Synthesis and biodistribution studies of two novel radioiodinated areno‐annelated estra‐1,3,5(10),16‐tetraene‐3‐ols as promising estrogen receptor radioligands

Two novel radioiodinated areno-annelated estra-1,3,5(10),16-tetraenes, [125I]2-iodo-1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol (2-[125I]-MEBE) and [125I]4-iodo-1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol, (4-[125I]-MEBE) were synthesized for evaluation as potential ligands for the estrogen receptor. Radioiodination of 1′-methoxybenzo[4′,3′:16,17]estra-1,3,5(10),16-tetraene-3-ol at the A ring was accomplished by electrophilic aromatic substitution using [125I] sodium iodide and chloramine-T as oxidant. After purification by reverse phase HPLC, the two radioisomers (2-[125I]-MEBE and 4-[125I]-MEBE) were obtained in a radiochemical yield of 42 and 48%, respectively, in a radiochemical purity of greater than 95% and a high specific activity. The effect of the site of radioiodination (C2 vs C4) on the biological behaviour of the molecules was evaluated through biodistribution studies in immature female Sprague-Dawley rats. Both 2-[125I]-MEBE and 4-[125I]-MEBE are stable in vivo and are mainly excreted through the hepatobiliary pathway. Both localize in the uterus and ovaries via a receptor-mediated process, where the 2-[125I]-MEBE isomer has the higher specific ER binding and uterus selectivity. The favourable in vitro/in vivo stability and biodistribution profiles suggest that these radioligands are good candidates for further exploration of their potential clinical application. Copyright © 2006 John Wiley & Sons, Ltd.