The global incidence of invasive fungal infections (IFIs) has increased over the past few decades, mainly in immunocompromised patients, and is associated with high mortality and morbidity. Aspergillus fumigatus is one of the most common and deadliest IFI pathogens. Major hurdles to treating fungal infections remain the lack of rapid and definitive diagnosis, including the frequent need for invasive procedures to provide microbiological confirmation, and the lack of specificity of structural imaging methods. To develop an Aspergillus -specific positron emission tomography (PET) imaging agent, we focused on fungal-specific sugar metabolism. We radiolabeled cellobiose, a disaccharide known to be metabolized by Aspergillus species, and synthesized 2-deoxy-2-[ 18 F]fluorocellobiose ([ 18 F]FCB) by enzymatic conversion of 2-deoxy-2-[ 18 F]fluoroglucose ([ 18 F]FDG) with a radiochemical yield of 60 to 70%, a radiochemical purity of >98%, and 1.5 hours of synthesis time. Two hours after [ 18 F]FCB injection in A. fumigatus pneumonia as well as A. fumigatus , bacterial, and sterile inflammation myositis mouse models, retained radioactivity was only seen in foci with live A. fumigatus infection. In vitro testing confirmed production of β-glucosidase enzyme by A. fumigatus and not by bacteria, resulting in hydrolysis of [ 18 F]FCB into glucose and [ 18 F]FDG, the latter being retained by the live fungus. The parent molecule was otherwise promptly excreted through the kidneys, resulting in low background radioactivity and high target-to-nontarget ratios at A. fumigatus infectious sites. We conclude that [ 18 F]FCB is a promising and clinically translatable Aspergillus -specific PET tracer.

中文翻译：

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2-脱氧 2-[ 18 F]氟纤维二糖作为曲霉菌特异性 PET 示踪剂的开发和临床前验证


过去几十年来，全球侵袭性真菌感染 (IFI) 的发病率有所增加，主要发生在免疫功能低下的患者中，并且与高死亡率和发病率相关。烟曲霉是最常见和最致命的 IFI 病原体之一。治疗真菌感染的主要障碍仍然是缺乏快速和明确的诊断，包括经常需要侵入性操作来提供微生物学确认，以及结构成像方法缺乏特异性。为了开发曲霉菌特异性正电子发射断层扫描（PET）成像剂，我们专注于真菌特异性糖代谢。我们对纤维二糖（一种已知可被曲霉属物种代谢的二糖）进行放射性标记，并通过 2-脱氧-2-[ 18 F]氟葡萄糖的酶促转化合成了 2-脱氧-2-[ 18 F]氟纤维二糖（[ 18 F]FCB）（ [ 18 F]FDG)，放射化学收率为60%至70%，放射化学纯度为>98%，合成时间为1.5小时。在烟曲霉肺炎以及烟曲霉、细菌性和无菌炎症性肌炎小鼠模型中注射[ 18 F]FCB 两小时后，仅在烟曲霉活感染病灶中观察到保留的放射性。体外测试证实烟曲霉而非细菌产生β-葡萄糖苷酶，导致[ 18 F]FCB 水解成葡萄糖和[ 18 F]FDG，后者被活真菌保留。否则，母体分子会迅速通过肾脏排出，导致烟曲霉感染部位的背景放射性较低，靶标与非靶标比率较高。我们得出的结论是，[ 18 F]FCB 是一种有前途且可临床翻译的曲霉菌特异性 PET 示踪剂。