68Ga-labelled desferrioxamine-B for bacterial infection imaging

Milos Petrik,Joachim Pfister,Clemens Decristoforo,Christian Mair,Eva Umlaufova,Marian Hajduch,Zbynek Novy,Miroslav Popper,Vladimir Havlicek,Vladislav Raclavsky,Andrea Palyzova

doi:10.1007/s00259-020-04948-y

Abstract

PurposeWith 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.MethodsIn 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.ResultsDFO-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.ConclusionDFO-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.

Highlights

Bacterial infections remain one of the leading cause of death globally [1]
DFO-B was radiolabelled with 68Ga (Fig. 1) with the molar activity up to 2 GBq/μmol and radiochemical purity > 95% confirmed by both reversed-phase high-performance liquid chromatography (RP-HPLC) and ITLC-SG methods
The analytical and in vitro characteristics data of [68Ga]Ga-DFO-B are summarized in Supplementary Fig. S1 and Table 1

Summary

Introduction

Bacterial infections remain one of the leading cause of death globally [1]. Currently, hospital-acquired infections (HAIs) are among the most important public health issues, associated with high mortality and dramatic impact on healthcare costs [2, 3]. Positive bacterial culture from the suspected sites (tissue and/or blood) is the current gold standard in the diagnosis of specific bacterial infection [9]. This method suffers from many limitations: (a) it can be invasive, (b) it is unable to determine extent of infection dissemination, (c) it lacks sensitivity often resulting in negative results, (d) is often only identified when it reached a systemic stage and (e) the time it takes to obtain results can often result in complications including fatality

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Results

Conclusion