CHAPTER 26 - ESTROGEN RECEPTOR-BASED AGENTS FOR IMAGING BREAST TUMORS: BINDING SELECTIVITY AS A BASIS FOR DESIGN AND OPTIMIZATION

Abstract

The presence of estrogen receptors in the majority of human breast tumors provides an opportunity for selective localization of γ-emitting estrogens. It is necessary that the radiopharmaceuticals be prepared with high specific activity (1000 Ci/mmole), and that they have both high affinity for receptor as well as low affinity for non-receptor proteins. The binding selectivity index (BSI) for an estrogen radiopharmaceutical is defined as the ratio of its affinity for the estrogen receptor to that of its affinity for non-receptor proteins. The BSI of any new compound can be evaluated by a combination of in vitro binding measurements and calculations based on octanol-water partition coefficients. We have prepared several steroidal and non-steroidal estrogen analogues, bearing halogen substituents in non-radiolabeled form, and we have prepared in radiolabeled form several of those whose BSI was high. The agents show highly selective uptakes by the uterus and by DMBA-induced mammary tumors in rats. The target tissue uptake selectivity (determined in vivo) parallels closely the BSI measured in vitro. Receptor binding affinity alone, however, is a poor predictor of the in vivo uptake selectivity. Images of DMBA-induced mammary tumors in rats were observed with 16-77 Br-bromoestradiol.