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Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging.

Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, Helbok A, Lass-Flörl C, Decristoforo C - Eur. J. Nucl. Med. Mol. Imaging (2012)

Bottom Line: In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus.In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability.In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus.

View Article: PubMed Central - PubMed

Affiliation: Clinical Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria. milospetrik@seznam.cz

ABSTRACT

Purpose: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).

Methods: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.

Results: (68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.

Conclusion: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.

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Dynamic PET images in infected rats show rapid uptake and no release of 68Ga-TAFC (a) and 68Ga-FOXE (b) in infected lung tissue (arrows) over time
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Fig5: Dynamic PET images in infected rats show rapid uptake and no release of 68Ga-TAFC (a) and 68Ga-FOXE (b) in infected lung tissue (arrows) over time

Mentions: MicroPET imaging in the rat infection model showed rapid focal accumulation of 68Ga-siderophores in the lungs, which increased with the severity of infection (Fig. 4). No uptake in the lung region was detected in noninfected animals in which the only visible organs were the kidneys and bladder (Fig. 4). Dynamic imaging (see Fig. 5 for 68Ga-FOXE) in severely infected rats revealed uptake in the infected lung area as early as 10–20 min after injection with improved contrast over time without detectable washout over the whole imaging period (60 min), whereas the activity rapidly accumulated in kidneys and decreased over time. Figure 6 shows a correlation between PET and CT scans for both compounds under study. In CT scans of severely infected rats the changes in infected tissue were visible as grey areas in the lung region that fully corresponded with radioactivity lung accumulation in PET scans. Fusing images of both modalities revealed matching uptake, clearly visible in the fused images. Target/non-target ratios as well as SUV values in infected animals were calculated from all imaging studies performed (n = 13) and were 5.81 ± 6.05 and 0.78 ± 0.75 for 68Ga-TAFC and 6.64 ± 2.91 and 1.00 ± 0.81 for 68Ga-FOXE, respectively (see Online Resource 5), showing no significant difference (P < 0.05) between the two compounds in terms of quantitative uptake behaviour.Fig. 4


Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging.

Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, Helbok A, Lass-Flörl C, Decristoforo C - Eur. J. Nucl. Med. Mol. Imaging (2012)

Dynamic PET images in infected rats show rapid uptake and no release of 68Ga-TAFC (a) and 68Ga-FOXE (b) in infected lung tissue (arrows) over time
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369139&req=5

Fig5: Dynamic PET images in infected rats show rapid uptake and no release of 68Ga-TAFC (a) and 68Ga-FOXE (b) in infected lung tissue (arrows) over time
Mentions: MicroPET imaging in the rat infection model showed rapid focal accumulation of 68Ga-siderophores in the lungs, which increased with the severity of infection (Fig. 4). No uptake in the lung region was detected in noninfected animals in which the only visible organs were the kidneys and bladder (Fig. 4). Dynamic imaging (see Fig. 5 for 68Ga-FOXE) in severely infected rats revealed uptake in the infected lung area as early as 10–20 min after injection with improved contrast over time without detectable washout over the whole imaging period (60 min), whereas the activity rapidly accumulated in kidneys and decreased over time. Figure 6 shows a correlation between PET and CT scans for both compounds under study. In CT scans of severely infected rats the changes in infected tissue were visible as grey areas in the lung region that fully corresponded with radioactivity lung accumulation in PET scans. Fusing images of both modalities revealed matching uptake, clearly visible in the fused images. Target/non-target ratios as well as SUV values in infected animals were calculated from all imaging studies performed (n = 13) and were 5.81 ± 6.05 and 0.78 ± 0.75 for 68Ga-TAFC and 6.64 ± 2.91 and 1.00 ± 0.81 for 68Ga-FOXE, respectively (see Online Resource 5), showing no significant difference (P < 0.05) between the two compounds in terms of quantitative uptake behaviour.Fig. 4

Bottom Line: In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus.In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability.In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus.

View Article: PubMed Central - PubMed

Affiliation: Clinical Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria. milospetrik@seznam.cz

ABSTRACT

Purpose: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).

Methods: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.

Results: (68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.

Conclusion: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.

Show MeSH
Related in: MedlinePlus