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

Abstract

The effect of 2- and 4-fluoro substitution on the estrogen receptor-mediated tissue localization of radioiodinated 16 alpha-iodoestradiol (16 alpha-IE2) and its 11 beta-methoxy analogue (11 beta-OMe-16 alpha-IE2) was evaluated. Electrophilic substitution of estrone or 11 beta-methoxyestrone with N-fluoropyridinium salt gave the 2- and 4-fluoro derivatives which were subsequently converted to the 3,17 beta-enol diacetate and brominated to yield exclusively the 16 alpha-bromo analogues. Epimerization gave the corresponding 16 beta-bromoestrones which were reduced to the 17 beta-hydroxy derivatives. Halogen exchange with NaI or Na[125I]I provided the A-ring fluorinated 16 alpha-iodoestradiols. The 4-F analogue exhibited higher affinity for estrogen receptors than the corresponding 2-F analogue, and these differences were more pronounced at higher incubation temperatures. Biodistribution studies in immature female rats showed that 4-fluoro substitution had only a moderate effect on receptor-mediated tissue uptake of the parent molecules whereas 2-fluoro substitution resulted in strongly diminished tissue specificity. The lower target selectivity of the 2-F, compared to the 4-F, analogue correlates to some extent with their different receptor binding properties; however, the rate of catabolism may also be involved. Differences in blood clearance further accentuated the localization properties to yield particularly high uterus to blood ratios in the case of the 4-F-11 beta-OMe-16 alpha-IE2, suggesting the potential of the analog labeled with 123I as a radiopharmaceutical for receptor imaging in nuclear medicine. The isopotential maps of the fluorinated steroids, obtained via semiempirical computer modeling on the molecular structures, show striking differences between the 4-F and 2-F derivatives reflecting their varying biological properties.

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). Among these derivatives, in vivo assays showed that a combination of 4-fluoro and 11b-methoxy substitution of 18 F-FES (e.g., 4-fluoro-11b-methoxy-16a- 18 F-FES [ 18 F-4FMFES]) displayed the highest uterine uptake and uterus-to-blood ratios in female rats (22).…”

Radioiodinated estradiol dimer for estrogen receptor targeted breast cancer imaging

“…Their uterus and thyroid uptakes were 0.46 ± 0.06%ID/g and 57.96 ± 9.47%ID/g for 2-F-16α-[ 125 I]IE 2 ; 2.7 ± 0.10%ID/g and 43.73 ± 5.67%ID/g for 4-F-16α-[ 125 I]IE 2 ; 4.72 ± 0.33%ID/g and 107.92 ± 24.31%ID/g for 2-F-11β-OMe-16α-[ 125 I]IE 2 (Yan et al, 2013); 6.35 ± 0.52%ID/g and 252 ± 11.75%ID/g for 7-Cyano-16α-[ 125 I]iodoestradiol; and 12.77 ± 0.61%ID/g and 118 ± 8.28%ID/g for 7-Cyano(17α,20E)[ 125 I]iodovinylestradiol (Ali et al, 2003) at 1 hr p.i., respectively. [ 131 I] ITE2 developed in this work showed a moderate uterine uptake (5.7 ± 0.4%ID/g) with good retention and obviously reduced thyroid uptake (2.3 ± 0.6%ID/g) when compared to the previously reported probes (Ali et al, 1993(Ali et al, , 2003Rijks et al, 1996Rijks et al, , 1998, indicating its binding affinity and good metabolic stability. Furthermore, the low non-specific uptake was fulfilled through the PEGylation of estrogen to reducing lipophilicity.…”

“…Among them, the most successful 18 F-labeled estrogen derivative, 16α-[ 18 F] fluoro-17β-estradiol ([ 18 F]FES), has a good affinity for ER+ tumors and predicts response to tamoxifen (Linden et al, 2006;Mortimer et al, 1996). 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).…”

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

“…Studies of the effect of A-ring substituents on the ER binding affinity of estradiol suggests a negative influence of groups of any size at C-1 [179,180]. Small groups are reasonably well tolerated at C-2 and C-4, whereas large groups and those that might involve an intramolecular hydrogen bond substantially reduce binding affinity [179,[181][182][183][184][185][186].…”