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Bromine-80m-labeled Estrogens: Auger Electron-emitting, Estrogen Receptor-directed Ligands with Potential for Therapy of Estrogen Receptor-positive Cancers¹

Ben May Institute [E. R. D., A. H.] and Department of Radiology [P. V. H., O. T. D., A. M. F.], The University of Chicago, Chicago, Illinois 60637; and Argonne National Laboratory [R. C. M., O. T. D., A. M. F.], Argonne, Illinois 60439

To assess their possible use for estrogen receptor (ER)-directed radio-therapy of estrogen receptor-containing cancers, two estrogens were synthesized with the Auger electron-emitting nuclide bromine-80m and administered to immature female rats. Both the triphenylethylene-based estrogen, [^80mBr]-2-bromo-1,1-bis(4-hydroxyphenyl)phenylethylene (Br-BHPE) and the steroidal estrogen [^80mBr]17-bromovinylestradiol, showed substantial diethylstilbestrol-inhibitable localization only in the estrogen target tissues, the uterus, pituitary, ovaries, and vagina and, except for the liver and intestines, generally lower concentrations in all other tissues at both 0.5 and 2 h. The [^80mBr]Br-BHPE (specific activity, 8700 Ci/mmol), was shown to bind specifically to the low salt extractable ER of the rat uterus. Comparing i.p., i.v., and s.c. administration of [^80mBr]BHPE the i.p. route was found to be particularly advantageous to effect maximum, DES-inhibitable concentrations of radiobromine in the ER-rich target organs in the peritoneal cavity. When the tissue distribution of the [^80mBr]Br-BHPE was compared with that of sodium bromide-80m, it was apparent that no substantial amounts of radiobromine were released from the bromoestrogen prior to its target tissue localization. The substantial concentration of these bromine-80m-labeled estrogens in ER-rich tissues, combined with previously reported evidence for the effective radiotoxicity of Auger electron-emitting nuclides within cell nuclei suggest a good potential for such ligands for therapy of ER positive cancers.

¹ Supported by the National Institutes of Health (CA27476, HD15513), Department of Energy contract W-31-109-ENG-38 and the Julius J. Reingold Fellowship Fund.

² To whom requests for reprints should be addressed, at The Ben May Institute, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637.

³ Present address: Medical Division, Brookhaven National Laboratory, Associated Universities, Inc., Upton, NY 11973.

⁴ Present address: Department of Medical Physics, University of Wisconsin Medical Center, 1300 University Avenue, Madison, WI 53706.

⁵ Deceased, to whose memory this manuscript is dedicated.

Received 6/26/87. Revised 10/26/87. Accepted 11/12/87.