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 68Ga for imaging of bacterial infections. METHODS: In vitro characterization of [68Ga]Ga-DFO-B included partition coefficient, protein binding and stability determination. Specific uptake of [68Ga]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 68Ga 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 [68Ga]Ga-DFO-B in selected strains of Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus agalactiae could be blocked with an excess of iron-DFO-B. [68Ga]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 [68Ga]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 68Ga and displayed suitable in vitro characteristics and excellent pharmacokinetics in mice. The high and specific uptake of [68Ga]Ga-DFO-B by P. aeruginosa and S. aureus was confirmed both in vitro and in vivo, proving the potential of [68Ga]Ga-DFO-B for specific imaging of bacterial infections. As DFO-B is used in clinic for many years and the estimated radiation dose is lower than for other 68Ga-labelled radiopharmaceuticals, we believe that [68Ga]Ga-DFO-B has a great potential for clinical translation.

Department of Analytical Chemistry Faculty of Science Palacky University Olomouc Czech Republic

Department of Microbiology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic

Department of Nuclear Medicine Medical University Innsbruck Anichstrasse 5 A 6020 Innsbruck Austria

Institute of Microbiology of the Czech Academy of Sciences v v i Prague Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University CZ 77900 Olomouc Czech Republic

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$a Petrik, Milos $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-77900, Olomouc, Czech Republic. milos.petrik@upol.cz

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$a 68Ga-labelled desferrioxamine-B for bacterial infection imaging / $c M. Petrik, E. Umlaufova, V. Raclavsky, A. Palyzova, V. Havlicek, J. Pfister, C. Mair, Z. Novy, M. Popper, M. Hajduch, C. Decristoforo

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$a 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 68Ga for imaging of bacterial infections. METHODS: In vitro characterization of [68Ga]Ga-DFO-B included partition coefficient, protein binding and stability determination. Specific uptake of [68Ga]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 68Ga 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 [68Ga]Ga-DFO-B in selected strains of Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus agalactiae could be blocked with an excess of iron-DFO-B. [68Ga]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 [68Ga]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 68Ga and displayed suitable in vitro characteristics and excellent pharmacokinetics in mice. The high and specific uptake of [68Ga]Ga-DFO-B by P. aeruginosa and S. aureus was confirmed both in vitro and in vivo, proving the potential of [68Ga]Ga-DFO-B for specific imaging of bacterial infections. As DFO-B is used in clinic for many years and the estimated radiation dose is lower than for other 68Ga-labelled radiopharmaceuticals, we believe that [68Ga]Ga-DFO-B has a great potential for clinical translation.

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$a Umlaufova, Eva $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-77900, Olomouc, Czech Republic

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$a Raclavsky, Vladislav $u Department of Microbiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic

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$a Palyzova, Andrea $u Institute of Microbiology of the Czech Academy of Sciences v.v.i., Prague, Czech Republic

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$a Havlicek, Vladimir $u Institute of Microbiology of the Czech Academy of Sciences v.v.i., Prague, Czech Republic $u Department of Analytical Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic

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$a Pfister, Joachim $u Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 5, A-6020, Innsbruck, Austria

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$a Mair, Christian $u Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 5, A-6020, Innsbruck, Austria

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$a Novy, Zbynek $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-77900, Olomouc, Czech Republic

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$a Popper, Miroslav $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-77900, Olomouc, Czech Republic

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$a Hajduch, Marian $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-77900, Olomouc, Czech Republic

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$a Decristoforo, Clemens $u Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 5, A-6020, Innsbruck, Austria. Clemens.Decristoforo@i-med.ac.at

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$w MED00007222 $t European journal of nuclear medicine and molecular imaging $x 1619-7089 $g Roč. 48, č. 2 (2021), s. 372-382

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