2-FLUORINATED AND 4-FLUORINATED 16-ALPHA-[I-125]IODOESTRADIOL DERIVATIVES - SYNTHESIS AND EFFECT ON ESTROGEN-RECEPTOR BINDING AND RECEPTOR-MEDIATED TARGET TISSUE UPTAKE

The effect of 2- and 4-fluoro substitution on the estrogen receptor-me diated tissue localization of radioiodinated 16a-iodoestradiol (16 alp ha-IE(2)) and its 11 beta-methoxy analogue (11 beta-OMe-16 alpha-IE(2) ) was evaluated. Electrophilic substitution of estrone or 11 beta-meth oxyestrone with N-fluoropyridinium salt gave the 2- and 4-fluoro deriv atives which were subsequently converted to the 3,17 beta-enol diaceta te and brominated to yield exclusively the 16 alpha-bromo analogues. E pimerization gave the corresponding 16 beta-bromoestrones which were r educed to the 17 beta-hydroxy derivatives. Halogen exchange with NaI o r Na[I-125]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 prono unced at higher incubation temperatures. Biodistribution studies in im mature female rats showed that 4-fluoro substitution had only a modera te effect on receptor-mediated tissue uptake of the parent molecules w hereas 2-fluoro substitution resulted in strongly diminished tissue sp ecificity. The lower target selectivity of the 2-F, compared to the 4- F, analogue correlates to some extent with their different receptor bi nding 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 ca se of the 4-F-11 beta-OMe-16 alpha-IE(2), suggesting the potential of the analog labeled with I-123 as a radiopharmaceutical for receptor im aging in nuclear medicine. The isopotential maps of the fluorinated st eroids, obtained via semiempirical computer modeling on the molecular structures, show striking differences between the 4-F and 2-F derivati ves reflecting their varying biological properties.