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¹²³I-Labeled Chitinase as Specific Radioligand for In Vivo Detection of Fungal Infections in Mice

¹ Laboratory of Radiopharmacy, Gent University, Gent, Belgium
² Department of Chemistry and Biotechnology, Agricultural University of Norway, Ås, Norway
³ Department of Nuclear Medicine, Gent University Hospital, Gent, Belgium

Given the scarcity of diagnostic tools for invasive fungal infections, the aim of this project was to develop new, specific radiopharmaceuticals for diagnosis of fungal infections. Chitin, which is expressed in the fungal cell wall but is absent in mammalian and bacterial cells, represents a potentially selective target for development of tracers for fungal infections. ChiB_E144Q (ChiB = chitinase B) from Serratia marcescens was labeled with ¹²³I, and in vitro and in vivo studies were assessed. Methods: ¹²³I labeling of ChiB_E144Q from S. marcescens by direct iodination was characterized by high-pressure liquid chromatography (HPLC), and stability was evaluated. The in vitro binding properties of the compound to living bacteria, Candida albicans, and Aspergillus fumigatus were examined. Scintigraphy was performed and in vivo characteristics were studied in mice with infected thigh muscles. Results: An average radiochemical yield of 35% was obtained. Radiochemical purity was >97% with a stability of >24 h as determined by HPLC and instant thin-layer chromatography. The average specific activity of the noncarrier-free ¹²³I-chitinase was 9.25 MBq/µg of enzyme. Binding assays showed virtually no binding to Eschericha coli and Staphylococcus aureus, and 2.4 x 10³ Bq per 1 x 10⁷ cells for A. fumigatus and 3.0 x 10³ Bq per 1 x 10⁷ cells for C. albicans (P < 0.05). Binding of the tracer dropped to almost zero for organisms previously incubated with a 50-fold excess of unlabeled enzyme. At 24 h after injection, target-to-nontarget (T/NT) ratios in mice were 20.6 ± 3.6 for C. albicans and 15.2 ± 3.7 for A. fumigatus infections, respectively, whereas T/NT ratios for S. aureus –and E. coli–infected thigh muscles or thigh muscles with a sterile inflammation did not exceed 4.9 ± 2.6, 3.0 ± 2.3, and 5.3 ± 2.8, respectively (P < 0.05). Target-to-blood ratios for fungus-infected thighs were always >1. Conclusion: Our results show that ¹²³I-ChiB_E144Q has affinity in vitro for fungi. In vivo, the tracer accumulates in tissue infected with C. albicans and A. fumigatus but not in tissue infected with gram-positive or gram-negative bacteria, or in sterile inflammations, proving it to be a valuable SPECT diagnostic.

Key Words: infection imaging • ¹²³I-chitinase • Candida albicans • Aspergillus fumigatus • bacteria

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