RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

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Estrogen receptors that are present in the majority of human breast tumors provide a selective uptake mechanism for estrogens. Thus, in principle, it should be possible to image human breast tumors with gamma-emitting estrogens haveing suitable binding selectivity and sufficiently high specific activity, and thus to locate primary and metastatic tumors that are estrogen receptor-positive and to assay their receptor content in situ. We have developed a measure of binding selectivity (the binding selectivity index) that can be used to assist in the development of optimal imaging agents. Using this index as a guide, we have prepared 16delta-bromo estrogens, labeled with Br-77 at high specific activity, and we have demonstrated that they are taken up with high selectivity by estrogen target tissues. They could also be used to image mammary tumors in animals and in human breast cancer patients, in preliminary studies. However, the effective use of tumor imaging agents in humans will require shorter half-life isotopes, capable of providing much higher resolution images. Thus, we are developing syntheses of several positron-emitting (F-18, C-11) estrogens that will be used in conjunction with positron tomographic detectors to provide three-dimensional images of human breast tumors. We will also study halofluorination and fluoride additions to iron pentadienyl cation complexes as part of a more general development of fluorination methods suitable for F-18 labeling without carrier dilution. The target tissue and mammary tumor uptake selectivity of the gamma-emitting estrogens will be studied in experimental animals. We will also try to validate a pharmacokinetic model that will enable receptor site concentration and affinity to be determined by analysis of target tissue and blood activity profiles. The successful development of such imaging agents should assist in the detection of breast tumors and improve the prediction of response to hormone therapy.