Novel fluorinated amino ester prodrugs for PET imaging of gliomas

用于神经胶质瘤 PET 成像的新型氟化氨基酯前药

• 批准号: 10006800
• 负责人: Jonathan Edward McConathy
• 金额: $ 17.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-03 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006800
• 关键词: Address; Adult; Aftercare; Amino Acid Transport System L; Amino Acid Transporter; Amino Acids; Area; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Caring; Cells; Chelating Agents; Contrast Media; Data; Development; Diagnosis; Diagnostic; Diffusion; Disease; Esters; Gadolinium; Glioblastoma; Glioma; Glutamine; Head; Hydrolysis; Image; Investigational Therapies; Label; Lead; Life Expectancy; Magnetic Resonance Imaging; Malignant - descriptor; Measures; Metabolic Pathway; Metabolism; Modeling; Newly Diagnosed; Patient-Focused Outcomes; Patients; Plasma; Play; Positron-Emission Tomography; Pre-Clinical Model; Primary Brain Neoplasms; Prodrugs; Property; Radiation necrosis; Radiolabeled; Rattus; Recurrence; Research; System; Techniques; Time; Tracer; Translations; Tumor Tissue; Tumor Volume; Tyrosine; Uncertainty; Visualization; accurate diagnosis; base; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain tissue; cancer imaging; clinically relevant; contrast enhanced; design; esterase; first-in-human; glutamine analog; imaging agent; imaging properties; imaging study; improved; improved outcome; in vivo; lipophilicity; neoplastic cell; neuro-oncology; neuroimaging; novel; novel therapeutics; overtreatment; preclinical evaluation; response; tool; treatment effect; treatment planning; treatment response; tumor; tumor specificity; uptake

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.

项目总结/摘要 胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，也是一种中位寿命 预计约14个月。GBM和其他胶质瘤的成像和治疗是 伴有血脑屏障（BBB）完整的肿瘤区域，难以区分治疗 对肿瘤的影响。许多常规的造影剂，包括用于磁共振成像的钆螯合物， 共振成像（MRI）和正电子发射断层扫描（PET）示踪剂不穿过BBB，因此， 无法看到整个肿瘤。一类领先的PET药物，放射性标记的氨基酸（AA）靶向 系统L氨基酸转运，可穿越血脑屏障。然而，系统L衬底由于以下原因而具有限制： 随着时间的推移，一些肿瘤的双向运输和洗脱。当前神经影像学的缺点 技术导致诊断的不确定性，导致许多模棱两可的成像研究，治疗延迟 由于假阳性成像结果（如放射性坏死）导致的复发、过度治疗，以及在某些情况下 无用的治疗 为了解决对改善GBM成像剂的迫切需求，我们开发了一种新的18F标记的 基于氨基酯前药的成像策略。我们的新型18F标记的氨基酯前药有望与 完整血脑屏障通过亲脂性扩散，经历酯酶的裂解，并向脑提供更高的肿瘤 比系统L示踪剂的比率通过在肿瘤细胞中通过AA转运蛋白系统的摄取浓缩。这些 预期这些性质导致检测存活肿瘤组织的更高灵敏度， 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， 最终改善患者的预后。此外，我们的进步将提供新的工具， 涉及不穿过BBB的AA的代谢途径，例如谷氨酰胺。该项目将继续 通过两个具体目标： 具体目标1：合成并表征脑酯酶对18F标记的氨基酯前药的裂解 并测量GBM细胞对相应游离氨基酸的摄取。 具体目标2：测量先导氨基酯前药的体内脑利用度和肿瘤成像特性 在GBM PDX模型中。