Positron Emission Tomography Imaging of Staphylococcus aureus Infection Using a Nitro-Prodrug Analogue of 2-[¹⁸F]F-p-Aminobenzoic Acid

Abstract

Deep-seated bacterial infections caused by pathogens such as Staphylococcus aureus are difficult to diagnose and treat and are thus a major threat to human health. In previous work we demonstrated that positron emission tomography (PET) imaging with 2-[18F]­F-p-aminobenzoic acid (2-[18F]­F-PABA) could noninvasively identify, localize, and monitor S. aureus infection with excellent sensitivity and specificity in a rodent soft tissue infection model. However, 2-[18F]­F-PABA is rapidly N-acetylated and eliminated, and in an attempt to improve radiotracer accumulation in bacteria we adopted a prodrug strategy in which the acid was protected by an ester and the amine was replaced with a nitro group. Metabolite analysis indicated that the nitro group of ethyl 2-[18F]­fluoro-4-nitrobenzoate (2-[18F]­F-ENB) is converted to the corresponding amine by bacteria-specific nitroreductases while the ester is hydrolyzed in vivo into the acid. PET/CT imaging of 2-[18F]­F-ENB and the corresponding acid 2-[18F]­F-NB in a rat soft tissue infection model demonstrated colocalization of the radiotracer with the bioluminescent signal arising from S. aureus Xen29, and demonstrated that the tracer could differentiate S. aureus infection from sterile inflammation. Significantly, the accumulation of both 2-[18F]­F-ENB and 2-[18F]­F-NB at the site of infection was 17-fold higher than at the site of sterile inflammation compared to 8-fold difference observed for 2-[18F]­F-PABA, supporting the proposal that the active radiotracer in vivo is 2-[18F]­F-NB. Collectively, these data suggest that 2-[18F]­F-ENB and 2-[18F]­F-NB have the potential for translation to humans as a rapid, noninvasive diagnostic tool to identify and localize S. aureus infections.

Synthesis and Evaluation of Novel Norfloxacin Isonitrile 99mTc Complexes as Potential Bacterial Infection Imaging Agents

“…At present, the distinction between infection and sterile inflammation is of great significance. A variety of radiopharmaceuticals have been developed to detect inflammation [9][10][11][12][13][14][15][16][17][18][19]. For example, 18 F-2-Fluoro-2-deoxy-D-glucose ([ 18 F]FDG) have already been used for infection imaging in clinics.…”

11C-Para-aminobenzoic acid PET imaging of S. aureus and MRSA infection in preclinical models and humans

“…In healthy human volunteers, we also observed a fast acetylation pattern in all participants, with rapid conversion of 11 C-PABA into 11 C-PAABA. To increase the amount of free 11 C-PABA that is available to bacteria after intravenous injection, Li et al recently used ethyl 2-18 F-4-nitrobenzoate (2-18 F-ENB) as a prodrug that is converted in vivo into 2-18 F-PABA (25). We used an alternative approach focused on enzyme kinetics to reduce the in vivo metabolism of 11 C-PABA.…”

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

“…The bioluminescent S.aureus strain Xen 29 has previously been used to monitor in vivo antibiotic efficacy using preclinical bioluminescence imaging non-invasively. [47][48][49][50] Therefore, before using S.aureus Xen 29 for in vivo therapy studies, the in vitro antibacterial activity of Galbofloxacin was accessed in S.aureus Xen 29. MIC assays were performed in Fe deficient media as described for the wt strains.…”