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

被引:26
作者
ALI, H [1 ]
ROUSSEAU, J [1 ]
GANTCHEV, TG [1 ]
VANLIER, JE [1 ]
机构
[1] UNIV SHERBROOKE,FAC MED,MRC,RADOAT SCI GRP,SHERBROOKE J1H 5N4,PQ,CANADA
关键词
D O I
10.1021/jm00078a016
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The effect of 2- and 4-fluoro substitution on the estrogen receptor-mediated tissue localization of radioiodinated 16a-iodoestradiol (16 alpha-IE(2)) and its 11 beta-methoxy analogue (11 beta-OMe-16 alpha-IE(2)) 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[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 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-IE(2), suggesting the potential of the analog labeled with I-123 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.
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页码:4255 / 4263
页数:9
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