RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

乳腺肿瘤显像剂的合理设计

• 批准号: 3167033
• 负责人: JOHN A. KATZENELLENBOGEN
• 金额: $ 17.61万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3167033
• 关键词: breast neoplasms; drug design /synthesis /production; drug metabolism; estradiol; estrogen analog; estrogen receptors; image processing; laboratory rat; neoplasm /cancer radionuclide diagnosis; radiopharmacology; radiotracer; receptor binding

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.

雌激素受体存在于许多乳腺肿瘤和靶区 提供了一种机制，通过这种机制，雌激素适当地被标记为 可摄取适当的放射性核素，从而提供图像 肿瘤或靶区的位置。我们已经成功地制备了雌激素 用正电子发射体氟-18标记，并证明了 受体阳性的大肿瘤和受累的腋窝淋巴结 成像效果非常好。这项建议的主旨是延长 这些药物对受体缺乏的小肿瘤的敏感性，(1)通过 增强它们的结合选择性(特定于非特定结合 比率)通过加入已知可提高受体结合或 降低亲脂性，以及(2)通过控制它们的代谢和 通过提供羟基进行直接结合来清除(第二阶段 定向制剂)或通过将F-18掺入代谢不稳定的 网站(诊断软性药物)。受体与非特异性结合 这些药物将在体外进行评估，并对其靶点摄取进行评估 效率和选择性以及代谢物产生和 再循环将在大鼠体内进行研究。最后，新的方法 将研究芳烃和烯醇体系的放射性氟化：氟化物 铁或锰与芳烃络合物的离子加成或取代 和氧化氟化方法，利用化学、阳极或 实现氟离子与芳烃或芳烃反应的光化学方法 烯醇阳离子基团或阳离子基团。成功地开发了 选择性有效的肿瘤和脑雌激素受体显像剂 将是有用的：它将有助于评估乳房肿瘤的范围 侵袭和转移，为激素提供预后指标 治疗，并协助评估雌激素对行为的影响。