Synthesis, receptor binding, and tissue distribution of 7.alpha.- and 11.beta.-substituted (17.alpha.,20E)- and (17.alpha.,20Z)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-diols

Abstract

The 11 beta-methoxy, 11 beta-ethoxy, and 7 alpha-methyl derivatives of the isomeric (17 alpha,20E)- and (17 alpha,20Z)-(iodovinyl)estradiols 3 and 6, and their no-carrier-added [125I]iodovinyl analogues, were evaluated for their relative target-tissue retention and binding affinity for the estrogen receptor. The isomeric iodovinyl and [125I]iodovinyl derivatives were prepared via destannylation of the corresponding tributylstannyl precursors in the presence of H2O2 or chloramine-T, with retention of configuration. The 20Z isomers 6 exhibited slightly higher receptor binding affinities than the 20E isomers 3, with all eight isomeric products giving relative binding affinity values in the 20-50 range. The 11 beta- and 7 alpha-substituted (iodovinyl)estradiols gave substantially higher estrogen receptor-mediated uterus uptake as compared to the nonsubstituted parent molecule. Synergism between the effect of 11 beta- or 7 alpha-substituents and the configuration of the iodovinyl group was evident from the in vivo distribution pattern of [125I]-3 and -6. The best uterus uptake was observed, at 2 h postinjection, with the 20E isomer of 11 beta-methoxy derivative 3b. However, at 5 h postinjection the 20Z isomer 6b reached higher uterus concentrations than the 20E isomer 3b, and furthermore, these values are now comparable to those observed with the 20Z isomer of the 11 beta-ethoxy derivative 6c. In the case of the 7 alpha-methyl derivatives the differences in in vivo stability between the 20E and 20Z isomers was less pronounced, whereas the 20Z isomer 6d reached somewhat higher uterus to blood as well as nontarget ratios.

Radioiodinated estradiol dimer for estrogen receptor targeted breast cancer imaging

“…While for the classical method of iodine‐125 labeled estradiol, it requires an overnight radiolabeling reaction with only 25 to 65% yield (Hochberg, 1979). Furthermore, the formation of 5‐[ 125/131 I]iodo‐1,2,3‐triazole was reported to be effective in preventing metabolic deiodination in vivo (Ali et al., 1991). However, the molar activity of [ 125/131 I]ITE2 (0.3 ± 0.2 GBq/µmol) is not as high as expected (2 − 3 GBq/μmol, Yan et al., 2013).…”

“…Meanwhile, a variety of radioiodine-labeled estrogen derivatives for SPECT imaging of ER+ breast cancer have also been reported (Ali et al, 1993(Ali et al, , 2003 | 1333 XU et al Ali et al, 1988;Hochberg, 1979;Rijks et al, 1998;Symes et al, 1985;Yan et al, 2013). 16α-[ 125 I]iodoestradiol, 11β-methoxy substituent [ 125 I]iodovinylestradiol, and its analogs had been reported as potential single-photon-emitting ER imaging agents (Ali et al, 1988;Ali, Rousseau, Ghaffari, & van Lier, 1991;Hochberg, 1979). However, their high thyroid radioactivity uptake suggested severe deiodination occurred in vivo.…”

Steroid Receptor Ligands for Breast Cancer Targeting: An Insight into Their Potential Role As Pet Imaging Agents

“…It is well known from previous studies that a 7 -methyl substituent may increase the binding affinity of estradiol to the estrogen receptor [280]. Thus, to evaluate whether a 7 -methyl would improve the in vitro binding characteristics and the in vivo tissue distribution of [ 18 F]-labelled estrogens, VanBrocklin et al [281] prepared four 18 Fig.…”

C7-Substituted Estranes and Related Steroids

“…Further elaboration to the target compounds involve functional group interconversions including the manipulation of protective groups at C17 within the steroidal frame, as well as the terminus of the C7 side chain. A number of groups [47][48][49][50][51][52][53] . In the first case, much 1,2-addition product is isolated, while in the latter case the reaction temperature plays a significant role for the outcome of the reaction.…”

“…Once the chain is introduced at C7 of the estrane derivative, it can be functionally transformed [48][49][50][70][71][72]84,85], depending on the substituents that have been concomitantly introduced. The conditions of linking the chain to the steroidal frame often make it impossible to introduce formyl, alcohol or amine functions directly with the introduction of the chain.…”