Radiochemical synthesis and tissue distribution of Tc-99-labeled 7alpha-substituted estradiol complexes

The diagnosis and staging of breast cancer could be improved by the development of radiopharmaceutical imaging agents that provide a noninvasive determination of the estrogen receptor (ER) status of tumor cells. Agents labeled with ^99mTc would be especially valuable in this regards. In attempting to achieve this goal, we synthesized four ^99mTc-labeled 7alpha-substituted estradiol complexes. One complex utilizes the "3+1" mixed ligand design to introduce the Tc metal, whereas the other three took advantage of the cyclopentadienyltricarbonylmetal (CpTM) design. The Tc moieties were attached to the 7alpha position of estradiol with a hexyl tether, a monoether tether, or a polyether tether. The corresponding rhenium compounds have binding affinities for the ER of 20-45% compared with estradiol. Radiochemical yields of the Tc-labeled compounds ranged from approximately 15% for the CpT-Tc complexes to 95% for the 3+1 inorganic complex. Tissue distribution studies in immature female rats showed low nonreceptor-mediated uptake in the target organs and high uptake in the nontarget organs such as liver and fat. These complexes represent the first time that estradiol has been labeled at the 7alpha position with ^99mTc and provide a further refinement of our understanding of ligand structure-binding affinity correlations for the ER: