title: 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.
authors.affiliation: MRC Group in the Radiation Sciences, Faculty of Medicine, University of Sherbrooke, Québec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Ali
authors.forename: J
authors.initials: J
authors.lastname: Rousseau
authors.forename: T G
authors.initials: TG
authors.lastname: Gantchev
authors.forename: J E
authors.initials: JE
authors.lastname: van Lier
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004970:Estrone / Q000737:chemistry; D005260:Female; D005461:Fluorine; D007457:Iodine Radioisotopes; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014599:Uterus / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D011960:Receptors, Estrogen; D005461:Fluorine; D004970:Estrone; D004958:Estradiol; C024871:16 alpha-iodoestradiol