Radiometal chelators for infection diagnostics

Abstract

Infection of native tissues or implanted devices is common, but clinical diagnosis is frequently difficult and currently available noninvasive tests perform poorly. Immunocompromised individuals (for example transplant recipients, or those with cancer) are at increased risk. No imaging test in clinical use can specifically identify infection, or accurately differentiate bacterial from fungal infections. Commonly used [¹⁸F]fluorodeoxyglucose (18FDG) positron emission computed tomography (PET/CT) is sensitive for infection, but limited by poor specificity because increased glucose uptake may also indicate inflammation or malignancy. Furthermore, this tracer provides no indication of the type of infective agent (bacterial, fungal, or parasitic). Imaging tools that directly and specifically target microbial pathogens are highly desirable to improve noninvasive infection diagnosis and localization. A growing field of research is exploring the utility of radiometals and their chelators (siderophores), which are small molecules that bind radiometals and form a stable complex allowing sequestration by microbes. This radiometal-chelator complex can be directed to a specific microbial target in vivo, facilitating anatomical localization by PET or single photon emission computed tomography. Additionally, bifunctional chelators can further conjugate therapeutic molecules (e.g., peptides, antibiotics, antibodies) while still bound to desired radiometals, combining specific imaging with highly targeted antimicrobial therapy. These novel therapeutics may prove a useful complement to the armamentarium in the global fight against antimicrobial resistance. This review will highlight current state of infection imaging diagnostics and their limitations, strategies to develop infection-specific diagnostics, recent advances in radiometal-based chelators for microbial infection imaging, challenges, and future directions to improve targeted diagnostics and/or therapeutics.

Keywords: PET/CT imaging; chelators; gallium-68; immunocompromised; infection diagnostics; radiometals; siderophores.

Figure 1

Individuals with increased risk of opportunistic and invasive microbial infection which require early and specific diagnostics. (A) Hematological malignancy, (B) vascular stents and grafts, (C) organ and stem cell transplantation, (D) Other medical implants devices/prostheses, (1 = Bone implant; 2 = Urinary catheter; 3 = Prosthetic leg; 4 = Knee implant; 5 = Hip replacement; 6 = Ventricular assisted device) and (E) other example diseases conditions with increased risk of prosthetic infection. HIV: Human Immunodeficiency Virus; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2. Created with BioRender.com.

Figure 2

(A) Bifunctional chelators (BFCs) and targeting biomolecules for diagnostic and therapeutic purposes. Created with BioRender.com. (B) BFCs for gallium-68. Reproduced from Ref. (23) with permission from the Royal Society of Chemistry under Creative Commons Attribution 3.0 Unported Licence. Reproduced with BioRender.com.

Figure 3

Mechanism of action of radionuclides for infection imaging in clinical practice. Autologous WBCs: Specific chemotactic activation; Anti-granulocyte: Increased capillary antibodies permeability and specific binding or uptake as antibody labelled granulocytes; Citrate: Transferrin and lactoferrin receptor binding; FDG: Upregulated glucose transporter-1 (GLUT-1) in activated granulocytes, lymphocytes, and monocytes. Created with BioRender.com.

Figure 4

Strategies to develop infection-specific radiotracers for infection diagnostics. (A) bacteria-specific strategies. (B) fungal-specific strategies. Created with BioRender.com.

Figure 5

Structure of some radiotracers mentioned in Section 3.2.1–3.2.3. Reproduced from References (117, 137) with permission under Creative Commons Attribution 4.0 International Licence. Reproduced with BioRender.com.

Figure 6

Representative structure of microbial siderophores. Triacetylfusarinine (TAFC), ferrichrome and coprogen are shown in the ferric form, In TAFC, R = acetyl. Reproduced from References (147, 148) with permission under Creative Commons Attribution 4.0 International Licence and Creative Commons Attribution 3.0 Unported Licence, respectively. Reproduced with BioRender.com.

Figure 7

Mechanisms of siderophore-mediated iron transport in Gram-positive bacteria, Gram-negative bacteria and fungi. PS: periplasmic space; CM: cell membrane; OM: outer membrane; CW: cell wall. Created with BioRender.com.

Figure 8

PET/CT imaging with [⁶⁸Ga]Ga-DFO-B-in vivo mice infection model. (A) structure of [⁶⁸Ga]Ga-DFO-B. (B) Static PET/CT imaging (coronal slices (1) and 3D volume rendered images (2)) of [⁶⁸Ga]Ga-DFO-B in P. aeruginosa infected (a) and S. aureus infected (b) Balb/c mice 45 min after injection. (C) Static PET/CT images of [⁶⁸Ga]Ga-DFO-B in pulmonary A. fumigatus-infected Lewis rats 45 min after injection: (a) CT coronal slice, (b) fused PET/CT coronal slice and (c) 3D volume rendered PET/CT image. White arrow indicates A. fumigatus infection, SI = site of injection, K = kidneys, UB = urinary bladder. Reproduced from References (183, 184) with permission under Creative Commons Attribution 4.0 International Licence. Reproduced with BioRender.com.

Figure 9

Structure of two artificial siderophores (7 and 15) and their cold gallium-complexes. Siderophores 7 and 15 were later radiolabeled with gallium-68, named as [⁶⁸Ga]Ga-7 and [⁶⁸Ga]Ga-15, respectively. Reproduced from Reference (240) with permission under CC BY-NC-ND 4.0. Reproduced with BioRender.com.

Figure 10

Prospects of ⁶⁸Ga-labeled siderophores for infection diagnostics, targeted therapy and treatment monitoring. Dotted arrow indicates replacement of ferric ion by gallium-68. Theranostic approaches where diagnostics and treatments are combined. Double question marks indicates yet to explored approach with ⁶⁸Ga-siderophores. Created with BioRender.com.