The estrogen receptor present in many breast tumors and targets regions of the brain offers a mechanism by which estrogens, suitably labeled with appropriate radionuclides, might be taken up, thereby providing an image of the tumor or target area. We have succeeded in preparing estrogens labeled with the positron-emitter fluorine-18 and have demonstrated that large, receptor-positive tumors and affected axillary lymph nodes can be imaged very effectively. The thrust of this proposal is to extend the sensitivity of these agents to small, receptor-poor tumors, (1) by enhancing their binding selectivity (specific to non-specific binding ratio) by incorporating substituents known to raise receptor binding or lower lipophilicity, and (2) by controlling their metabolism and clearance by providing a hydroxyl group for direct conjugation (phase II directed agents) or by incorporating the F-18 at a metabolically labile site (diagnostic soft drugs). The receptor and non-specific binding of these agents will be evaluated in vitro and their target site uptake efficiency and selectivity and the extent of metabolite generation and recirculation will be studied in rats in vivo. Finally, novel approaches to radiofluorination of arene and enol systems will be studied: fluoride ion addition or substitution of arene complexes with iron or manganese and an oxidative fluorination approach utilizing chemical, anodic or photochemical means to achieve reaction of fluoride ions with arene or enol cation radicals or dications. The successful development of selective and effective tumor and brain estrogen receptor imaging agents would be useful: It would aid in evaluating the extent of breast tumor invasion and metastasis, provide a prognostic indicator for hormone therapy, and assist in evaluating estrogen effects on behavior.