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

ABSTRACT: Tools for noninvasive detection of bacterial pathogens are needed but are not currently available for clinical use. We have previously shown that para-aminobenzoic acid (PABA) rapidly accumulates in a wide range of pathogenic bacteria, motivating the development of related PET radiotracers. In this study, 11C-PABA PET imaging was used to accurately detect and monitor infections due to pyogenic bacteria in multiple clinically relevant animal models. 11C-PABA PET imaging selectively detected infections in muscle, intervertebral discs, and methicillin-resistant Staphylococcus aureus-infected orthopedic implants. In what we believe to be first-in-human studies in healthy participants, 11C-PABA was safe, well-tolerated, and had a favorable biodistribution, with low background activity in the lungs, muscles, and brain. 11C-PABA has the potential for clinical translation to detect and localize a broad range of bacteria.

SUBMITTER: Ordonez AA

PROVIDER: S-EPMC8765043 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Ordonez Alvaro A AA Parker Matthew Fl MF Miller Robert J RJ Plyku Donika D Ruiz-Bedoya Camilo A CA Tucker Elizabeth W EW Luu Justin M JM Dikeman Dustin A DA Lesniak Wojciech G WG Holt Daniel P DP Dannals Robert F RF Miller Lloyd S LS Rowe Steven P SP Wilson David M DM Jain Sanjay K SK

JCI insight 20220111 1

Tools for noninvasive detection of bacterial pathogens are needed but are not currently available for clinical use. We have previously shown that para-aminobenzoic acid (PABA) rapidly accumulates in a wide range of pathogenic bacteria, motivating the development of related PET radiotracers. In this study, 11C-PABA PET imaging was used to accurately detect and monitor infections due to pyogenic bacteria in multiple clinically relevant animal models. 11C-PABA PET imaging selectively detected infec ...[more]

PMID: 35014627

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Project description:UnlabelledNociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, (11)C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of (11)C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile.MethodsAfter intravenous injection of (11)C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V(T); a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise's bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose).ResultsAfter (11)C-NOP-1A injection, the peak concentration of radioactivity in brain was high (∼5-7 standardized uptake values), occurred early (∼10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent V(T) identifiability (∼1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional V(T) values (mL·cm(-3)) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. V(T) was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of (11)C-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 V(T) values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. (11)C-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 μSv/MBq), and the effective dose was 4.3 μSv/MBq.Conclusion(11)C-NOP-1A is a promising radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other (11)C-labeled radioligands, allowing multiple scans in 1 subject.

Project description:PurposeThere is a clinical need for agents that target glioma cells for non-invasive and intraoperative imaging to guide therapeutic intervention and improve the prognosis of glioma. Matrix metalloproteinase (MMP)-14 is overexpressed in glioma with negligible expression in normal brain, presenting MMP-14 as an attractive biomarker for imaging glioma. In this study, we designed a peptide probe containing a near-infrared fluorescence (NIRF) dye/quencher pair, a positron emission tomography (PET) radionuclide, and a moiety with high affinity to MMP-14. This novel substrate-binding peptide allows dual modality imaging of glioma only after cleavage by MMP-14 to activate the quenched NIRF signal, enhancing probe specificity and imaging contrast.MethodsMMP-14 expression and activity in human glioma tissues and cells were measured in vitro by immunofluorescence and gel zymography. Cleavage of the novel substrate and substrate-binding peptides by glioma cells in vitro and glioma xenograft tumors in vivo was determined by NIRF imaging. Biodistribution of the radiolabeled MMP-14-binding peptide or substrate-binding peptide was determined in mice bearing orthotopic patient-derived xenograft (PDX) glioma tumors by PET imaging.ResultsGlioma cells with MMP-14 activity showed activation and retention of NIRF signal from the cleaved peptides. Resected mouse brains with PDX glioma tumors showed tumor-to-background NIRF ratios of 7.6-11.1 at 4 h after i.v. injection of the peptides. PET/CT images showed localization of activity in orthotopic PDX tumors after i.v. injection of 68Ga-binding peptide or 64Cu-substrate-binding peptide; uptake of the radiolabeled peptides in tumors was significantly reduced (p < 0.05) by blocking with the non-labeled-binding peptide. PET and NIRF signals correlated linearly in the orthotopic PDX tumors. Immunohistochemistry showed co-localization of MMP-14 expression and NIRF signal in the resected tumors.ConclusionsThe novel MMP-14 substrate-binding peptide enabled PET/NIRF imaging of glioma models in mice, warranting future image-guided resection studies with the probe in preclinical glioma models.

Dataset Information

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

Publications

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

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