Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[ 18F]Fluoroestradiol-17β and 16β-[ 18f]fluoromoxestrol in isolated hepatocytes

Abstract

16β-[ 18F]Fluoromoxestrol ([ 18F]βFMOX) is an analog of 16α-[ 18F]fluoroestradiol-17β ([ 18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [ 18F]βFMOX was predicted to be as effective an imaging agent as [ 18F]FES. However, in a preliminary PET imaging study with [ 18F]βFMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [ 18F]βFMOX was observed. In search for an explanation for the unsuccessful [ 18F]βFMOX clinical trial, we have examined the rate of metabolism of [ 18F]βFMOX and [ 18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [ 18F]FES better than [ 18F]βFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [ 18F]FES 31 times faster than [ 18F]βFMOX, whereas mature rat cells metabolized [ 18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [ 18F]βFMOX. In the presence of SHBG, the metabolic consumption rate for [ 18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [ 18F]βFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-à-vis [ 18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [ 18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [ 18F]βFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [ 18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.