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%的患者在确诊时存在明显的转移疾病，中位生存期为10个月，所有肾癌患者中有25%后来会出现转移疾病，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成分来诊断和表征疾病提供了机会。放射性分子选择性地与特定的肿瘤细胞表面蛋白结合，允许使用非侵入性成像技术，如分子成像或核医学，来检测肿瘤相关蛋白的存在和数量，从而提供与诊断和疾病程度、预后和治疗方案相关的重要信息。这项建议的目标是开发一系列新型的基于~(99m)Te(99mTC)的分子成像药物，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在85-95%的人肾透明细胞癌中通过肿瘤抑制基因Von-Hippel-Lindau的失活而表达，但在正常肾脏和大多数正常组织中都不表达。CA-IX表达的结构性上调提供了通过探测肿瘤的表型特征来诊断和表征肾癌的机会。该研究计划将高亲和力靶向分子与配位的螯合剂结合起来，以协调诊断或治疗放射性核素。在主要文献中已经描述了几类选择性和细胞膜不透膜的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被合成为非放射性标记的Re络合分子，并在生化和细胞检测中验证与CA-IX的结合。显示与CA-IX高亲和力结合的化合物随后将被99mTc放射性标记，并在携带人肾癌异种移植瘤的小鼠身上检查细胞结合、肿瘤摄取和滞留。由于CA-IX是一种细胞表面蛋白，通过直接的药代动力学分析，靶标将很容易获得。~(99m)Tc的使用将通过试剂盒的制备和SPECT扫描仪在医疗机构的普及而得到广泛应用。我们认为，99m-Tc标记的CA-IX放射性示踪剂可用于肾透明细胞癌的诊断、分期和预后。 公共卫生相关性：NCI估计，2008年美国将有超过5.4万例新的肾细胞癌病例，它将夺走超过1.3万美国人的生命。25%的患者在确诊时存在明显的转移疾病，中位生存期为10个月，所有肾癌患者中有25%后来会出现转移疾病，并最终死于癌症。这项建议的目标是开发一系列针对碳酸氢酶IX的新型成像药物，该蛋白通过灭活肿瘤抑制基因Von Hippel Lindau在85-95%的人类透明细胞肾癌中表达，但在正常肾脏和大多数正常组织中都不表达，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.