PDF(Pubmed)
Abstract：
Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.
摘要：
结核病仍然是一个巨大的全球疾病负担，其治疗方案旷日持久，难以监测疾病活动。现有的检测方法几乎完全依赖于来自痰的细菌培养物,这限制了对肺表面上的生物体的采样。监测结核性病变的进展已经利用了常见的葡萄糖苷[18F]FDG，但缺乏对病原体结核分枝杆菌（Mtb）的特异性，因此与病原体活力没有直接关系。在这里，我们显示了一种密切的模拟物，也是非哺乳动物Mtb二糖海藻糖-2-[18F]氟-2-脱氧海藻糖（[18F]FDT）的正电子发射-是一种基于机制的分枝杆菌-体内选择性酶活性的报告基因。[18F]FDT在多种疾病模型中的Mtb成像中的应用，包括非人灵长类动物,成功地共同选择Mtb介导的海藻糖处理，以允许TB相关病变的特异性成像并监测治疗效果。无热原，其放射化学合成的直接酶催化方法允许从全球最丰富的含18F的有机分子中立即生产[18F]FDT，[18F]FDG。完整的，生产方法和[18F]FDT的临床前验证现在创建了一个新的，用于临床评估的细菌选择性候选物。我们预计这种可分配技术可以直接从广泛使用的临床试剂[18F]FDG中生成临床级[18F]FDT，不需要定制的放射性同位素生成或专业的化学方法和/或设施，现在可以迎来全球，民主化获得结核病特异性PET示踪剂。
