VEGF-driven PET imaging of tumor angiogenesis

描述（由申请人提供）：本项目的总体目标是开发靶向PET探针，用于血管内皮生长因子（VEGF）受体的分子成像，VEGF是肿瘤患者的关键药物靶点。用FDG进行的肿瘤成像以及用血池造影剂进行的肿瘤脉管系统成像提供了关于肿瘤大小和肿瘤细胞代谢活性的重要一般信息。然而，特异性药物靶点的分子成像将极大地促进新药的开发、患者的合理选择和个性化治疗方案的开发。在我们于2005年1月12日提交的原始申请和2006年1月4日提交的第一次重新申请中，我们提出在体内合成和测试基于VEGF的Cu PET放射性示踪剂，用于成像肿瘤血管中的64种VEGF受体。到目前为止，我们的主要放射性示踪剂，命名为scVEGF/Cu，已经开发并在小鼠肿瘤模型中验证。scVEGF/Cu选择性和特异性地成像肿瘤血管中的VEGF受体。相反，功能失活或阻断的scVEGF/Cu在肿瘤中仅显示可忽略的积累。scVEGF/Cu提供了极好的PET图像，显示出异常低的非特异性器官摄取，在清除时间内基本上不降解或解离，并且缺乏可检测的肿瘤刺激作用。最后，荧光scVEGF为基础的探针共定位与内皮细胞标志物在体内。鉴于这些结果，我们现在可以继续验证scVEGF/Cu的潜在临床用途。由于VEGF受体的分子PET成像的目标是表征其在个体患者中的患病率，因此现在有必要确定scVEGF/Cu成像如何与VEGF受体患病率相关，以及内源性肿瘤VEGF和肿瘤灌注在放射性示踪剂摄取中发挥什么作用。我们提出了一种综合的实验方法来回答这些问题，这些问题对于理解scVEGF/Cu放射性示踪剂如何在个体患者中用于表征VEGF受体患病率至关重要。实现本提案的特定目标将为本项目II期的GMP生产、正式毒理学和初始临床试验提供合理依据。

DESCRIPTION (provided by applicant): The overall goal of this project is development of targeted PET probes for molecular imaging of receptors for vascular endothelial growth factor (VEGF), a crucial drug target in oncology patients. Tumor imaging with FDG, as well as imaging of tumor vasculature with blood pool contrast agents, provides important general information on tumor size and metabolic activity of tumor cells. However, molecular imaging of specific drug targets would greatly facilitate development of new drugs, rational selection of patients, and development of personalized treatment regiments. In our original submission on 12/01/2005 and the first resubmission on 04/01/2006 we proposed to synthesize and test in vivoa VEGF-based Cu PET radiotracer for imaging 64 VEGF receptors in tumor vasculature. By now, our lead radiotracer, named scVEGF/Cu, has been developed and validated in mouse tumor models. scVEGF/Cu selectively and specifically image VEGF receptors in tumor vasculature. In contrast, either functionally inactivated or blocked scVEGF/Cu display only negligible accumulation in tumor. scVEGF/Cu provides excellent PET images, displays unusually low non-specific organ uptake, essentially does not degrade or dissociate through the clearance time, and lacks detectable tumor-stimulating effects. Finally, a fluorescent scVEGF-based probe colocalizes with endothelial cell markers in vivo. In view of these results, we can now proceed with validation of scVEGF/Cu for a potential clinical use. Since the goal of molecular PET imaging of VEGF receptors is to characterize their prevalence in individual patients, it is now necessary to establish how imaging with scVEGF/Cu is linked to VEGF receptor prevalence and what roles play endogenous tumor VEGF and tumor perfusion in uptake of radiotracer. We propose an integrated experimental approach to answer these questions that are crucial for understanding how scVEGF/Cu radiotracer can be used in individual patients for characterizing of VEGF receptor prevalence. Accomplishing Specific Aims of this proposal will provide a rational basis for GMP-production, formal toxicology and initial clinical trials in Phase II of this project.