The estrogen receptor present in many breast tumors offers a mechanism by which estrogens, suitably labeled with appropriate radionuclides, might be taken up and retained selectively, thereby providing an image of the tumor. We have succeeded in preparing estrogens labeled with the positron- emitting radionuclide fluorine-18, and we have demonstrated that receptor- positive primary breast tumors, affected axillary lymph nodes, and metastatic tumors can be imaged very effectively. We have also improved the sensitivity of these agents by enhancing their binding selectivity (specific to non-specific binding ratio), through the incorporation of substituents known to raise receptor binding or lower lipophilicity, and by controlling their metabolism and clearance. Such agents could provide in estrogen receptor-positive tumors a characterization of the hormone receptivity of the cancer in situ (useful prognostic information on the likelihood of response to endocrine therapy) and a functional staging of the disease (information that may be important in selection of the most appropriate surgical interventions and follow-up therapy). The primary aim of the studies in the present application is to make a major extension of this methodology to the more widely available radionuclide technetium-99m, by carefully designing metal bis-amine bis- thiol complexes that are close structural mimics of high affinity steroidal and non-steroidal ligands for the estrogen receptor; the design is based on a novel superposition of molecular templates derived from metal complex geometry with steroidal and non-steroidal ligands.
The second aim of the studies in this application are to develop methods for the synthesis of estrogens labeled with carbon-11. These agents are designed to have high receptor binding affinity and enhanced rates of clearance, so that good images can be obtained with this short-lived radionuclide, minimizing radiation dose to the patient and permitting repeat studies in one sitting that might assist in quantitation of estrogen receptor levels in tumors. All of these agents will be evaluated in terms of their estrogen binding affinity, their non-specific binding and affinity for certain serum binding proteins, and their tissue distribution in rats. The development of these novel agents for diagnostic imaging of estrogen receptor-positive breast tumors should extend and refine the process of staging of the cancer in individual patients, providing a more convenient and complete assessment of the degree of spread and the hormonal responsiveness of the cancer, and a more accurate prognosis for the effectiveness of various alternative forms of treatment.
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