RATIONAL DESIGN OF BREAST TUMOR IMAGING AGENTS

乳腺肿瘤显像剂的合理设计

• 批准号: 2087403
• 负责人: JOHN A. KATZENELLENBOGEN
• 金额: $ 26.43万
• 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/2087403
• 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， 用适当的放射性核素适当标记的雌激素可能是 选择性地被摄取和保持，从而提供所述图像的图像。 肿瘤我们已经成功地制备了用正电子标记的雌激素- 发射放射性核素氟-18，我们已经证明了受体- 阳性原发性乳腺肿瘤，受累腋窝淋巴结，和 转移性肿瘤可以非常有效地成像。我们还改进了 通过增强这些试剂的结合选择性 （特异性与非特异性结合比率），通过掺入 已知提高受体结合或降低亲脂性的取代基，和 通过控制它们的代谢和清除。这些药物可以提供 在雌激素受体阳性肿瘤中， 原位癌的接受性（关于癌症的有用预后信息） 对内分泌治疗反应的可能性）和 疾病（信息可能是重要的，在选择最 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进行以下研究： 这一方法的主要扩展， 放射性核素锝-99m，通过精心设计金属双胺双， 巯基复合物是高亲和性的紧密结构模拟物， 雌激素受体的甾体和非甾体配体;设计 基于一种新的分子模板叠加， 具有甾族和非甾族配体的金属络合物几何形状。的 本申请研究的第二个目的是开发用于 碳11标记的雌激素的合成。这些试剂 设计为具有高受体结合亲和力和增强的 间隙，这样就可以获得好的图像， 放射性核素，最大限度地减少对患者的辐射剂量， 在一次会议上重复研究，可能有助于定量 肿瘤中雌激素受体的水平。所有这些特工都将接受评估 就雌激素结合亲和力而言， 和对某些血清结合蛋白的亲和力，以及它们的组织 在大鼠中的分布 这些新的雌激素诊断显像剂的发展 受体阳性的乳腺肿瘤应该扩展和细化的过程， 癌症分期在个别患者，提供了一个更方便的 并对扩散程度和激素水平进行全面评估 癌症的反应性，以及更准确的预后， 各种替代治疗方式的有效性。