RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

雌激素受体存在于许多乳腺肿瘤中， 提供了一种机制，通过这种机制，雌激素，适当地标记为 适当的放射性核素，从而提供图像 肿瘤或靶区的位置。 我们成功地制备了雌激素 用正电子发射体氟-18标记，并证明， 大的受体阳性肿瘤和受累的腋窝淋巴结可以 非常有效地成像。 这项建议的主旨是扩大 这些药物对小的受体缺乏的肿瘤的敏感性，（1）通过 增强它们的结合选择性（特异性结合至非特异性结合 比率）通过并入已知提高受体结合的取代基，或 较低的亲脂性，和（2）通过控制它们的代谢， 通过提供用于直接缀合的羟基清除（阶段II 定向试剂）或通过在代谢不稳定的位置掺入F-18， 诊断性软性药物（diagnostic soft drugs） 的受体和非特异性结合 这些药物将在体外进行评价， 效率和选择性以及代谢产物生成的程度， 将在大鼠体内研究再循环。 最后，新方法 对芳烃和烯醇体系的辐射稳定性进行了研究：氟化物 芳烃络合物与铁或锰的离子加成或取代 以及利用化学、阳极或 光化学手段，以实现氟离子与芳烃或 烯醇阳离子基团或双阳离子。 的研制成功 选择性和有效的肿瘤和脑雌激素受体显像剂 将是有用的：它将有助于评估乳腺肿瘤的程度 侵袭和转移，为激素提供了预后指标 治疗，并协助评估雌激素对行为的影响。

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.