Tumor targeted radiotherapy with antibody- or peptide-based macromolecular bioconjugates presents a formidable problem of radiotoxicity of critical non-target tissues. Small-molecule radiopharmaceuticals can overcome these problems. However, for estrogen receptor (ER) positive tumors, the development of radiation pharmaceuticals for targeted radiotherapy is hampered by the loss of ER binding and the lack of in vivo target tissue uptake of these small molecules. This project will develop novel small molecule radiopharmaceuticals for targeted molecular radiotherapy of ER positive tumors. The approach involves the isosterical substitution of a rhenium or a phosphorous atom for a carbon atom in the estradiol framework, and the introduction of coordinating groups at appropriate locations to render the entire molecule topologically similar to estradiol. In Phase I, three Re-186 or P-32 containing estrogen mimics, based on estrone and estradiol molecular structures, will be synthesized and their specificity to ER and binding to sex hormone binding globulin (SHBG) will be determined. The steps in the process are: (1) synthesize N2S2 rhenium-estrone and estradiol mimics, and N2O phosphorous estradiol mimic; (2) determine the stability of the estrogen mimics; (3) assess the affinity of the rhenium and phosphorous estrogen mimics to ER subtypes by in vitro receptor binding assays; (4) determine the in vitro SHBG binding property and affinity of the estrogen mimics; and (5) determine the binding characteristics of estrogen mimics to cell membrane bound SHBG.
Commercial Applications and Other Benefits as described by the awardee: The primary clinical application of the estrogen mimics is for targeted molecular radiotherapy of breast carcinomas. However, they also should find use in the targeted radiotherapy of other ER+ tumors such as ovarian, endometrial, and prostate cancers, and ER-beta+ tumors such as osteosarcomas of osteoblasts, osteoclasts, and condrocytes. Further, the current approach could be directly applied to boron-neutron capture (BNCT) therapy by substituting a boron atom in the steroidal framework
