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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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Johnson, George S
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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Bowlby, Deborah A; Brown, Theodore J; Hochberg, Richard B et al. (2016) In vitro Autoradiographic Analysis of Regional Changes in Estrogen Receptor Alpha in the Brains of Cycling Female Rats. Neuroendocrinology 103:538-51
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Olmsted, Sandra L; Tongcharoensirikul, Pakamas; McCaskill, Emmett et al. (2012) Synthesis and evaluation of 17?-E-20-(heteroaryl)norpregn-1,3,5(10),20 tetraene-3,17?-diols [17?-(heteroaryl)vinyl estradiols] as ligands for the estrogen receptor-? ligand binding domain (ER?-LBD). Bioorg Med Chem Lett 22:977-9
Haddad, Terra; Gershman, Rachel; Dilis, Robert et al. (2012) Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor. Bioorg Med Chem Lett 22:5999-6003
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Hanson, Robert N; Hua, Edward; Labaree, David et al. (2012) Convergent synthesis of a steroidal antiestrogen-mitomycin C hybrid using ""click"" chemistry. Org Biomol Chem 10:8501-8
Nettles, Kendall W; Bruning, John B; Gil, German et al. (2008) NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol 4:241-7
McCarthy, Thomas L; Hochberg, Richard B; Labaree, David C et al. (2007) 3-ketosteroid reductase activity and expression by fetal rat osteoblasts. J Biol Chem 282:34003-12
Kahn, Michael G C; Konde, Emmanuel; Dossou, Francis et al. (2006) Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids, potential glucocorticoid receptor-mediated imaging agents. Bioorg Med Chem Lett 16:3454-8

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