BIOLOGICALLY ACTIVE STEROID ANALOGS

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This laboratory synthesized the first biologically active gamma- emitting steroid with the requisite characteristics for a steroid receptor ligand. This steroid, an estrogen, 16alpha-iodoestradiol (16alpha-IE2) is extremely stable and binds to the estrogen receptor with high affinity. Because it can be synthesized carrier-free, 2,200 Ci/mmol, it is widely used for the sensitive analysis of the estrogen receptor. Recently we have synthesized an analog of this iodinated C18-steroid, 11beta-methoxy-16alpha- iodoestradiol (11beta-CH3O-16alphaIE2) which is also an excellent ligand for the estrogen receptor, but unlike 16alpha-IE2, the 11beta-methoxy analog also has excellent estrogenic properties in vivo. This steroid is an extremely potent estrogen, and when labelled with radioiodine it concentrates in estrogen target tissues in high levels and for prolonged periods. Furthermore, the 11beta-methoxy analog produces extremely high levels of radioactivity in the target tissues relative to all other tissues. These characteristics make 11beta-CH3-16alpha-IE2 a unique probe of the estrogen receptor, and we will synthesize this 11beta-methoxy analog labelled with 2-123I and 125I and use the radiotracers to study estrogen responsive tissue. We intend to synthesize 11beta-CH3O-16alpha-123EI2 as a receptor based imaging agent for the detection and monitoring of estrogen receptor containing tumors. The 123I-labelled estrogen will be characterized for estrogen receptor binding in vitro; target tissue uptake in vivo. We will administer 11beta-CH3O-123IE2 to patients with breast and endometrial cancer in order to image their cancer and metastases with a gamma-camera. After surgery, the estrogen receptor content of the tumors will be quantified to demonstrate that the in vivo detection of this tracer correlates with estrogen receptor content of the tumor. In addition, we will utilize this unique ligand labelled with 125I to investigate other aspects of estrogen action, such as the autordiographic study of estrogen receptor containing regions of the brain, and the specific cytotoxic destruction of estrogen sensitive cells and genes. We will continue the design and synthesis of specific probes of other hormone receptors, including: characterization of the biological activity and the specific binding of two 125I-ligands we have recently synthesized for the progesterone receptor, one of which is also a photoaffinity label; the synthesis of 125I-ligands for the glucocorticoid and androgen receptors, as well as, biotinylated and fluorescent ligands for the glucocorticoid and estrogen receptors. We are synthesizing and testing a series of metabolically labile estrogens. These compounds bind to the estrogen receptor with high affinity, and are estrogenically active when tested directly. But because they are biologically labile, they are rapidly enzymatically converted into estrogenically inactive metabolites. Consequently, these estrogens appear to be systemically inactive. They show great promise as therapeutic local estrogens for the safe treatment of vaginal atrophy caused by estrogen deprivation or antiestrogen treatment, in women with or at risk for estrogen sensitive tumors.