Androgen and Glucocorticoid Receptor Ligands

该提案寻求支持，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，这些衍生物和类似物保留了对其细胞受体的亲和力，并且可以通过允许掺入以下物质的程序制备： 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。放射性卤化的雄激素将具有很大的效用，用于含雄激素受体（AR）的组织的体内成像，其中碘-123标记的化合物可以 由于氟-18标记的雄激素在正电子发射断层扫描（PET）中的应用，它们将是重要的。这些敏感的方法对于检测雄激素反应性肿瘤（如前列腺癌）以及可能发生的转移非常重要。因此，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将在使用SPECT（[123] 1标记化合物）和PET对脑的糖皮质激素受体（GR）丰富区域进行绘图和成像中具有价值。 （[18] F标记化合物）。这些研究在定义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，皮质类固醇被认为与精神疾病如抑郁症和压力管理有关。该实验室已成功开发了放射性标记的孕激素、雄激素，最近还开发了糖皮质激素。该提案旨在优化我们对雄激素的合成工作，以及开发旨在改善组织摄取和代谢稳定性的酯衍生物和氘代类似物，从而产生更有效的成像剂。同样，我们寻求扩大和扩大我们的成功，在糖皮质激素受体的高亲和力配体的发展，通过优化合成程序，探索新的配体，并纳入旨在提高组织吸收的功能。因此，雄激素和糖皮质激素受体的几种潜在的碘化或氟化配体的合成，如 及其衍生物将被追求和优化。这些化合物将在这项合作研究中测试它们竞争结合整个类固醇受体阵列的能力。这些非放射性卤代类固醇类似物的相同前体将用于合成显示有利结合特性的那些类似物和衍生物的放射性卤代形式。这些放射性类固醇将在一系列体外和体内激素测定中进行研究，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。

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.