Abstract
PurposeAspergillus fumigatus produces the siderophore triacetylfusarinine C (TAFC) for iron acquisition which is essential for its virulence. Therefore, TAFC is a specific marker for invasive aspergillosis. We have shown previously that positron emission tomography (PET) imaging with [68Ga]TAFC exhibited excellent targeting properties in an A. fumigatus rat infection model. In this study, we aimed to prepare TAFC analogs modifying fusarinine C (FSC) by acylation with different carbon chain lengths as well as with charged substituents and investigated the influence of introduced substituents on preservation of TAFC characteristics in vitro and in vivo.ProceduresFifteen TAFC derivatives were prepared and labeled with gallium-68. In vitro uptake assays were carried out in A. fumigatus under iron-replete as well as iron-depleted conditions and distribution coefficient was determined. Based on these assays, three compounds, [68Ga]tripropanoyl(FSC) ([68Ga]TPFC), [68Ga]diacetylbutanoyl(FSC) ([68Ga]DABuFC), and [68Ga]trisuccinyl(FSC) ([68Ga]FSC(suc)3), with high, medium, and low in vitro uptake in fungal cultures, were selected for further evaluation. Stability and protein binding were evaluated and in vivo imaging performed in the A. fumigatus rat infection model.ResultsIn vitro uptake studies using A. fumigatus revealed specific uptake of mono- and trisubstituted TAFC derivatives at RT. Lipophilicities as expressed by logD were 0.34 to − 3.80. The selected compounds displayed low protein binding and were stable in PBS and serum. Biodistribution and image contrast in PET/X-ray computed tomography of [68Ga]TPFC and [68Ga]DABuFC were comparable to [68Ga]TAFC, whereas no uptake in the infected region was observed with [68Ga]FSC(suc)3.ConclusionsOur studies show the possibility to modify TAFC without losing its properties and specific recognition by A. fumigatus. This opens also new ways for multimodality imaging or theranostics of fungal infection by introducing functionalities such as fluorescent dyes or antifungal moieties.
Highlights
Due to the lack of sensitivity and specificity of current diagnostic methods, invasive fungal diseases are a major cause of high mortality rates and elevated healthcare costs in Europe [3]
We have shown that [68Ga]triacetylfusarinine C (TAFC) and [68Ga]ferrioxamine E ([68Ga]FOXE) are able to detect A. fumigatus infection in a rat pulmonary aspergillosis model using positron emission tomography (PET) imaging [17, 18] and [68Ga]TAFC is more specific to A. fumigatus in vitro [19]. [68Ga]TAFC exhibits very rapid renal elimination, resulting in a short-term bioavailability
We have investigated the influence of TAFC modifications on the recognition by the specific siderophore system of A. fumigatus and report the biodistribution as well as PET/computed tomography (CT) images of selected compounds in comparison to [68Ga]TAFC
Summary
Due to the lack of sensitivity and specificity of current diagnostic methods, invasive fungal diseases are a major cause of high mortality rates (up to 50 % [1, 2]) and elevated healthcare costs in Europe [3]. Various clinical tests and techniques as well as X-ray computed tomography (CT) have shown unsuccessful diagnosis in terms of specificity and sensitivity Scintigraphic techniques such as single photon emission computer tomography (SPECT) and positron emission tomography (PET) have been applied for imaging fungal infections using non-specific radiotracers including [99mTc]leucocytes, [99mTc]peptides, [99mTc]antigranulocyte antibody, [67Ga]citrate (inflammation radiotracer), and even 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) [5]. These tracers have revealed only suboptimal characteristics for fungal detection
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