This laboratory has pioneered the design and synthesis of gamma-emitting biologically active ligands for steroid hormone receptors that are widely used for clinical and basic studies of hormone action. Recently, we have developed a novel technique of in vitro autoradiography that allows the specific detection of occupied (activated) as well as unoccupied estrogen receptor. This technique, which uses our estrogenic ligand, 11beta- methoxy-16alpha[125]iodoestradiol, allows quantification of estrogen receptor in heterogeneous tissues within 24 hours. The occupied receptor represents that portion of the receptor population that has been activated by hormone in vivo, and is tightly associated with DNA. It mirrors the physiologically relevant receptor population. It can provide an excellent determinant of estrogen sensitivity of breast cancer, an estrogen stimulated marker similar to progesterone receptor. We will measure the total and occupied estrogen receptor in breast tumor specimens using this technique and compare the results with the immunohistochemical analysis of these tumors for estrogen receptor and progesterone receptor. Recently, we have synthesized 7alpha[125]iodo-5alpha-dihydrotestosterone, a novel ligand for the androgen receptor with good affinity, excellent specificity as well as very low non-specific binding. We will synthesize several 7 alpha- [125]iodo-analogs designed to increase affinity and protect the steroid nucleus from metabolism for use in in vivo imaging. These [125] labeled estrogens and androgens will be used in studies of hormone action in the brain. We have synthesized several analogs of estradiol that have been modified with carboxylic acids, and have little or no affinity for the estrogen receptor and are therefore not estrogenic. When converted to nonpolar short chain esters these non-charged derivatives bind with high affinity tot he estrogen receptor and produce marked local estrogenic effects. Since they are readily cleaved by esterases into the charged carboxylic compounds which are not estrogenic they are very labile and do not induce generalized estrogenic effects when administered intravenously or subcutaneously. They are a novel class of highly potent locally acting estrogen. We intend to synthesize a series of these alkyl esters of varying chain length at specific positions in the nucleus of estradiol and perform a structure activity analysis to determine the best candidate for use as a locally active estrogen. This unique estrogen would provide an important therapeutic agent for menopausal women suffering from vaginal atrophy but for whom systemic estrogens are contraindicated. Several of these carboxyl compounds will be converted to amides in order to design a pure antiestrogen for use in the treatment of estrogen sensitive breast cancer. These studies will provide unique agents for the diagnosis and treatment of women with breast cancer as well as probes of hormone action.
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