Diagnosis of low-grade glial tumors using 11C glutamine isotopomers

使用 11C 谷氨酰胺同位素诊断低级别胶质瘤

基本信息

批准号：
10316820
负责人：
Javier Villanueva-Meyer
金额：
$ 20.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316820
关键词：
Address Amino Acids Anabolism Applications Grants Benign Brain Carbon Dioxide Cell Line Cells Chemicals Citric Acid Cycle Clinical Complement Development Diagnosis Disease Enzymes Evaluation Glial Differentiation Glioma Glutamine Goals Human Hybrids Image Imaging technology In Vitro Institutional Review Boards Investigational Drugs Isocitrate Dehydrogenase Label Lead Lesion Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant - descriptor Metabolic Metabolic Pathway Metabolism Methodology Methods Mus Mutation Neurosurgeon Nutrient Oncologist Pathologic Pathway interactions Patients Performance Positioning Attribute Positron Positron-Emission Tomography Process Production Protocols documentation Protons Publishing Radiation Radiation Oncologist Radioisotopes Radionuclide therapy Radiopharmaceuticals Reporting Research Safety Signal Transduction Site Specificity Spectrum Analysis Techniques Technology Tissues Toxicity Tests Tracer Translating Tricarboxylic Acids Validation Work Workplace Xenograft procedure analog L base biological systems clinically relevant clinically translatable cohort dosimetry experimental study first-in-human gamma-Aminobutyric Acid human disease imaging modality improved in vivo interdisciplinary collaboration molecular imaging mutant programs radiologist radiotracer recruit tool tumor uptake

项目摘要

This proposal focuses on the development and validation of glutamine-derived 11C isotopomers for positron emission tomography. Specifically, the 1- and 5-positions of exogenously administered glutamine have different metabolic fates, depending on the dominant mechanisms of conversion present. We will therefore synthesize both L-[1-11C]glutamine ([1-11C]gln) and L-[5-11C]glutamine ([5-11C]gln), and investigate their use in detecting the isocitrate dehydrogenase mutation (IDHm), seen in several benign and malignant clinical diseases including low-grade glioma (LGG). Improved diagnosis of LGG would address a major challenge that neuro-radiologists, neuro-oncologists, radiation oncologists and neuro-surgeons encounter frequently, namely differentiating glial tumor from other brain entities. Patients with IDH-mutant (IDHm) glioma harbor the oncometabolite 2-hydroxyglutarate (2HG), which represents a promising way to detect LGG. We are motivated by a recent report establishing rapid conversion of exogenous glutamine to 2HG in IDHm lesions, representing a way to sequester the 11C radionuclide. The central hypothesis of this proposal is that a positron- labelled metabolic precursor of 2HG, [1-11C]gln, can be used to detect IDHm. We further predict significant advantages in using [1-11C]gln versus the reported [5-11C]gln isotopomer, based on the suppression of background signals related to tricarboxylic acid (TCA) cycle metabolism. When validated, this approach would set the stage for clinical use of [1-11C]gln PET in evaluating LGG and other IDHm lesions. We propose a multi-PI and interdisciplinary collaboration to validate [1-11C]gln PET as an IDHm-specific tool and perform the first patient studies using [1-11C]gln to further support the methodology. We will first develop the first radiosynthesis of [1-11C]gln, via adaptation of reported methods using [11C]CO2 and [11C]CN-. We will then compare the accumulation of [1-11C]gln to that of [5-11C]gln in IDHm versus IDH-wildtype (IDHwt) cells, both in vitro and in vivo (Specific Aim 1). In Specific Aim 2, all regulatory work and site approvals needed to study [1-11C]gln at UCSF will be accomplished. In Specific Aim 3, we will translate [1-11C]gln under the Radioactive Drug Research Committee (RDRC) program and study its performance in patients suffering from LGG. While this application focuses on LGG, a clinically translatable IDHm-specific tracer would revolutionize the workup and management of a large variety of clinically relevant lesions. Furthermore, robust methods to synthesize and evaluate amino-acid derived 11C isotopomers will dramatically improve the ability of PET to detect metabolic reprogramming in human disease.

该提案重点关注谷氨酰胺衍生的正电子 11C 同位素异构体的开发和验证发射断层扫描。具体而言，外源施用的谷氨酰胺的1-和5-位具有不同的代谢命运，取决于存在的主要转化机制。因此我们将合成L-[1-11C]谷氨酰胺（[1-11C]gln）和L-[5-11C]谷氨酰胺（[5-11C]gln），并研究它们在检测异柠檬酸脱氢酶突变（IDHm），常见于多种良性和恶性临床疾病，包括低级别胶质瘤（LGG）。改进 LGG 的诊断将解决一个重大挑战神经放射科医生、神经肿瘤科医生、放射肿瘤科医生和神经外科医生经常遇到，即将神经胶质瘤与其他脑实体区分开来。 IDH 突变（IDHm）神经胶质瘤患者具有致癌代谢物 2-羟基戊二酸 (2HG)，代表了检测 LGG 的一种有前途的方法。我们充满动力最近的一份报告证实，IDHm 病变中外源性谷氨酰胺快速转化为 2HG，代表一种隔离 11C 放射性核素的方法。该提案的中心假设是正电子标记的 2HG 代谢前体 [1-11C]gln 可用于检测 IDHm。我们进一步预测基于抑制，使用 [1-11C]gln 与报道的 [5-11C]gln 同位素异构体相比具有显着优势与三羧酸（TCA）循环代谢相关的背景信号。经过验证，该方法将为 [1-11C]gln PET 评估 LGG 和其他 IDHm 病变的临床应用奠定基础。我们提出多 PI 和跨学科合作来验证 [1-11C]gln PET 作为 IDHm 特定工具并使用 [1-11C]gln 进行第一个患者研究以进一步支持该方法。我们首先会开发首次放射合成 [1-11C]gln，通过使用 [11C]CO2 和 [11C]CN- 报道的方法进行调整。我们将然后比较 IDHm 与 IDH 野生型 (IDHwt) 细胞中 [1-11C]gln 的积累与 [5-11C]gln 的积累，体外和体内（具体目标 1）。在具体目标 2 中，所有监管工作和场地审批都需要加州大学旧金山分校的[1-11C]gln研究即将完成。在具体目标 3 中，我们将把 [1-11C]gln 翻译为放射性药物研究委员会 (RDRC) 计划并研究其在患有以下疾病的患者中的表现 LGG。虽然该应用的重点是 LGG，但临床上可翻译的 IDHm 特异性示踪剂将彻底改变各种临床相关病变的检查和处理。此外，稳健的方法合成并评估氨基酸衍生的 11C 同位素异构体将显着提高 PET 的能力检测人类疾病中的代谢重编程。