Novel fluorinated amino ester prodrugs for PET imaging of gliomas

项目摘要/摘要 胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤，是一种平均寿命较短的致命性疾病 预计大约14个月。GBM和其他胶质瘤的影像和治疗 并发血脑屏障完整的肿瘤区，难以辨别治疗 来自活体肿瘤的影响。许多传统的造影剂，包括用于磁学的Gd螯合物 磁共振成像(MRI)和正电子发射断层扫描(PET)示踪剂不会穿过血脑屏障，因此， 无法看到整个肿瘤。一类领先的PET试剂--放射性标记氨基酸(AAs)靶向 L系统的氨基酸转运，可以跨越血脑屏障。然而，系统L基板有局限性，因为 随着时间的推移，一些肿瘤的双向转移和洗脱。当前神经成像技术的不足 技术导致诊断的不确定性，导致大量模棱两可的影像研究，延误治疗 复发、因假阳性的影像结果(如放射性坏死)而过度治疗，在某些情况下 徒劳的治疗。 为了满足对改进的GBM显像剂的迫切需求，我们开发了一种新型的18F标记的显像剂 以氨基酯前药为基础的成像策略。我们的新型18F标记氨基酯前药有望跨越 完整的血脑屏障通过脂性扩散，被酯酶切割，为脑部提供更高的肿瘤 L通过AA转运蛋白系统摄取在肿瘤细胞中的浓集进行追踪。这些 属性有望导致更高的灵敏度来检测存活的肿瘤组织，更准确地定义 肿瘤边界，以及比MRI和目前可用的PET更好的治疗反应评估 追踪器。这种方法将改善GBM的诊断、治疗计划和反应评估， 最终导致患者结果的改善。此外，我们的进展将为评估提供新的工具 涉及不通过血脑屏障的AAs的代谢途径，如谷氨酰胺。该项目将继续进行 通过两个具体目标： 具体目标1：合成和表征脑酯酶对18F标记的氨基酯前药的裂解作用 并测量GBM细胞对相应游离氨基酸的摄取。 具体目标2：测量氨基酸酯铅前体药的体内脑利用度和肿瘤显像学性质 在GBM PDX型号中。

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most common primary brain tumor in adults and a deadly disease with a median life expectancy of approximately fourteen months. The imaging and treatment of GBM and other gliomas is complicated by tumor regions with an intact blood-brain barrier (BBB) and difficulty in distinguishing treatment effects from viable tumor. Many conventional contrast agents including gadolinium chelates for magnetic resonance imaging (MRI) and positron emission tomography (PET) tracers do not cross the BBB and, therefore, cannot visualize the entire tumor. A leading class of PET agents, radiolabeled amino acids (AAs) targeting system L amino acid transport, can cross the BBB. However, system L substrates have limitations due to bidirectional transport and washout from some tumors over time. The shortcomings of current neuroimaging techniques result in diagnostic uncertainty, leading to numerous equivocal imaging studies, delays in treatment of recurrences, overtreatment due to false positive imaging results such as radiation necrosis, and in some cases futile therapies. To address the urgent critical need for improved GBM imaging agents, we have developed a novel 18F-labeled amino ester prodrug-based imaging strategy. Our novel 18F-labeled amino ester prodrugs are expected to cross the intact BBB through lipophilic diffusion, undergo cleavage by esterases, and provide higher tumor to brain ratios than system L tracers by concentrating in tumor cells through uptake by AA transporter systems. These properties are expected to lead to higher sensitivity for detecting viable tumor tissue, more accurate definition of tumor boundaries, and better assessment of treatment response than with MRI and currently available PET tracers. This approach will improve the diagnosis, treatment planning, and response assessment in GBM, ultimately leading to improved patient outcomes. In addition, our advance will provide new tools for assessing metabolic pathways involving AAs that do not cross the BBB, such as glutamine. This project will pursued through two Specific Aims: Specific Aim 1: Synthesize and characterize the cleavage of 18F-labeled amino ester prodrugs by brain esterases and measure the uptake of the corresponding free amino acids by GBM cells. Specific Aim 2: Measure in vivo brain availability and tumor imaging properties of the lead amino ester prodrugs in GBM PDX models.