BACKGROUND: Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type. RESULTS: Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection. CONCLUSIONS: The 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

• Klíčová slova
• Imaging, Infection, Positron emission tomography, Siderophore, Stereoisomers,
• Publikační typ
• časopisecké články MeSH

This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection. Replacing iron in siderophores by radionuclides, the most prominent Ga-68 for PET, opens approaches for targeted imaging of infection; the proof of principle has been reported for fungal infections using 68Ga-triacetylfusarinine C (TAFC). Additionally, fluorescent siderophores and therapeutic conjugates have been described and may be translated to optical imaging and theranostic applications. Siderophores have also been applied as bifunctional chelators, initially DFO as chelator for Ga-67 and more recently for Zr-89 where it has become the standard chelator in Immuno-PET. Improved DFO constructs and bifunctional chelators based on cyclic siderophores have recently been developed for Ga-68 and Zr-89 and show promising properties for radiopharmaceutical development in PET. A huge potential from basic biomedical research on siderophores still awaits to be utilized for clinical and translational imaging.

• Klíčová slova
• Bifunctional chelator, Desferrioxamine, Infection, Siderophores, Triacetylfusarinine C,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The ferric uptake regulator gene (fur), its promoter region and Fur box of pvdS gene involved in siderophore-mediated iron uptake system were sequenced in the parent strain Pseudomonas aeruginosa PAO1 and in the fur mutant FPA121 derived from the strain PAO1. We identified the gene fur 179 bearing a novel, single-point mutation that changed the amino acid residue Gln60Pro in the DNA-binding domain of the Fur protein. The synthesis of pyoverdine was studied in cultures of the strains PAO1 and FPA121 grown in iron-deplete and iron-replete (60 μmol/L FeIII) medium. The amino acid replacement in the regulatory Fur protein is responsible for the overproduction of pyoverdine in iron-deplete and iron-replete medium. No mutation was identified in the Fur box of the gene pvdS.

• MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• kultivační média chemie   MeSH
• mutační analýza DNA MeSH
• mutantní proteiny genetika   metabolismus   MeSH
• oligopeptidy biosyntéza   MeSH
• Pseudomonas aeruginosa genetika   metabolismus   MeSH
• represorové proteiny genetika   metabolismus   MeSH
• substituce aminokyselin * MeSH
• vazebná místa MeSH
• železité sloučeniny metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bakteriální proteiny MeSH
• DNA vazebné proteiny MeSH
• ferric uptake regulating proteins, bacterial MeSH Prohlížeč
• kultivační média MeSH
• mutantní proteiny MeSH
• oligopeptidy MeSH
• pyoverdin MeSH Prohlížeč
• represorové proteiny MeSH
• železité sloučeniny MeSH