16 beta-([18F]fluoro)estrogens: systematic investigation of a new series of fluorine-18-labeled estrogens as potential imaging agents for estrogen-receptor-positive breast tumors.

In order to understand the structural features that might lead to an estrogen receptor (ER) based breast tumor imaging agent with improved uptake characteristics, we have synthesized several new analogs of 16 beta-fluoroestradiol (beta FES) and studied their tissue distribution in immature rats. The compounds we prepared were 11 beta-methoxy-beta FES (7a), 11 beta-ethyl-beta FES (7b), 17 alpha-ethynyl-beta FES (8c), 17 alpha-ethynyl-11 beta-methoxy-beta FES (8a), and 11 beta-ethyl-17 alpha-ethynyl-beta FES (8b). All of the analogs exhibit good affinity for ER, ranging at 25 degrees C from 10 to 460, with estradiol equal to 100. Measurement of their octanol/water partition coefficients by an HPLC method allowed us to estimate their level of nonspecific binding and thereby to predict their binding selectivity indices (BSI, i.e., the ratio of their ER-specific to nonspecific binding); the BSI values of three fluorine-substituted analogs exceed that of estradiol. These ligands have been labeled in the 16 beta position with fluorine-18 by the nucleophilic displacement of an alpha-disposed trifluoromethanesulfonate by [18F]fluoride ion. Reduction with lithium aluminum hydride produced the estradiol series ([18F]-7a-c), while treatment with lithium trimethylsilylacetylide afforded the ethynylated series ([18F]-8a-c). The synthesis time was 85 min for [18F]-7a-c and 120 min for [18F]-8a-c, with radiochemical yields ranging from 16 to 43%, and effective specific activities being 90-2900 Ci/mmol (3.3-107 TBq/mmol). In tissue distribution studies in immature female rats, all of the labeled analogs demonstrated ER-selective uptake in the principal target tissues, the uterus and the ovaries, and also in organs with lower titers of ER, the secondary target sites kidney, thymus, fat, and muscle. Although factors other than specific and nonspecific binding obviously affect the tissue distribution of these 16 beta-fluoroestrogens, we find that their ER-specific uptake by both the principal and the secondary target tissues correlates with their BSI values at a high level of statistical significance in most cases. The ethynylated-11 beta-methoxy analog [18F]-8a had high selectivity (uterus to blood ratio) after 3 h and exhibited the highest uterine uptake (percent injected dose/gram) of any fluorine-substituted estradiol ligand we have studied to date. This compound has been chosen for more detailed studies (to be described elsewhere), including clinical trials in human patients diagnosed with primary breast cancer.