THE SYNTHESIS OF 7-ALPHA-METHYL-SUBSTITUTED ESTROGENS LABELED WITH F-18 - POTENTIAL BREAST-TUMOR IMAGING AGENTS

The 7 alpha-methyl substituent is reported to increase the binding affinity of estradiol for the estrogen receptor (ER). In older to evaluate whether this substituent would improve the in vitro binding characteristics and the in vivo tissue distribution of F-18 labeled estrogens that we ale developing as positron emission tomographic (PET) imaging agents for ER-positive breast tumors, we have prepared four F-18 labeled analogs of 7 alpha-methylestradiol. These ligands were labeled in the 16 alpha or 16 beta position with F-18 by nucleophilic displacement of the corresponding epimeric estrone trifluoromethanesulfonates with F-18 fluoride ion. Lithium aluminum hydride reduction afforded the estradiol (E(2)) series, while lithium trimethylsilylacetylide addition provided the 17 alpha-ethynylestradiol (EE(2)) series. The decay-corrected yields were 2-35% for a synthesis time of 85 minutes for the E(2) series, and 120 minutes for the EE(2) series, and the effective specific activities were 158-1213 Ci/mmol. In nearly every case, the 7 alpha-methyl substituent increases ER binding affinity (measured at 25 C) and decreases binding to high affinity serum steroid binding proteins, alphafetoprotein, and sex steroid binding protein, this substituent, however, increases the lipophilicity and the predicted non-specific binding (estimated from octanol-water partition coefficients determined by reverse-phase high-pressure liquid chromatography/[HPLC]), with the result that the ratio of ER binding to non-specific binding is nearly the same for the 7 alpha-methyl substituted analogs as for the corresponding unsubstituted analogs. In vivo distribution studies demonstrated a high level of receptor-mediated uptake in receptor-rich target tissues (uterus, ovaries), and in some cases, other tissues with low ER titers (secondary target tissues, e.g., muscle, thymus) showed significant displaceable uptake, presumed to be receptor-mediated. The uterus to blood ratios were higher for the EE(2) series, reflecting mainly a diminished level of blood activity in the EE(2) series. These analogs exhibited in vitro and in vivo characteristics comparable to the clinically useful 16 alpha-fluoroestradiol; however, in some cases, the uptake of the 7 alpha-methyl substituted analogs, by low ER-titer secondary target tissues, is more specific.