Synthesis and biological properties of 7α-cyano derivatives of the (17α,20 E/Z)-[ 125I]iodovinyl- and 16α-[ 125I]iodo-estradiols

Abstract

The synthesis, receptor binding affinity, estrogenic potency and tissue distribution of the 7α-cyano derivatives of the (17α,20 E/Z)-[ 125 I ]iodovinyl-(CIVE) and 16α-[ 125 I ]iodo-estradiols (CIE) are reported. The iodovinyl derivatives were prepared via the (17α,20 E/Z)-tri- n-butylstannyl intermediates, derived from the addition of tri- n-butyl tin hydride to the 17α-ethynyl group of the 7α-cyano-17α-ethynylestradiol, using triethylborane as a catalyst. The no-carrier-added [ 125 I ]-CIVE isomers were prepared via the same stereospecific reaction. [ 125 I ]-CIE was prepared from 7α-cyano-16β-bromoestradiol via halogen exchange with Na 125 I . Addition of the 7α-cyano group to 16α-iodoestradiol did not affect estrogen receptor binding affinity (RBA of CIE is 115). However the estrogenic potential of CIE, as measured by the capacity to stimulate the expression of the pS2 gene, was reduced to 1% as compared to that of estradiol. Addition of a 7α-cyano group to the (17α,20 E/Z)-IVE isomers reduced the RBA to 21 and 36, respectively, while the estrogenic potential was reduced to 2–3% of that of estradiol. Uterus uptake in immature rats of the 125 I -labeled CIVE 20 E-isomer and the 16α-iodo CIE peaked at 0.5 h post injection while the (17α,20 Z)-CIVE isomer showed a maximum only past 5 h post injection. Uptake of all three 125 I -labeled 7α-cyanoestrogens was suppressed by the co-injection of non-radioactive estradiol confirming the role of estrogen receptors in the localization process. Uterus retention pattern differ substantially from those of the analogues 7α-methylestrogens, which were previously shown to give high maximum 125 I -uptake values at 2 h post injection. Overall our data indicate that addition of a 7α-cyano group to 123 I -labeled estrogens does not improve their potential to serve as SPECT agents for the imaging of estrogen receptor densities in breast cancer.