Development of 18F-labeled positron emission tomography tracers for non-invasive assessment of isocitrate dehydrogenase (IDH) mutations in cerebral gliomas

开发 18F 标记的正电子发射断层扫描示踪剂，用于无创评估脑胶质瘤异柠檬酸脱氢酶 (IDH) 突变

• 批准号: 513201378
• 负责人: Professor Dr. Bernd Neumaier
• 金额: --
• 依托单位: INM-5: Nuklearchemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513201378?language=en
• 关键词: Development; 18F; labeled; positron; emission

After meningiomas, cerebral gliomas are the most common primary brain tumors in adults. Despite aggressive, multidisciplinary treatment (resection, radiotherapy, chemotherapy), especially high-grade gliomas like glioblastomas are still associated with a poor prognosis. As a consequence, intense ongoing research efforts have been aimed at identifying molecules involved in tumor growth that could provide novel targets for personalized treatment approaches in these patients. Studies in large cohorts of glioma patients revealed that >65% of low-grade gliomas and >85% of secondary glioblastomas but only <5% of primary glioblastomas exhibit mutations in the enzyme isocitrate dehydrogenase (IDH), which are associated with increased production of the oncometabolite 2-hydroxyglutarate. As these mutations occur early during tumorigenesis and affect the whole tumor tissue, the mutant enzymes could serve as both, diagnostic biomarkers and potential targets for therapeutic approaches. However, detection of IDH mutations is still mostly achieved through immunohistochemistry and genomic sequencing, which require tissue samples retrieved by e.g. biopsy or during an operation and are thus not suitable for disease progression monitoring or longitudinal studies. Aim of this work is the development of IDH-specific probes for non-invasive assessment of IDH expression in gliomas by positron emission tomography (PET). Our focus will be on the development of brain-permeable radiotracers that selectively address the mutant IDH isoform. To this end, radiofluorination protocols previously developed by the applicants will be used to label different specific inhibitors currently undergoing phase I clinical trials with fluorine-18, a radionuclide with ideal properties for preclinical and clinical PET imaging. Apart from the production of sufficiently accessible radiolabeling precursors, the radiolabeling conditions will be optimized with regard to synthesis duration and radiochemical yields. In parallel, the developed tracers will be evaluated for their affinity, selectivity, stability, brain permeability, pharmacokinetic and pharmacodynamics properties using enzymatic and functional inhibition assays, in vitro cell uptake studies with several tumor cell lines as well as ex vivo and in vivo studies with the same tumor cell lines inoculated into embryonated chicken eggs. For the most promising candidates, the results thus obtained will be validated in an orthotopic glioblastoma model in the rat and their radiosynthesis will be transferred to an automated synthesis module for clinical tracer production.

继脑膜瘤之后，脑胶质瘤是成人中最常见的原发性脑肿瘤。尽管积极的，多学科的治疗（切除，放疗，化疗），特别是高级别的胶质瘤，如胶质母细胞瘤仍然与预后不良。因此，正在进行的大量研究工作旨在鉴定参与肿瘤生长的分子，这些分子可以为这些患者的个性化治疗方法提供新的靶点。在大群胶质瘤患者中的研究显示，>65%的低级别胶质瘤和>85%的继发性胶质母细胞瘤，但仅<5%的原发性胶质母细胞瘤表现出异柠檬酸脱氢酶（IDH）的突变，这与癌代谢产物2-羟基戊二酸的产生增加有关。由于这些突变发生在肿瘤发生的早期并影响整个肿瘤组织，因此突变酶可以作为诊断生物标志物和治疗方法的潜在靶点。然而，IDH突变的检测仍然主要通过免疫组织化学和基因组测序来实现，这需要通过例如活组织检查或在手术期间获取组织样品，因此不适合疾病进展监测或纵向研究。这项工作的目的是开发IDH特异性探针，通过正电子发射断层扫描（PET）非侵入性评估IDH在胶质瘤中的表达。我们的重点将是开发脑渗透性放射性示踪剂，选择性地解决突变IDH亚型。为此，申请人先前开发的放射性核素方案将用于标记目前正在进行I期临床试验的不同特异性抑制剂，其中氟-18是一种具有临床前和临床PET成像理想特性的放射性核素。除了生产足够容易获得的放射性标记前体外，还将在合成持续时间和放射化学产率方面优化放射性标记条件。与此同时，将使用酶和功能抑制试验、几种肿瘤细胞系的体外细胞摄取研究以及接种到鸡胚中的相同肿瘤细胞系的离体和体内研究，评价开发的示踪剂的亲和力、选择性、稳定性、脑渗透性、药代动力学和药效学特性。对于最有希望的候选物，将在大鼠原位胶质母细胞瘤模型中验证由此获得的结果，并将其放射合成转移到用于临床示踪剂生产的自动合成模块中。