Radiolabeled Inhibitors of Carbonic Anhydrase IX

放射性标记的碳酸酐酶 IX 抑制剂

• 批准号: 7611838
• 负责人: John Louis Joyal
• 金额: $ 20.44万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611838
• 关键词: Affinity; American; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Binding; Biochemical; Biological Assay; Cancer cell line; Carbonic Anhydrase Inhibitors; Cell Surface Proteins; Cell membrane; Cell surface; Cells; Cellular Assay; Chelating Agents; Class; Complex; Conventional (Clear Cell) Renal Cell Carcinoma; Cultured Tumor Cells; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Enzymes; Erythrocytes; Evaluation; Exhibits; Foundations; Goals; Human; Image; Imaging Techniques; In Vitro; Institution; Kidney; Label; Lead; Life; Literature; Malignant Neoplasms; Malignant neoplasm of kidney; Measures; Medical; Medical center; Membrane Proteins; Mus; Normal tissue morphology; Organ; Patients; Penetration; Permeability; Pharmacologic Substance; Preparation; Prevalence; Proteins; Public Health; Radioactive; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Renal Cell Carcinoma; Renal carcinoma; Research; Rhenium; Series; Species Specificity; Staging; Standards of Weights and Measures; Structure; Sulfonamides; Surface; Technetium 99m; Techniques; Testing; Text; Therapeutic; Time; Tomography, Computed, Scanners; Tumor Suppressor Proteins; United States; Up-Regulation; Work; Xenograft procedure; analog; base; carbonate dehydratase; design; enzyme activity; in vivo; inhibitor/antagonist; molecular imaging; neoplastic cell; novel; outcome forecast; radiochemical; radiotracer; single photon emission computed tomography; success; tumor; uptake

DESCRIPTION (provided by applicant): The NCI estimates that in 2008 there will be more than 54,000 new cases of renal cell cancer in the United States and that it will claim the lives of more than 13,000 Americans. Overt metastatic disease is present at the time of diagnosis in 25% of patients, with a median survival of 10 months, and 25% of all patients with renal cancer will later manifest metastatic disease and ultimately succumb to their cancer. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis and therapeutic management options. The goal of this proposal is to develop a series of novel techenium-99m (99mTc) based molecular imaging pharmaceuticals that target the cell surface protein, carbonic anhydrase IX (CA-IX) for imaging by single photon emission computed tomography (SPECT). CA-IX is constitutively expressed in 85- 95% of human clear cell renal carcinomas through inactivation of the tumor suppressor, Von-Hippel-Lindau, but neither in normal kidney nor most normal tissues. The constitutive upregulation of CA-IX expression offers the opportunity to diagnose and characterize renal cell carcinoma by probing the phenotypic identity of the tumor. The research plan combines high affinity targeting molecules with the conjugation of a chelator for coordination of a diagnostic or therapeutic radionuclide. Several classes of selective and cell membrane impermeable CA-IX inhibitors have been described in the primary literature representing a foundation for the design of radiotracers. Analogs of CA-IX inhibitors will be synthesized first as non-radiolabeled rhenium complexed molecules and tested to verify binding to CA-IX in biochemical and cellular assays. Compounds demonstrating high affinity binding to CA-IX will then be radiolabeled with 99mTc and examined for cell binding, and tumor uptake and retention in mice bearing human renal cancer xenografts. As CA-IX is a cell surface protein, the target will be readily accessible, with a straightforward pharmacokinetic analysis. The use of 99mTc will lead to widespread application through kit preparation and the prevalence of SPECT scanners in medical institutions. We believe that the 99m-Tc labeled CA-IX radiotracers could be exploited for the diagnosis, staging, and prognosis of patients with clear cell renal carcinoma. PUBLIC HEALTH RELEVANCE: The NCI estimates that in 2008 there will be more than 54,000 new cases of renal cell cancer in the United States and that it will claim the lives of more than 13,000 Americans. Overt metastatic disease is present at the time of diagnosis in 25% of patients, with a median survival of 10 months, and 25% of all patients with renal cancer will later manifest metastatic disease and ultimately succumb to their cancer. The goal of this proposal is to develop a series of novel imaging pharmaceuticals targeting carbonic anhydrase IX, a protein constitutively expressed in 85-95% of human clear cell renal carcinomas through inactivation of the tumor suppressor, Von Hippel Lindau, but neither in normal kidney nor most normal tissues, that may be exploited for the diagnosis, staging, and prognosis of patients with clear cell renal carcinoma.

描述（由申请人提供）：NCI 估计 2008 年美国将有超过 54,000 例新发肾细胞癌病例，并将夺走超过 13,000 名美国人的生命。 25% 的患者在诊断时存在明显的转移性疾病，中位生存期为 10 个月，所有肾癌患者中有 25% 随后会出现转移性疾病并最终死于癌症。肿瘤细胞表面不同蛋白质的表达为通过探测肿瘤的表型特征和生化组成来诊断和表征疾病提供了机会。选择性结合特定肿瘤细胞表面蛋白的放射性分子允许使用无创成像技术，例如分子成像或核医学，来检测肿瘤相关蛋白的存在和数量，从而提供与疾病的诊断和程度、预后和治疗管理选择相关的重要信息。该提案的目标是开发一系列基于锝-99m (99mTc) 的新型分子成像药物，以细胞表面蛋白碳酸酐酶 IX (CA-IX) 为靶标，通过单光子发射计算机断层扫描 (SPECT) 进行成像。 CA-IX 通过肿瘤抑制因子 Von-Hippel-Lindau 的失活而在 85-95% 的人透明细胞肾癌中组成型表达，但在正常肾脏和大多数正常组织中均不表达。 CA-IX 表达的组成性上调为通过探索肿瘤的表型特征来诊断和表征肾细胞癌提供了机会。该研究计划将高亲和力靶向分子与螯合剂结合起来，以协调诊断或治疗放射性核素。原始文献中已经描述了几类选择性且细胞膜不可渗透的 CA-IX 抑制剂，为放射性示踪剂的设计奠定了基础。 CA-IX 抑制剂的类似物将首先作为非放射性标记的铼络合分子合成，并进行测试以验证在生化和细胞测定中与 CA-IX 的结合。然后，用 99mTc 放射性标记与 CA-IX 具有高亲和力结合的化合物，并检查携带人肾癌异种移植物的小鼠的细胞结合、肿瘤摄取和保留情况。由于 CA-IX 是一种细胞表面蛋白，因此可以通过简单的药代动力学分析轻松获得靶标。 99mTc的使用将通过试剂盒的制备和SPECT扫描仪在医疗机构中的普及而得到广泛应用。我们相信 99m-Tc 标记的 CA-IX 放射性示踪剂可用于透明细胞肾癌患者的诊断、分期和预后。 公共健康相关性：NCI 估计，2008 年美国将出现超过 54,000 例肾细胞癌新病例，并将夺走超过 13,000 名美国人的生命。 25% 的患者在诊断时存在明显的转移性疾病，中位生存期为 10 个月，所有肾癌患者中有 25% 随后会出现转移性疾病并最终死于癌症。该提案的目标是开发一系列针对碳酸酐酶 IX 的新型成像药物，碳酸酐酶 IX 是一种通过灭活肿瘤抑制因子 Von Hippel Lindau 在 85-95% 的人类透明细胞肾癌中组成型表达的蛋白质，但不在正常肾脏和大多数正常组织中表达，可用于透明细胞肾癌患者的诊断、分期和预后 肾癌。