Effective management of breast cancer requires early diagnosis, accurate staging, prediction of the responsiveness to endocrine therapy, and early determination of therapeutic response. The role of the estrogen receptor (ER) as a predictive marker in breast cancer is well recognized, as is the effectiveness of hormonal agents such as the antiestrogen tamoxifen or aromatase inhibitors such as letrozole for treating certain cancers. The overall goal of this project-to improve the diagnosis and treatment of hormone- responsive breast cancer-is organized around three specific aims: (1) Develop Imaging Agents Specific for ERa and ERft: The ERa subtype in breast tumors is generally found together with the more recently discovered ERp subtype, which is thought to have a restraining effect on the proliferative drive of ERa. Thus, it is important to determine both ERa and ERp levels in breast tumors by imaging. We have selected two clinically promising ERp-selective ligands for labeling with F-18 or Br-76 for PET imaging of ERp in breast tumors. We will also prepare an ERa ligand with enhanced characteristics for imaging, using a diaryliodonium salt approach for introducing F-18 into phenols. (2) Develop Tc-99m Labeled Breast Tumor Imaging Agents: To make imaging of ER in breast tumors more readily accessible and less expensive, we will prepare ER ligands labeled with Tc-99m. The large radiometal will be accommodated in a manner that does not interfere with receptor binding by using recently developed methods to place a tricarbonyltechnetium organometallic unit into the interior of a non-steroidal ligand, producing compact metal- integrated ligands that have high affinity for the ER. This approach for integrated ligand design could be of general utility for nuclear receptor radiopharmaceutical development. (3) Develop ER-Guided Radiotherapeutic Agents: Estrogens labeled with Auger-emitting radionuclides have promise as ER-guided radiotherapy agents, because ER binds to gene regulatory sites in chromatin. To develop such an agent, we have selected for labeling with bromine radioisotopes an ER ligand that has both very high affinity and very low non-specific binding ER ligands, giving it the long target tissue retention needed for radiotherapy. The work we propose on the three components of this project should lead to improved methods for breast cancer diagnosis and therapy. Relevance: The estrogen receptor is a well recognized prognostic factor and therapeutic target for breast cancer. The aim of this project is to develop specialized radioactive agents (radiopharmaceuticals) to image this receptor non-invasively and to direct radiotoxic isotopes specifically to receptor-containing cancers. These agents could improve the selection of patients for individualized and optimized hormone therapy, sparing them the morbidity associated with standard radiation and chemotherapy which would provide them with no further benefit. [unreadable] [unreadable] [unreadable]