Synthesis of A-ring fluorinated derivatives of iodine-125-labeled (17.alpha.,20E/Z)-iodovinylestradiols: effect on receptor binding and receptor-mediated target tissue uptake

Abstract

We have prepared a series of 2- and 4-fluoro derivatives of the isomeric (17 alpha,20E)- and (17 alpha, 20Z)iodovinylestradiols (IVE2) and also the analogs substituted with either a 7 alpha-methyl (7 alpha-Me-IVE2) or 11 beta-methoxy group (11 beta-OMe-IVE2) and evaluated their in vitro and in vivo properties. Electrophilic substitution of the estrone derivatives with N-fluoropyridinium salt gave the 2- and 4-fluoro analogs which were subsequently converted to the 17 alpha-ethynyl derivatives. The tributylstannyl intermediates were obtained from the corresponding 17 alpha-ethynyl analogs using azobisisobutyronitrile or triethylborane as catalyst. All 12 products were also prepared as their no-carrier-added [125I]iodovinyl analogs via destannylation of the tributylstannyl precursors. Binding affinity for the estrogen receptor (ER) was in general higher for the 4-F derivatives as compared to the 2-F derivatives, while the 20Z isomers of the same compounds showed somewhat higher ER binding affinity as compared to the 20E isomers. The combination of an A-ring fluoro and 7 alpha- or 11 beta-substituent decreased ER binding affinity. Substitution of a fluoro atom at C-4 on either the 17 alpha-ethynylestradiol or isomeric 17 alpha-IVE2 enhanced the affinity of the parent molecule for the ER. A-ring fluorination of all other analogues tested had no effect or depressed ER binding affinity. Varying incubation conditions showed substantial differences in ER binding kinetics between the 20E and 20Z isomers. Tissue distribution in immature female rats showed that the highest uterus uptake and uterus to blood/nontarget ratios in the IVE2 series were obtained with the 4-F-(17 alpha,20Z)IVE2 isomer. The combination of A-ring fluoro and 7 alpha- or 11 beta-substitution decreased uterus uptake but had little or no effect on uterus to blood/nontarget ratios. The highest uterus to blood ratios were observed for the 4-F-(17 alpha,20E)11 beta-OMe-IVE2 (75 at 6 h and 125 at 12 h pi) reflecting rapid blood clearance and in vivo stability, as confirmed by the low levels of thyroid radioactivity. The lack of correlation between ER binding affinities and uterus uptake, and/or uptake ratios, suggests that other factors, including nonspecific binding and metabolic processes, also are involved in the tissue localization process. Our data suggest that 4-F substitution onto (17 alpha,20Z)IVE2 and (17 alpha,20E)11 beta-OMe-IVE2 enhances the potential of these compounds to function as SPECT imaging agents of ER-rich tissues.

2- and 4-Fluorinated 16.alpha.-[125I]iodoestradiol derivatives: synthesis and effect on estrogen receptor binding and receptor-mediated target tissue uptake

“…In contrast, the addition of fluorine at C-4 enhances catechol formation.17 Whereas 4-F addition onto estradiol has little effect on ER binding affinities, 2-F addition results on a marked decrease in receptor affinity.18 Radioiodinated 17a-iodovinylestradiol derivatives constitute another class of promising ligands where uptake by ER-rich target tissues has been shown to improve substantially upon 11/3-or 7a-substitution.19 We have recently shown that addition of a 2or 4-fluoro atom to 17a-iodovinylestradiol (IVE2) derivatives significantly altered the in vitro and in vivo behavior of the steroid. 20 On account of this, we extended this study to include the effect of 2-and 4-fluorine substitution onto 16a- [126I]IE2 and the 11/3-methoxy analogue (ll/3-OMe-16a-IE2). The 126I-labeled products were prepared via a rapid halogen exchange reaction, and tissue distribution and ERmediated uterus uptake was established in immature female rats.…”

Improved Estrogen Receptor Assessment by PET Using the Novel Radiotracer 18F-4FMFES in Estrogen Receptor–Positive Breast Cancer Patients: An Ongoing Phase II Clinical Trial

“…To improve the metabolic stability and overall performance of 18 F-FES for ER imaging, many modifications of the parent estradiol molecule were made and the biologic effect evaluated over the past few decades (15)(16)(17)(18). A series of 11b-methoxy-or A-ring fluorinesubstituted 18 F-FES derivatives were synthesized by our research group (19)(20)(21).…”

Design and Synthesis of Estrogen Derivative

“…There are many procedures for development of new estrogen derivatives. Nevertheless, despite its wide scope, have some drawbacks e.g., several agents used have a limited stability and their preparation require condition specials [11][12][13][14] . Analyzing these data, in this study we report a straightforward route for synthesis of an estrogen derivative using some strategies.…”