Antibiotic-Derived Radiotracers for Positron Emission Tomography: Nuclear or "Unclear" Infection Imaging?

Abstract

The excellent features of non-invasive molecular imaging, its progressive technology (real-time, whole-body imaging and quantification), and global impact by a growing infrastructure for positron emission tomography (PET) scanners are encouraging prospects to investigate new concepts, which could transform clinical care of complex infectious diseases. Researchers are aiming towards the extension beyond the routinely available radiopharmaceuticals and are looking for more effective tools that interact directly with causative pathogens. We reviewed and critically evaluated (challenges or pitfalls) antibiotic-derived PET radiopharmaceutical development efforts aimed at infection imaging. We considered both radiotracer development for infection imaging and radio-antibiotic PET imaging supplementing other tools for pharmacologic drug characterization; overall, a total of 20 original PET radiotracers derived from eleven approved antibiotics.

Keywords: antibiotic-derived PET; imaging of infection; positron emission tomography; radiolabeling; radiotracers.

Figure 1

PET radio‐antibiotics evaluated as infection imaging agents and their respective cellular targets. Abbreviated content: G+: Gram‐positive specific; M: Mycobacteria‐specific; B: broad spectrum; FQL: fluoroquinolones; TMP: trimethoprim; INH: isoniazid (including PT70 and PT119); PZA: pyrazinamide; RIF: rifampin; LNZ: linezolid; BDQ: bedaquiline; ERM: erythromycin; DHFR: dihydrofolate reductase; KatG: mycobacterial catalase–peroxidase; InhA: enoyl‐ACP reductase; FAS II: type II fatty acid synthase system; Pzase: pyrazinamidase; PanD: aspartate 1‐decarboxylase; PABA: p‐aminobenzoic acid; DHF: dihydrofolate; THF: tetrahydrofolate; NADH: nicotinamide adenine dinucleotide; L‐ASP: L‐aspartic acid; β‐Ala: β‐alanine; CoA: co‐enzyme A; ATP: adenosine triphosphate. Created with Biorender.com.

Figure 2

A) Illustration showing the parameters that influence the “binding potential” of a tracer to its target, a concept used in receptor imaging with radiopharmaceuticals that display a saturable binding mechanism; B) Scatchard plot showing a typical equilibration curve for a ligand binding to a saturable receptor population, and how different tracer dosages may influence specific uptake levels normalized to background noise. Additionally, this concept is used in receptor imaging where quantitative PET enables measurement of specific binding at equilibrium at various concentrations (often 6–12) of the radioligand to determine receptor number (B _max) and affinity (K _d) in situ. Created with Biorender.com.

Figure 3

Enzyme–drug interaction characteristics of antibiotics, and their influencers, which should be taken into consideration before the development of an antibiotic radiotracer. Created with Biorender.com.

Figure 4

Pharmacokinetic/pharmacodynamic characteristic guidelines for selecting a prospective antibiotic for radiopharmaceutical development. Created with Biorender.com.

Figure 5

Current and potential applications of radiolabeled antibiotics. Created with Biorender.com.