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

The diagnosis and staging of breast cancer could be improved by the develop ment of imaging radiopharmaceuticals that provide a noninvasive determinati on of the estrogen receptor status in the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing 7 alpha-substituted estra diol complexes. The introduction of the 7 alpha side chain involves the alk ylation of tetrahydropyranyloxy-protected 6-keto estradiol. The methods use d to introduce the rhenium metal involve "3 + 1" and "4 + 1" mixed ligand c omplexes (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 h igh as 45% for the "3 + 1" complex 2c) when compared to the native ligand e stradiol. The polarity of some complexes (4ab) was modified to improve biod istribution properties by introducing (poly)ether linkages into the 7 alpha side chain (6, 7). These complexes provide a further refinement of our und erstanding of ligand structure-binding affinity correlations mr the estroge n receptor, and they furnish the synthetic groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor imaging agent s.