Imaging of fungal infections

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Abstract

Summary: Changes over the last year: 1. Evaluation of radiolabeled sugars: we have recently synthesized 2-deoxy-2-[18F]fluorocellobiose ([18F]FCB) by enzymatic conversion of 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) with radiochemical yield of 60-70%, radiochemical purity of > 98% and 1.5 h synthesis time. Two hours after [18F]FCB injection in fungal, bacterial and sterile inflammation myositis models, retained radioactivity in infected mice was only seen in live A. fumigatus foci. 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 getting retained by the live fungus. The parent molecule is otherwise promptly excreted through the kidneys resulting in very low background radioactivity and very high target to non-target ratios in A. fumigatus infectious sites. We conclude that [18F]FCB is a highly-promising and clinically translatable Aspergillus-specific PET ligand. Further applications in other fungal infections and translation to humans are underway with IND application and preparation of human protocol We are also testing usefulness of [18F]FCB in other fungal infections like mucormycosis. we have published our results. Multiple other publications are being prepared. 2. Using radiolabeled antibodies and nanobodies specific for chitin and laminarin: we are currently evaluating a full antibody against fungal cell component laminarin as well as Fab Fragment. Although we found uptake of labeled antibody in fungal infection, we also saw uptake of an isotype antibody to the same extent suggesting antibodies are too large and end up accumulating nonspecifically in areas of inflammation due to increased endothelial permeability. When we used Fab antibody fragments, we found uptake of the Fab in the infected animals but no uptake in uninfected animals. Isotype Fab did not accumulate neither in infected nor in uninfected animals. We found some cross reactivity with E coli myositis. we have published our results. Multiple other publications are being prepared. 3. We are also evaluating single chain antibodies (nanobodies) to improve the specificity of targeting fungal infections. Results pending.