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.