68Ga-labelled desferrioxamine-B for bacterial infection imaging

Abstract

Purpose With the increase of especially hospital-acquired infections, timely and accurate diagnosis of bacterial infections is crucial for effective patient care. Molecular imaging has the potential for specific and sensitive detection of infections. Siderophores are iron-specific chelators recognized by specific bacterial transporters, representing one of few fundamental differences between bacterial and mammalian cells. Replacing iron by gallium-68 without loss of bioactivity is possible allowing molecular imaging by positron emission tomography (PET). Here, we report on the preclinical evaluation of the clinically used siderophore, desferrioxamine-B (Desferal®, DFO-B), radiolabelled with 68 Ga for imaging of bacterial infections. Methods In vitro characterization of [ 68 Ga]Ga-DFO-B included partition coefficient, protein binding and stability determination. Specific uptake of [ 68 Ga]Ga-DFO-B was tested in vitro in different microbial cultures. In vivo biodistribution was studied in healthy mice and dosimetric estimation for human setting performed. PET/CT imaging was carried out in animal infection models, representing the most common pathogens. Results DFO-B was labelled with 68 Ga with high radiochemical purity and displayed hydrophilic properties, low protein binding and high stability in human serum and PBS. The high in vitro uptake of [ 68 Ga]Ga-DFO-B in selected strains of Pseudomonas aeruginosa , Staphylococcus aureus and Streptococcus agalactiae could be blocked with an excess of iron-DFO-B. [ 68 Ga]Ga-DFO-B showed rapid renal excretion and minimal retention in blood and other organs in healthy mice. Estimated human absorbed dose was 0.02 mSv/MBq. PET/CT images of animal infection models displayed high and specific accumulation of [ 68 Ga]Ga-DFO-B in both P. aeruginosa and S. aureus infections with excellent image contrast. No uptake was found in sterile inflammation, heat-inactivated P. aeruginosa or S. aureus and Escherichia coli lacking DFO-B transporters. Conclusion DFO-B can be easily radiolabelled with 68 Ga and displayed suitable in vitro characteristics and excellent pharmacokinetics in mice. The high and specific uptake of [ 68 Ga]Ga-DFO-B by P. aeruginosa and S. aureus was confirmed both in vitro and in vivo, proving the potential of [ 68 Ga]Ga-DFO-B for specific imaging of bacterial infections. As DFO-B is used in clinic for many years and the estimated rad...

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

“…A recent study of Petrik et al also shows the promising application of 68 Ga(III)/DFOB complex for molecular imaging by the PET technique in animal models. These results also revealed the potential application of the 68 Ga(III)/DFOB complex for the molecular imaging of different bacterial infections, including Pseudomonas aeruginosa and Staphylococcus aureus [ 87 ].…”

Leveraging copper import by yersiniabactin siderophore system for targeted PET imaging of bacteria

“…Any new diagnostic probe must be evaluated against a reliable "gold standard," so we compared the specificity of our probe with the clinically available 18 F-FDG. We noticed that, unlike 64 Cu-YbT, 18 F-FDG accumulated uniformly in muscles harboring pathogenic bacteria, irrespective of their Gram specifications or species differences (Figure 2, F-H). Subsequently, we compared sensitivity of 64 Cu-YbT to 18 F-FDG by administering the probes in mice infected with 10 3 , 10 4 , 10 5 , and 10 6 cfu of 2 different FyuA-expressing bacteria, E. coli UTI89 and K. pneumoniae.…”

“…We noticed that, unlike 64 Cu-YbT, 18 F-FDG accumulated uniformly in muscles harboring pathogenic bacteria, irrespective of their Gram specifications or species differences (Figure 2, F-H). Subsequently, we compared sensitivity of 64 Cu-YbT to 18 F-FDG by administering the probes in mice infected with 10 3 , 10 4 , 10 5 , and 10 6 cfu of 2 different FyuA-expressing bacteria, E. coli UTI89 and K. pneumoniae. Figure 3 shows the rapid detection of as little as 10 4 cfu of both E. coli UTI89 and K. pneumoniae by 64 Cu-YbT within 2 hours, which is similar to the detection sensitivity of 18 F-FDG.…”

“…Since bacteria are evolutionarily and phylogenetically distinct from mammalian cells, fundamental differences in metabolism and cellular structures can be leveraged to develop bacteria-specific imaging agents. Some of the recent approaches that have focused on targeting metabolic pathways and proteins unique to bacteria include 11 C-para-aminobenzoic acid (2), involved exclusively in the bacterial folate pathway; 18 F-maltohexaose (3), which specifically targets the maltodextrin transporter in bacteria; and 18 F-fluorodeoxysorbitol, a synthetic analog of 18 F-FDG that selectively localizes in Gram-negative Enterobacteriaceae (4). However, these radiotracers do not possess the ability to distinguish one genus or species from another.…”

Highlights of 33rd EANM Annual Congress 2020, virtual edition

“…The siderophore-based iron uptake system differs between bacterial and mammalian cells. Petrik et al [1,6] demonstrated that deferoxamine, a siderophore marketed under the brand name Desferal (DFO), can be radiolabeled with gallium-68 without loss of bioactivity. In vitro characterisation was tested in different microbial cultures, whereas in vivo biodistribution was studied in healthy mice.…”