Synthesis, radiolabeling and tissue distribution of 11β-fluoroalkyl- and 11β-fluoroalkoxy-substituted estrogens: Target tissue uptake selectivity and defluorination of a homologous series of fluorine-18-labeled estrogens

We have synthesized six estrogens substituted at the 11β-position with a fluoroalkyl or fluoroalkoxy substituent. These compounds bind to the estrogen receptor with moderate to high affinity, with the fluoroalkyl analogs being higher affinity binders than the fluoroalkoxy ones. All of these fluorine-substituted estrogens were prepared in fluorine-18-labeled form, with high radiochemical purity and at effective specific activities (15.4-50.4 TBq/mmol; 415-1362 Ci/mmol) adequate for biodistribution studies. In immature female rats, five of the six fluoroestrogens showed selective uptake by the uterus, with uterine uptake as a percent of the injected dose per gram being 4-9% at 1 h, and uterus-to-blood or uterus-to-muscle ratios being 10-40. Selective uterine uptake was eliminated by co-administration of a blocking dose of unlabeled estradiol. The only compound that did not show selective uterine uptake was 11β-fluoropropoxyl estradiol; its rapid metabolism and its low affinity for the estrogen receptor, particularly at 25 °C, may account for its lack of specific uptake. The level of bone activity, an index of metabolic defluorination, shows that the defluorination rates of these six estrogens are a complex function of structure and functionality. Least prone to defluorination is 11β-(2-fluoroethoxy)estradiol and most prone is 11β-(2-fluoroethyl)estradiol. The extent of defluorination of the remaining compounds shows weak evidence for the protective effect of a heteroatom-substituted beta to the site of metabolism (the CH bonds on the fluorine-bearing carbon atom). The binding affinity, tissue distribution and metabolism of these 11β-fluoroalkyl- and fluoroalkoxy-substituted estrogens further our understanding of the behavior of fluorine-18-labeled estrogens as potential imaging agents for estrogen receptor-positive breast cancer.