Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[F-18]fluoroestradiol-17 beta and 16 beta-[F-18]fluoromoxestrol in isolated hepatocytes

16 beta-[F-18]Fluoromoxestrol ([F-18]beta FMOX) is an analog of 16 alpha-[F -18]fluoroestradiol-17 beta ([F-18]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, [F-18]beta FMOX w as predicted to be as effective an imaging agent as [F-18]FES. However, in a preliminary PET imaging study with [F-18]beta FMOX of 12 patients, 3 of w hom had ER+ breast cancer, no tumor localization of [F-18]beta FMOX was obs erved. In search for an explanation for the unsuccessful [F-18]beta FMOX cl inical trial, we have examined the rate of metabolism of [F-18]beta FMOX an d [F-18]FES in isolated rat, baboon, and human hepatocytes. We have also st udied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [F-18]FES better than [F-18]beta FMOX, on these rates of metabo lism. Immature rat hepatocytes were found to metabolize [F-18]FES 31 times faster than [F-18]beta FMOX, whereas mature rat cells metabolized [F-18]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [F-18]beta FMOX. In the presence of SHBG, the metabolic consumption ra te for [F-18]FES in mature rat hepatocytes decreased by 26% Thus, the very favorable target tissue uptake characteristics of [F-18]beta FMOX determine d in the rat probably result from its comparative resistance to metabolism (vis-a-vis [F-18]FES) in this species, an advantage that is strongly reflec ted in comparative metabolism rates in rat hepatocytes. In the baboon and h uman, [F-18]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 m etabolism of this compound in baboon and human hepatocytes relative to [F-1 8]beta FMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake o f [F-18]FES in ER+ tumors by selectively protecting this ligand from metabo lism and ensuring its delivery to receptor containing cells. In addition to current screening methods for F-18 estrogens that involve evaluating in vi vo ER-mediated uptake in the immature female rat, studies comparing the met abolism of the new receptor ligands in isolated hepatocytes, especially tho se from primates or humans, may assist in predicting the potential of these ligands for human PET imaging. NUCL MED BIOL 26;1:123-130, 1999. (C) 1998 Elsevier Science Inc.