Radiotracer Development for Bacterial Imaging

Abstract

Bacterial infections remain a major threat to humanity and are a leading cause of death and disability. Antimicrobial resistance has been declared as one of the top ten threats to human health by the World Health Organization, and new technologies are urgently needed for the early diagnosis and monitoring of deep-seated and complicated infections in hospitalized patients. This review summarizes the radiotracers as applied to imaging of bacterial infections. We summarize the recent progress in the development of pathogen-specific imaging and the application of radiotracers in understanding drug pharmacokinetics as well as the local biology at the infection sites. We also highlight the opportunities for medicinal chemists in radiotracer development for bacterial infections, with an emphasis on target selection and radiosynthetic approaches. Imaging of infections is an emerging field. Beyond clinical applications, these technologies could provide unique insights into disease pathogenesis and expedite bench-to-bedside translation of new therapeutics.

Figure 1.

Molecular targets for bacteria-specific imaging agents. PTS, phosphotransferase system; DHPS, dihydropteroate synthetase; DHP, dihydrofolic acid; THF, tetrahydrofolic acid.

Figure 2.

Radiosynthesis of sugar-based radiotracers used in bacterial imaging. (A) ¹⁸F-FDS is obtained from reduction of ¹⁸F-FDG. (B) MH¹⁸F and (C) 6″-¹⁸F-fluoromaltotriose are radiolabeled by nucleophilic substitution with ¹⁸F-fluoride, followed by deprotection of the hydroxyl groups.,

Figure 3.

Radiosynthesis of radiotracers based on folate metabolism. (A) ¹¹C-PABA is prepared by nucleophilic addition of a Grignard reagent to cyclotron-generated ¹¹CO₂. (B) 2-¹⁸F-PABA can be prepared in three steps by nucleophilic aromatic substitution with ¹⁸F-fluoride, followed by hydrolysis of a nitrile to carboxylic acid, and reduction of a nitro group to a primary amine. (C) ¹⁸F-FPTMP is radiolabeled in a one-pot two-step reaction by nucleophilic substitution of the boc-protected mesylate precursor followed by acidic deprotection.

Figure 4.

Radiosynthesis of ⁶⁸Ga-siderophores for imaging of bacterial iron metabolism: ⁶⁸Ga-PVD–PAO1 is prepared by generator-produced ⁶⁸Ga in the form of ⁶⁸Ga-gallium citrate in aqueous solution.

Figure 5.

Radiosynthesis of nucleic acid¹²⁴I-FIAU and radiotracers targeting bacterial cell wall components and intracellular proteins. (A) ¹²⁴I-FIAU is obtained by radioiodination of 1-(2′-deoxy-1-β-d-arabinofuranosyl)-uracil. (B) ¹¹C-d-Met is radiolabeled by methylation of d-homocysteinethiolactone. (C) ⁶⁸Ga-NOTA–UBI-29–41 is obtained by chelation of ⁶⁸Ga using a NOTA ligand attached the peptide.

Figure 6.

Considerations for the design and development of pathogen-specific PET imaging agents.

Figure 7.

Radiosynthesis of antimycobacterials and analogues. (A) ¹¹C-Isoniazid is obtained by treating iodopyridine with ¹¹C-HCN to generate ¹¹C-cyanopyridine, which is then converted into a hydrazine by nucleophilic attack and subsequently hydrolyzed, in a three-step one-pot reaction.(B) 2-¹⁸F-Fluoroisoniazide is radiolabeled by ¹⁸F nucleophilic substitution on an ammonium-leaving group through the intermediate ¹⁸F-fluoroisonicotiate. (C) ¹¹C-Rifampin can be radiolabeled through N-methylation with ¹¹CH₃I. (D) ⁷⁶Br-Bedaquiline is obtained by copper-mediated nucleophilic radiobromination of the boronic pinacol ester precursor.

Figure 8.

Radiosynthetic strategies for fluoroquinolones. (A) ¹⁸F-Ciprofloxacin can be radiolabeled through ¹⁹F–¹⁸F-isotopic exchange in two steps. (B) ¹⁸F-Fleroxacin is obtained through ¹⁸F nucleophilic substitution of a mesylate precursor.

Figure 9.

Chemical structures of selected radiotracers used for PET imaging of the host response at infection sites.