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

这项建议的重点是开发和验证谷氨酰胺衍生的正电子11C同位素 发射断层扫描。具体地说，外源性给予谷氨酰胺的1位和5位有 不同的代谢命运，取决于主导的转化机制。因此，我们将 L-[1-11C]谷氨酰胺([1-11C]Gln)和L-[5-11C]谷氨酰胺([5-11C]Gln)的合成及其在生物合成中的应用 检测异柠檬酸脱氢酶突变(IDHm)，可见于几种良恶性临床 包括低级别胶质瘤(LGG)在内的疾病。改善对LGG的诊断将解决以下重大挑战 神经放射科医生、神经肿瘤学家、放射肿瘤学家和神经外科医生经常遇到 神经胶质瘤与其他脑实体的区别。IDH突变型(IDHm)胶质瘤患者存在 代谢物2-羟基戊二酸(2HG)，是一种很有前途的检测LGG的方法。我们有动力 根据最近的一份报告，在IDHm皮损中，外源性谷氨酰胺迅速转化为2HG，代表着 一种隔离11C放射性核素的方法。这个提议的中心假设是，一个正电子-- 标记的2HG代谢前体[1-11C]Gln可用于检测IDHm。我们进一步预测 基于抑制作用，使用[1-11C]Gln与已报道的[5-11C]Gln同位素异构体相比具有显著优势 与三羧酸(TCA)循环代谢有关的背景信号。经过验证后，此方法 将为临床使用[1-11C]Gln PET评估LGG和其他IDHm病变奠定基础。 我们提出了一种多PI和跨学科的协作来验证[1-11C]Gln PET是IDHm特定的工具 并使用[1-11C]Gln进行第一次患者研究，以进一步支持该方法。我们将首先发展 首次辐射合成[1-11C]Gln，通过改编已报道的使用[11C]CO2和[11C]CN-的方法。我们会 然后比较[1-11C]Gln和[5-11C]Gln在IDHm和IDH-野生型(IDHwt)细胞中的积累， 体外和体内(特定目标1)。在具体目标2中，所有监管工作和现场审批都需要 加州大学旧金山分校的[1-11C]Gln研究将完成。在具体目标3中，我们将翻译[1-11C]Gln在 放射性药物研究委员会(RDRC)计划并研究其在患有 LGG。虽然这一应用程序主要针对LGG，但临床上可翻译的IDHm特异性示踪剂将带来革命性的变化 对各种临床相关病变的检查和处理。此外，健壮的方法可以 合成和评价氨基酸衍生的~(11)C同位异构体将极大地提高PET的能力 检测人类疾病中的代谢重编程。

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.