Limits...
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.

Show MeSH

Related in: MedlinePlus

Ex vivo uptake in the lungs 2 h after injection of 68Ga-TAFC or 68Ga-FOXE measured in a γ-counter
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369139&req=5

Fig3: Ex vivo uptake in the lungs 2 h after injection of 68Ga-TAFC or 68Ga-FOXE measured in a γ-counter

Mentions: In summary, 20 rats were treated with 68Ga-TAFC and 19 rats with 68Ga-FOXE. For 68Ga-TAFC, five rats developed severe and five rats mild lung infection, and ten rats showed no signs of infection. In the case of 68Ga-FOXE, six rats developed severe lung infection and six rats mild lung infection, and seven rats showed no sign of infection. In the severely infected animals, high levels of 68Ga-siderophores accumulated in the infected lungs, whereas in the noninfected animals, 68Ga-siderophores were rapidly excreted via the kidneys with low levels of accumulation in other organs. A significant difference (P < 0.05) between mildly infected and noninfected rats was observed. Figure 3 shows lung uptake values in the different groups of rats 2 h after administration of 68Ga-siderophores. The highest uptake was observed in severely infected rats injected with 68Ga-FOXE (3.45 ± 1.00 %ID/g, n = 5), followed by 0.95 ± 0.37 %ID/g (n = 4) in severely infected rats injected with 68Ga-TAFC. In the group of mildly infected animals, 68Ga-FOXE again showed slightly higher uptake 0.48 ± 0.54 %ID/g (n = 4) in comparison with 68Ga-TAFC (0.29 ± 0.12 %ID/g; n = 3). The control group showing no infection displayed similar results for both 68Ga-siderophores (0.04 ± 0.02 %ID/g for 68Ga-FOXE, n = 5; 0.04 ± 0.01 %ID/g for 68Ga-TAFC, n = 9). Rats pretreated with iron showed a comparable dependence of uptake on the severity of infection, with absolute values being somewhat lower than in the nonpretreated group, in particular for 68Ga-FOXE; however, none of the differences was statistically significant (P < 0.05). Online Resource 4 shows a comparison of lung uptake and target/non target ratios of 68Ga-siderophores in the different rat infection models.Fig. 3


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)

Ex vivo uptake in the lungs 2 h after injection of 68Ga-TAFC or 68Ga-FOXE measured in a γ-counter
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Ex vivo uptake in the lungs 2 h after injection of 68Ga-TAFC or 68Ga-FOXE measured in a γ-counter
Mentions: In summary, 20 rats were treated with 68Ga-TAFC and 19 rats with 68Ga-FOXE. For 68Ga-TAFC, five rats developed severe and five rats mild lung infection, and ten rats showed no signs of infection. In the case of 68Ga-FOXE, six rats developed severe lung infection and six rats mild lung infection, and seven rats showed no sign of infection. In the severely infected animals, high levels of 68Ga-siderophores accumulated in the infected lungs, whereas in the noninfected animals, 68Ga-siderophores were rapidly excreted via the kidneys with low levels of accumulation in other organs. A significant difference (P < 0.05) between mildly infected and noninfected rats was observed. Figure 3 shows lung uptake values in the different groups of rats 2 h after administration of 68Ga-siderophores. The highest uptake was observed in severely infected rats injected with 68Ga-FOXE (3.45 ± 1.00 %ID/g, n = 5), followed by 0.95 ± 0.37 %ID/g (n = 4) in severely infected rats injected with 68Ga-TAFC. In the group of mildly infected animals, 68Ga-FOXE again showed slightly higher uptake 0.48 ± 0.54 %ID/g (n = 4) in comparison with 68Ga-TAFC (0.29 ± 0.12 %ID/g; n = 3). The control group showing no infection displayed similar results for both 68Ga-siderophores (0.04 ± 0.02 %ID/g for 68Ga-FOXE, n = 5; 0.04 ± 0.01 %ID/g for 68Ga-TAFC, n = 9). Rats pretreated with iron showed a comparable dependence of uptake on the severity of infection, with absolute values being somewhat lower than in the nonpretreated group, in particular for 68Ga-FOXE; however, none of the differences was statistically significant (P < 0.05). Online Resource 4 shows a comparison of lung uptake and target/non target ratios of 68Ga-siderophores in the different rat infection models.Fig. 3

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