Synthesis and binding affinities of novel re-containing 7α-substituted estradiol complexes: Models for breast cancer imaging agents

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor status in the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing 7α-substituted estradiol complexes. The introduction of the 7α side chain involves the alkylation of tetrahydropyranyloxy-protected 6-keto estradiol. The methods used to introduce the rhenium metal involve '3 + 1' and '4 + 1' mixed ligand complexes (2a-c and 5, respectively), tricarbonyl dithioether complexes (3), and the cyclopentadienyltricarbonylmetal organometallic system (4ab, 6, 7). These complexes showed binding affinities for the estrogen receptor (as high as 45% for the '3 + 1' complex 2c) when compared to the native ligand estradiol. The polarity of some complexes (4ab) was modified to improve biodistribution properties by introducing (poly)ether linkages into the 7α side chain (6, 7). These complexes provide a further refinement of our understanding of ligand structure-binding affinity correlations for the estrogen receptor, and they furnish the synthetic groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor imaging agents.