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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要胶质母细胞瘤 (GBM) 是成人中最常见的原发性脑肿瘤，也是一种具有中位寿命的致命疾病预计大约十四个月。 GBM 和其他神经胶质瘤的影像学和治疗是由于肿瘤区域具有完整的血脑屏障（BBB），因此难以区分治疗活肿瘤的影响。许多常规造影剂，包括用于磁性的钆螯合物磁共振成像 (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。领先的 PET 试剂，放射性标记氨基酸 (AA) 靶向系统L氨基酸转运，可穿越血脑屏障。然而，L 系统基板存在以下局限性：随着时间的推移，一些肿瘤的双向运输和清除。目前神经影像学的缺点技术导致诊断的不确定性，导致大量模棱两可的影像学研究，延误治疗复发、由于放射坏死等假阳性成像结果导致的过度治疗，以及在某些情况下无效的治疗。为了满足改进 GBM 显像剂的迫切需求，我们开发了一种新型 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交叉完整的BBB通过亲脂性扩散，被酯酶裂解，并向大脑提供更高的肿瘤通过 AA 转运系统的摄取而集中在肿瘤细胞中，从而比系统 L 示踪剂的比率更高。这些预计这些特性将导致检测活肿瘤组织的灵敏度更高，肿瘤组织的定义更准确与 MRI 和目前可用的 PET 相比，可以更好地评估肿瘤边界，并更好地评估治疗反应示踪剂。这种方法将改善 GBM 的诊断、治疗计划和反应评估，最终改善患者的治疗效果。此外，我们的进步将提供新的评估工具涉及不穿过 BBB 的 AA 的代谢途径，例如谷氨酰胺。本项目将继续推进通过两个具体目标：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可用性和肿瘤成像特性在 GBM PDX 模型中。