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.

该提案重点介绍谷氨酰胺衍生的11C同位素的开发和验证排放断层扫描。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，具体取决于当前转化的主要机制。因此，我们会合成L- [1-11C]谷氨酰胺（[1-11C] GLN）和L- [5-11C]谷氨酰胺（[5-11C] GLN），并研究它们在在几种良性和恶性临床包括低级神经胶质瘤（LGG）在内的疾病。改进的LGG诊断将解决一个重大挑战神经射线科医生，神经肿瘤学家，辐射肿瘤学家和神经外科医生经常遇到，即将神经胶质肿瘤与其他大脑实体区分开。 IDH突变（IDHM）神经胶质瘤的患者港口 oncometabolite 2-羟基戊二酸（2HG），它代表了检测LGG的一种有希望的方法。我们很有动力通过最近的一份报告，建立了外源谷氨酰胺在IDHM病变中快速转化为2HG 一种隔离11C放射性核素的方法。该提议的核心假设是标记的2Hg的代谢前体[1-11c] GLN可用于检测IDHM。我们进一步预测基于抑制与三羧酸（TCA）周期代谢有关的背景信号。验证后，这种方法将在评估LGG和其他IDHM病变时临床使用[1-11C] GLN PET的临床使用阶段。我们提出了一个多PI和跨学科的合作，以验证[1-11c] GLN PET作为IDHM特定工具并使用[1-11C] GLN进行首次患者研究以进一步支持该方法。我们将首先发展 [1-11c] GLN的第一个放射性合成是通过使用[11C] CO2和[11C] CN-的改编方法的适应。我们将然后将[1-11c] GLN的积累与IDHM与IDH-WildType（IDHWT）细胞中的[5-11C] GLN的积累，体外和体内都有（特定目标1）。在特定的目标2中，所有的监管工作和现场批准都需要将完成UCSF的研究[1-11c] GLN。在特定目标3中，我们将在下面翻译[1-11c] gln 放射性药物研究委员会（RDRC）计划并研究其在患者患者中的表现 lgg。虽然该应用程序着重于LGG，但临床上可翻译的IDHM特定示踪剂会革新多种临床相关病变的检查和管理。此外，强大的方法合成和评估氨基酸衍生的11C同位素剂将显着提高PET的能力检测人类疾病中的代谢重编程。