11β-Methoxy-, 11β-Ethyl- and 17α-Ethynyl-Substituted 16α-Fluoroestradiols: Receptor-Based Imaging Agents with Enhanced Uptake Efficiency and Selectivit

Martin G. Pomper, Andrea M. Thieme, Ralph D. Thomas, Dale O. Kiesewetter, Kathryn E. Carlson, Henry VanBrocklin, Carla J. Mathias, Michael J. Welch, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

We have prepared three analogues of 16α-fluoroestradiol (FES) substituted either with an 11β-methoxy group (1,11β-MeO-FES), an 11β-ethyl group (2,11β-Et-FES), or a 17α-ethynyl group (3,17α-ethynyl-FES). These substituents all lower the binding of FES to the serum proteins alphafetoprotein and sex steroid binding protein, but their effect on estrogen receptor binding varies: Receptor binding is increased by the 11β-ethyl and 17α-ethynyl groups, but decreased by the 11β-methoxy group. These substituents also have a parallel effect on the lipophilicity, and hence the nonspecific binding estimated for these compounds. All three compounds were prepared in fluorine-18 labeled form, at effective specific activities of 90-1600 Ci/mmol, by fluoride ion displacement reactions as done previously with FES. Tissue distribution studies in immature rats show high uptake selectivity by target tissue (uterus) and effective competition by an excess of unlabeled estradiol. Percent injected dose per gram values (% ID/g) at 1 h are 6% for 11/3-MeO-FES and 11-13% for 11/3-Et-FES and 17a-ethynyl-FES (FES itself has a % ID/g of 9%). Uptake selectivity in terms of uterus to blood or muscle ratios at 1 h is highest for 11/3-MeO-FES and 17a-ethynyl-FES (43-149). Metabolic consumption studies show that most activity in uterus is unmetabolized and in blood is rapidly and nearly completely metabolized. In muscle, FES and the substituted estrogens show intermediate levels of metabolic consumption; in some cases activity in muscle extracts is nearly unmetabolized. Thus, the substituents on FES cause major alterations in receptor and nonreceptor binding affinity, uptake efficiency and selectivity, and extent of metabolism. It is not readily clear, however, whether the alterations in uptake efficiency and selectivity are the result of differences in receptor or nonreceptor binding or lipophilicity, or altered patterns of metabolism. Nevertheless, these compounds should be useful in providing a spectrum of uptake properties that could be used for imaging different estrogen-receptor-containing structures.

Original languageEnglish (US)
Pages (from-to)3143-3155
Number of pages13
JournalJournal of medicinal chemistry
Volume33
Issue number12
DOIs
StatePublished - Dec 1990

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Pomper, M. G., Thieme, A. M., Thomas, R. D., Kiesewetter, D. O., Carlson, K. E., VanBrocklin, H., Mathias, C. J., Welch, M. J., & Katzenellenbogen, J. A. (1990). 11β-Methoxy-, 11β-Ethyl- and 17α-Ethynyl-Substituted 16α-Fluoroestradiols: Receptor-Based Imaging Agents with Enhanced Uptake Efficiency and Selectivit. Journal of medicinal chemistry, 33(12), 3143-3155. https://doi.org/10.1021/jm00174a009