Swati Shah, Jianhao Lai, Falguni Basuli, Neysha Martinez-Orengo, Reema Patel, Mitchell L. Turner, Benjamin Wang, Zhen-Dan Shi, Suman Sourabh, Morteza Peiravi, Anna Lyndaker, Sichen Liu, Seyedmojtaba Seyedmousavi, Peter R. Williamson, Rolf E. Swenson, Dima A. Hammoud
{"title":"Development and preclinical validation of 2-deoxy 2-[18F]fluorocellobiose as an Aspergillus-specific PET tracer","authors":"Swati Shah, Jianhao Lai, Falguni Basuli, Neysha Martinez-Orengo, Reema Patel, Mitchell L. Turner, Benjamin Wang, Zhen-Dan Shi, Suman Sourabh, Morteza Peiravi, Anna Lyndaker, Sichen Liu, Seyedmojtaba Seyedmousavi, Peter R. Williamson, Rolf E. Swenson, Dima A. Hammoud","doi":"10.1126/scitranslmed.adl5934","DOIUrl":null,"url":null,"abstract":"<div >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. <i>Aspergillus fumigatus</i> 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 <i>Aspergillus</i>-specific positron emission tomography (PET) imaging agent, we focused on fungal-specific sugar metabolism. We radiolabeled cellobiose, a disaccharide known to be metabolized by <i>Aspergillus</i> species, and synthesized 2-deoxy-2-[<sup>18</sup>F]fluorocellobiose ([<sup>18</sup>F]FCB) by enzymatic conversion of 2-deoxy-2-[<sup>18</sup>F]fluoroglucose ([<sup>18</sup>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 [<sup>18</sup>F]FCB injection in <i>A. fumigatus</i> pneumonia as well as <i>A. fumigatus</i>, bacterial, and sterile inflammation myositis mouse models, retained radioactivity was only seen in foci with live <i>A. fumigatus</i> infection. In vitro testing confirmed production of β-glucosidase enzyme by <i>A. fumigatus</i> and not by bacteria, resulting in hydrolysis of [<sup>18</sup>F]FCB into glucose and [<sup>18</sup>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 <i>A. fumigatus</i> infectious sites. We conclude that [<sup>18</sup>F]FCB is a promising and clinically translatable <i>Aspergillus</i>-specific PET tracer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adl5934","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
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