Distributable, Metabolic PET Reporting of Tuberculosis

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 [18 F]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-[ 18 F]fluoro-2-deoxytrehalose ([18 F]FDT) – is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18 F]FDT in the imaging of Mtb in diverse models of disease,  including non-human primates, successfully co-opts Mtb-specific 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 [18 F]FDT from the most globally-abundant organic 18F-containing molecule, [18 F]FDG. The full, pre-clinical validation of both production method and [18 F]FDT now creates a new, bacterium selective, clinical diagnostic candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18 F]FDT directly from the widelyavailable clinical reagent [18 F]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.

结核病仍是全球重大疾病负担，其治疗方案冗长且疾病活动度监测难度颇高。现有检测方法几乎完全依赖痰液细菌培养，这使得采样仅能覆盖肺表面的病原体。结核病灶监测技术的进展曾利用常用葡糖苷[¹⁸F]FDG，但该方法无法特异性识别致病病原体结核分枝杆菌（Mycobacterium tuberculosis, Mtb），因此无法直接反映病原体的存活状态。本研究证实，一种针对非哺乳类结核分枝杆菌二糖海藻糖的近似模拟物且兼具正电子放射性的标记物——2-[¹⁸F]氟-2-脱氧海藻糖（[¹⁸F]FDT），可作为体内分枝杆菌选择性酶活性的机制型报告探针。将[¹⁸F]FDT用于包括非人灵长类在内的多种疾病模型中的结核分枝杆菌成像，可有效利用结核分枝杆菌对海藻糖的特异性加工过程，实现结核相关病灶的特异性成像并监测治疗效果。其放射化学合成采用无热源、直接酶催化工艺，可从全球丰度最高的含¹⁸F有机分子[¹⁸F]FDG便捷制备[¹⁸F]FDT。目前对该合成方法与[¹⁸F]FDT的全部临床前验证工作，已开发出一种全新的细菌选择性临床诊断候选药物，可供临床评估。我们预计，这项可推广的技术可直接从广泛可用的临床试剂[¹⁸F]FDG制备临床级[¹⁸F]FDT，无需定制放射性同位素制备流程或专业化学方法与设施，有望推动全球范围内结核病特异性正电子发射断层显像（PET）示踪剂的普惠化可及。