Radiotracer Development for Fungal-Specific Imaging: Past, Present, and Future

Abstract

Invasive fungal infections have become a major challenge for public health, mainly due to the growing numbers of immunocompromised patients, with high morbidity and mortality. Currently, conventional imaging modalities such as computed tomography and magnetic resonance imaging contribute largely to the noninvasive diagnosis and treatment evaluation of those infections. These techniques, however, often fall short when a fast, noninvasive and specific diagnosis of fungal infection is necessary. Molecular imaging, especially using nuclear medicine-based techniques, aims to develop fungal-specific radiotracers that can be tested in preclinical models and eventually translated to human applications. In the last few decades, multiple radioligands have been developed and tested as potential fungal-specific tracers. These include radiolabeled peptides, antifungal drugs, siderophores, fungal-specific antibodies, and sugars. In this review, we provide an overview of the pros and cons of the available radiotracers. We also address the future prospects of fungal-specific imaging.

Keywords: PET; immunoPET; invasive fungal infection; radionuclide imaging; siderophores.

Figure 1.

Graphical summary of various fungal imaging tracers and their targeting strategies. Abbreviations: ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; GLUT, Glucose transporter; ¹⁸F-FDS, ¹⁸F-fluorodeoxysorbitol; ⁶⁸Ga-DFO-E, ⁶⁸Ga-desferrioxamine; ⁶⁸Ga-TAFC, ⁶⁸Ga-triacetylfusarinine; ^99mTc-UBI(29–41), ^99mTc-ubiquicidin(29–41); ¹²³I-ChiB, ¹²³I-chitinase B; AFUM, A. fumigatus species-specific MORF oligomer; AGEN, Aspergillus genus-specific MORF oligomer; MORF, morpholino.

Figure 2.

A, In vitro ¹⁸F-FDG uptake seen in live but not HK Aspergillus fumigatus and Escherrichia coli (adapted with permission from lai et al. [9]). B, Coronal sections of PET/CT images of FDG in myositis models of A. fumigatus, Staphylococcus aureus, and E. coli infection (both live and HK) or LPS inoculation. Uptake is seen in all infectious foci and in inflammation, consistent with lack of specificity of FDG for fungal infection. Error bars represent SEM values. Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; HK, heat killed; LPS, lipopolysaccharide; PET, positron-emission tomography; SUV, standardized uptake value; SEM, standard error of the mean.

Figure 3.

Coronal plane (A) and 3-dimensional volume-rendered (B) PET/CT images of ⁶⁸Ga-TAFC in pulmonary infected and non-infected Lewis rats 45 min after injection; arrows in B show accumulation of ⁶⁸Ga-TAFC in A. fumigatus pneumonia foci but not in normal lungs. Abbreviations: ⁶⁸Ga-TAFC, ⁶⁸Ga-triacetylfusarinine C; CT, computed tomography; PET, positron-emission tomography.

Figure 4.

ImmunoPET imaging of invasive pulmonary aspergillosis using ⁶⁴Cu-radiolabeled aspergillosis-specific hJF5 antibody, ⁶⁴Cu-hJF5. A, MIP of the distribution of ⁶⁴Cu-hJF5 radiotracer in a healthy mouse (control, left) with corresponding MRI and overlay (fusion), and corresponding imaging results in a mouse infected Aspergillus fumigatus spores (right) showing high radiotracer uptake in the infected lungs. Inserts are magnification of the lungs (adapted from Henneberg et al [20] under CCBY4.0 license). B, Clinical imaging of suspected aspergillosis using CT (left column), MRI (middle column), and overlaid PET/MRI (right column) using ⁶⁴Cu-hJF5. Top row patient shows no specific uptake and was confirmed IPA negative based on EORTC/MSGERC consensus definitions of invasive fungal diseases. Bottom row patient shows high uptake in the main lesion and was confirmed as probable IPA based on EORTC/MSGERC consensus definitions of invasive fungal diseases (adapted from Schwenck et al [23] with permission). Abbreviations: CT, computed tomography; EORTC/MSGERC, European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium; ID, injected dose; IPA, invasive pulmonary aspergillosis; MIP, maximum intensity projection; MRI, magnetic resonance imaging; PET, positron-emission tomography; STIR, Short Tau Inversion Recovery; SUV, standardized uptake value.

Figure 5.

PET imaging with ⁸⁹Zr-labeled fungal cell wall-specific or isotype control antibodies in mouse models with Aspergillus myositis. PET imaging at 72 hours following injection shows high accumulation of both the specific and nonspecific antibodies in infected thighs and, to a lesser extent, in the thighs injected with HK Aspergillus spores. Abbreviations: HK, heat killed; mAb, monoclonal antibody; PET, positron-emission tomography; SUV, standardized uptake value.