Technetium-99m labelled fluconazole and antimicrobial peptides for imaging of Candida albicans and Aspergillus fumigatus infections

Abstract

The aim of this study was to investigate whether technetium-99m labelled fluconazole can distinguish fungal from bacterial infections. Fluconazole was labelled with (99m)Tc and radiochemical analysis showed less than 5% impurities. The labelling solution was injected into animals with experimental infections. For comparison, we used two peptides for infection detection, i.e. UBI 29-41 and hLF 1-11, and human IgG, all labelled with (99m)Tc. Mice were infected with Candida albicans or injected with heat-killed C. albicans or lipopolysaccharides to induce sterile inflammation. Also, mice were infected with Staphylococcus aureus or Klebsiella pneumoniae. Next, accumulation of (99m)Tc-fluconazole and (99m)Tc-labelled peptides/IgG at affected sites was determined scintigraphically. (99m)Tc-fluconazole detected C. albicans infections (T/NT ratio=3.6+/-0.47) without visualising bacterial infections (T/NT ratio=1.3+/-0.04) or sterile inflammatory processes (heat-killed C. albicans: T/NT ratio=1.3+/-0.2; lipopolysaccharide: T/NT ratio=1.4+/-0.1). C. albicans infections were already seen within the first hour after injection of (99m)Tc-fluconazole (T/NT ratio=3.1+/-0.2). A good correlation (R(2)=0.864; P<0.05) between T/NT ratios for this tracer and the number of viable C. albicans was found. Although (99m)Tc-UBI 29-41 and (99m)Tc-hLF 1-11 were able to distinguish C. albicans infections from sterile inflammatory processes in mice, these (99m)Tc-labelled peptides did not distinguish these fungal infections from bacterial infections. It is concluded that (99m)Tc-fluconazole distinguishes infections with C. albicans from bacterial infections and sterile inflammations.

The Pharmacology of Radiolabeled Cationic Antimicrobial Peptides

“…33 In order to evaluate the role of inflammatory cells to the accumulation of 99m Tc-UBI 29-41 a series of experiments with leukocytopenic mice was carried out. 52 The accumulation of the peptide was not significantly different from the accumulation in immunocompetent mice, having an infection with the same number of micro-organisms as in the immunocompetent mice, once more indicating that the binding of 99m Tc-UBI 29-41 to bacteria is the main factor in the visualization of the infection site, rather than binding of the 53,54 shows similar pharmacokinetics and targeting of bacterial infected tissues as we determined in animal studies. 58,59 …”

“…A vast amount of data has been generated showing various aspects of the pharmacology of the various radiolabeled UBI peptides in mice, rats, and rabbits, 33,47,51,52 and recently in humans for the UBI 29-41 peptide 53,54 Recently, the preferential binding of one specific (radiolabeled) synthetic fragment from UBI, UBI 29-41, to various bacteria and fungi over mammalian cells was established and enabled accumulation and visualization of experimental infections 47,55,56 and the monitoring of antimicrobial therapy. 57 As is shown in Table 3, after intravenous injection, 99m Tc-UBI peptides are rapidly (halflives between 17 and 142 min) removed from the circulation.…”

The molecular imaging approach to image infections and inflammation by nuclear medicine techniques

“…99m Tc-labeled fluconazole, which binds to fungal cytochrome P450, was developed for the specific detection of C. albicans and A. fumigatus infections in mice. It preferentially accumulated in C. albicans-induced infections in vivo, while accumulation in bacterial infections, A. fumigatus infections and sterile inflammation was significantly lower [26].…”

Receptor Binding Ligands to Image Infection

“…99m Tc-labeled fluconazole was developed by Lupetti et al for the specific detection of C. albicans and A. fumigatus infections in mice [75]. 99m Tc-fluconazole preferentially accumulated in C. albicans-induced infections in vivo, while accumulation in bacterial infections, A. fumigatus infections and sterile inflammation was significantly lower.…”