Radiolabeled Inhibitors of Carbonic Anhydrase IX

描述（由申请人提供）：NCI估计，2008年美国将有超过54，000例新的肾细胞癌病例，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，25%的肾癌患者后来会出现转移性疾病并最终死于癌症。不同蛋白质在肿瘤细胞表面的表达提供了通过探测肿瘤的表型身份和生化组成来诊断和表征疾病的机会。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非侵入性成像技术，例如分子成像或核医学，用于检测肿瘤相关蛋白的存在和量，从而提供与疾病的诊断和程度、预后和治疗管理选项相关的重要信息。本提案的目标是开发一系列基于99 mTc的新型分子成像药物，其靶向细胞表面蛋白碳酸酐酶IX（CA-IX）用于单光子发射计算机断层扫描（SPECT）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表达的组成性上调提供了通过探测肿瘤的表型身份来诊断和表征肾细胞癌的机会。该研究计划将高亲和力靶向分子与螯合剂结合，用于诊断或治疗放射性核素的协调。在主要文献中描述了几类选择性和细胞膜不可渗透的CA-IX抑制剂，代表了放射性示踪剂设计的基础。CA-IX抑制剂的类似物将首先合成为非放射性标记的非放射性络合分子，并在生物化学和细胞测定中进行测试以验证与CA-IX的结合。然后用99 mTc放射性标记证明与CA-IX具有高亲和力结合的化合物，并在携带人肾癌异种移植物的小鼠中检查细胞结合以及肿瘤摄取和保留。由于CA-IX是一种细胞表面蛋白，因此靶标将易于获得，并具有简单的药代动力学分析。99 mTc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导致广泛应用。我们相信，99 m-Tc标记的CA-IX放射性示踪剂可用于肾透明细胞癌患者的诊断，分期和预后。 公共卫生相关性：NCI估计，2008年美国将有超过54，000例新的肾细胞癌病例，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，25%的肾癌患者后来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是一种通过肿瘤抑制因子Von Hippel Lindau失活而在85-95%的人透明细胞肾癌中组成性表达的蛋白质，但在正常肾脏和大多数正常组织中均不表达，可用于透明细胞肾癌患者的诊断，分期和预后。

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.