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′‐methoxybenzo4′,3′:16,17]estra‐1,3,5(10),16‐tetraene‐3‐ol ( 2 ‐ ¹²⁵ I ]‐ MEBE ) and ¹²⁵I]4‐iodo‐1′‐methoxybenzo4′,3′:16,17]estra‐1,3,5(10),16‐tetraene‐3‐ol, ( 4 ‐ ¹²⁵ I ]‐ MEBE ) were synthesized for evaluation as potential ligands for the estrogen receptor. Radioiodination of 1′‐methoxybenzo4′,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 ‐ ¹²⁵ I ]‐ MEBE and 4 ‐ ¹²⁵ I ]‐ 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 ‐ ¹²⁵ I ]‐ MEBE and 4 ‐ ¹²⁵ I ]‐ 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 ‐ ¹²⁵ I ]‐ 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.