RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

乳腺肿瘤显像剂的合理设计

• 批准号: 2087404
• 负责人: JOHN A. KATZENELLENBOGEN
• 金额: $ 25.94万
• 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 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2087404
• 关键词: breast neoplasms; diagnosis quality /standard; drug design /synthesis /production; drug metabolism; early diagnosis; estrogen analog; estrogen receptors; fluorine; image processing; laboratory rat; mammography; neoplasm /cancer classification /staging; neoplasm /cancer radionuclide diagnosis; prognosis; radiopharmacology; receptor binding; technetium

The estrogen receptor present in many breast tumors offers a mechanism by which estrogens, suitably labeled with appropriate radionuclides, might be taken up and retained selectively, thereby providing an image of the tumor. We have succeeded in preparing estrogens labeled with the positron- emitting radionuclide fluorine-18, and we have demonstrated that receptor- positive primary breast tumors, affected axillary lymph nodes, and metastatic tumors can be imaged very effectively. We have also improved the sensitivity of these agents by enhancing their binding selectivity (specific to non-specific binding ratio), through the incorporation of substituents known to raise receptor binding or lower lipophilicity, and by controlling their metabolism and clearance. Such agents could provide in estrogen receptor-positive tumors a characterization of the hormone receptivity of the cancer in situ (useful prognostic information on the likelihood of response to endocrine therapy) and a functional staging of the disease (information that may be important in selection of the most appropriate surgical interventions and follow-up therapy). The primary aim of the studies in the present application is to make a major extension of this methodology to the more widely available radionuclide technetium-99m, by carefully designing metal bis-amine bis- thiol complexes that are close structural mimics of high affinity steroidal and non-steroidal ligands for the estrogen receptor; the design is based on a novel superposition of molecular templates derived from metal complex geometry with steroidal and non-steroidal ligands. The second aim of the studies in this application are to develop methods for the synthesis of estrogens labeled with carbon-11. These agents are designed to have high receptor binding affinity and enhanced rates of clearance, so that good images can be obtained with this short-lived radionuclide, minimizing radiation dose to the patient and permitting repeat studies in one sitting that might assist in quantitation of estrogen receptor levels in tumors. All of these agents will be evaluated in terms of their estrogen binding affinity, their non-specific binding and affinity for certain serum binding proteins, and their tissue distribution in rats. The development of these novel agents for diagnostic imaging of estrogen receptor-positive breast tumors should extend and refine the process of staging of the cancer in individual patients, providing a more convenient and complete assessment of the degree of spread and the hormonal responsiveness of the cancer, and a more accurate prognosis for the effectiveness of various alternative forms of treatment.

许多乳腺肿瘤中存在的雌激素受体提供了一种机制，通过 哪些雌激素，适当地用适当的放射性核素标记，可能是 有选择地获取和保留，从而提供了 肿瘤。我们已经成功地制备了标记有正电子的雌激素- 释放放射性核素氟-18，我们已经证明了受体- 原发乳腺肿瘤阳性，腋窝淋巴结受累，以及 转移性肿瘤可以非常有效地成像。我们也有了进步 通过提高它们的结合选择性来提高这些试剂的灵敏度 (特定于非特定结合比)，通过并入 已知可提高受体结合或降低亲脂性的取代基，以及 通过控制它们的新陈代谢和清除。这样的代理可以提供 雌激素受体阳性肿瘤中激素的特征 原位癌的可接受性(关于 对内分泌治疗有反应的可能性)和功能分期 疾病(可能对选择大多数 适当的手术干预和后续治疗)。 本申请中的研究的主要目的是使 这一方法的主要扩展到更广泛的可用 放射性核素~(99)m，通过精心设计金属双胺双- 高亲和力的紧密结构模拟的硫醇络合物 雌激素受体的类固醇和非类固醇配体的设计 是基于一种新的分子模板叠加，分子模板源于 具有甾体和非甾体配体的金属络合物几何构型。这个 本申请中研究的第二个目标是开发方法 碳-11标记的雌激素的合成。这些特工是 设计成具有高受体结合亲和力和增强的 过关，这样才能获得好的图像，这是短暂的 放射性核素，最大限度地减少对患者的辐射剂量，并允许 在一次会议上重复研究可能有助于量化 肿瘤中的雌激素受体水平。所有这些特工都将接受评估 就它们的雌激素结合亲和力而言，它们的非特异性结合 以及对某些血清结合蛋白及其组织的亲和力 在大鼠体内的分布。 雌激素诊断显像剂的研究进展 受体阳性的乳腺肿瘤应该延长和完善 对个别患者的癌症分期，提供了更方便的 以及对扩散程度和荷尔蒙的全面评估 癌症的反应性，以及更准确的预后 各种替代治疗形式的有效性。