Abstract:
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-[18F]fluorocellobiose ([18F]FCB) by enzymatic conversion of 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) with a radiochemical yield of 60 to 70%, a radiochemical purity of >98%, and 1.5 hours of synthesis time. Two hours after [18F]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 [18F]FCB into glucose and [18F]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 [18F]FCB is a promising and clinically translatable Aspergillus-specific PET tracer.
摘要:
在过去的几十年中,全球侵袭性真菌感染(IFIs)的发病率有所增加。主要是免疫功能低下的患者,并与高死亡率和高发病率相关。烟曲霉是一种最常见和最致命的IFI病原体。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程序来提供微生物确认,结构成像方法缺乏特异性。为了开发曲霉特异性正电子发射断层扫描(PET)显像剂,我们专注于真菌特异性糖代谢。我们放射性标记了纤维二糖,一种已知被曲霉属物种代谢的二糖,并通过酶促转化2-脱氧-2-[18F]氟葡萄糖([18F]FDG)合成2-脱氧-2-[18F]氟二糖([18F]FCB),放射化学产率为60%至70%,放射化学纯度>98%,和1.5小时的合成时间。在[18F]FCB注射烟曲霉肺炎和烟曲霉后两小时,细菌,和无菌炎症肌炎小鼠模型,保留的放射性仅在有活的烟曲霉感染的病灶中可见。体外测试证实,烟曲霉而不是细菌产生β-葡萄糖苷酶,导致[18F]FCB水解为葡萄糖和[18F]FDG,后者由活真菌保留。否则母体分子会通过肾脏迅速排泄,导致烟曲霉感染部位的低背景放射性和高靶与非靶比率。我们得出的结论是,[18F]FCB是一种有前途的临床可翻译的曲霉特异性PET示踪剂。