射性卤化版本，这些类似物和衍生物具有良好的结合特性。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合成和其他化学研究提供资金。