BIOLOGICALLY ACTIVE STEROID ANALOGS

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Radioactive steroids that are labelled with gamma-emitting isotopes are unusual probes of hormone action. When labelled with radioiodine, such biologically active steroid hormones are extremely sensitive ligands for the study of steroid receptors and they make possible the external imaging of human tumors that contain steroid hormone receptors. The first biologically active gamma-emitting steroid hormone 16alpha-[125I]iodo-17beta-estradiol was synthesized in this laboratory. It and our modified analog, 11beta-methoxy- 16alpha-[125I]iodo-17beta-estradiol, have been used extensively for the sensitive detection and quantification of the estrogen receptor. We are synthesizing other analogs of 16alpha-iodo-17beta-estradiol which may have superior estrogen receptor properties and will test them for in vivo concentration in estrogen target tissues. We will label the best of these analogs with [123I] for in vivo imaging of estrogen receptor containing human breast cancer. Recently we have succeeded in the synthesis of a long sought for steroidal probe, a gamma-emitting androgen, E-17alpha-(2'-iodovinyl-4,9-estradiene- 17beta-ol-3-one, E-MIVNT. We have synthesized E-MIVNT labelled with [125I] in carrier free form (2,200 Ci/mmol) and have found that is binds to the androgen receptor with very affinity and low nonspecific binding. E-[125I]MIVNT binds only poorly if it at all to other steroid receptors. We are testing E-MIVNT and other 17alpha- iodovinyl analogs for their androgenic potency, metabolism and ability to concentrate in vivo in tissues that contain the androgen receptor. The most suitable of these androgens will be synthesized with [123I] and used for imaging studies in males with prostatic cancer. We will synthesize the [125I]androgen and estrogen as probes in collaborative studies of androgen and estrogen action in the brain. We will synthesize an [123I]labelled glucocorticoid for Single Photon Emission Computed Tomography of glucocorticoid receptor rich regions of the primate brain. Using this ligand we will attempt to determine in vivo the kinetics of glucocorticoid interaction with its receptor. This [123I]glucocorticoid would provide a probe for investigating defects in the brain glucocorticoid receptor, which have been hypothesized to be involved in several disorders, including depression and stress. In our synthesis of gamma-emitting estrogens we have searched for regions of the steroid nucleus that are both accessible to chemical reactions and transparent to receptor interactions when bulky groups are substituted. In these studies we have found compounds that are unique estrogens and antiestrogens. In addition we have uncovered analogs that are active estrogens but extremely labile. We are synthesizing other derivatives of these steroids which may have important therapeutic actions for use as locally active estrogens in the menopause.