A novel radiolabelled salmochelin derivative for bacteria-specific PET imaging: synthesis, radiolabelling and evaluation

Margeta, Renato; Schelhaas, Sonja; Hermann, Sven; Schäfers, Michael; Niemann, Silke; Faust, Andreas

doi:10.1039/d4cc00255e

Cited by 3 publications

(5 citation statements)

References 32 publications

(36 reference statements)

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“…The most clinically advanced pathogen-specific PET tracer is 2-deoxy-2-[ 18 F]fluoro-D-sorbitol([ 18 F]FDS), which has recently been studied in numerous infected patients . Other pathogen-targeted PET tracers depend on microbial sugar metabolism, − cell wall structure, ,, folic acid biosynthesis, ,− iron transport, − and other mechanisms. Despite encouraging results for [ 18 F]FDS and other newer tracers in humans, questions about their clinical feasibility persist, based on several factors including variable bacterial burden and biofilm development in clinical infections.…”

Section: Discussionmentioning

confidence: 99%

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography

Pandey,

Chopra,

Cleary

et al. 2024

ACS Infect. Dis.

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Understanding how the host immune system engages complex pathogens is essential to developing therapeutic strategies to overcome their virulence. While granzymes are well understood to trigger apoptosis in infected host cells or bacteria, less is known about how the immune system mobilizes individual granzyme species in vivo to combat diverse pathogens. Toward the goal of studying individual granzyme function directly in vivo, we previously developed a new class of radiopharmaceuticals termed “restricted interaction peptides (RIPs)” that detect biochemically active endoproteases using positron emission tomography (PET). In this study, we showed that secreted granzyme B proteolysis in response to diverse viral and bacterial pathogens could be imaged with [64Cu]Cu-GRIP B, a RIP that specifically targets granzyme B. Wild-type or germline granzyme B knockout mice were instilled intranasally with the A/PR/8/34 H1N1 influenza A strain to generate pneumonia, and granzyme B production within the lungs was measured using [64Cu]Cu-GRIP B PET/CT. Murine myositis models of acute bacterial (E. coli, P. aeruginosa, K. pneumoniae, and L. monocytogenes) infection were also developed and imaged using [64Cu]Cu-GRIP B. In all cases, the mice were studied in vivo using mPET/CT and ex vivo via tissue-harvesting, gamma counting, and immunohistochemistry. [64Cu]Cu-GRIP B uptake was significantly higher in the lungs of wild-type mice that received A/PR/8/34 H1N1 influenza A strain compared to mice that received sham or granzyme B knockout mice that received either treatment. In wild-type mice, [64Cu]Cu-GRIP B uptake was significantly higher in the infected triceps muscle versus normal muscle and the contralateral triceps inoculated with heat killed bacteria. In granzyme B knockout mice, [64Cu]Cu-GRIP B uptake above the background was not observed in the infected triceps muscle. Interestingly, live L. monocytogenes did not induce detectable granzyme B on PET, despite prior in vitro data, suggesting a role for granzyme B in suppressing their pathogenicity. In summary, these data show that the granzyme response elicited by diverse human pathogens can be imaged using PET. These results and data generated via additional RIPs specific for other granzyme proteases will allow for a deeper mechanistic study analysis of their complex in vivo biology.

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Section: Discussionmentioning

confidence: 99%

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography

Pandey,

Chopra,

Cleary

et al. 2024

ACS Infect. Dis.

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“…Margeta et al (Margeta et al 2024 ) utilised salmochelin, an enterobactin-based siderophore, to radiolabel the salmochelin-derivate, RMA693, with 68 Ga with the aim of targeting E. coli -induced infections. The synthesis of the precursor seems quite complicated, but subsequent [ 68 Ga]Ga-RMA693 (see Fig.…”

Section: Main Textmentioning

confidence: 99%

“…High accumulation in E. coli reported Peukert et al ( 2021 ) [ 68 Ga]Ga-ORNB-C6 PET 68 Ge/ 68 Ga generator Simple manual synthesis None High accumulation in B. multivorans and significantly lower uptake in S. aureus and P. aeruginosa . No accumulation in E. coli Bendova et al ( 2023 ) [ 68 Ga]Ga-RMA693 (enterobactin-based siderophore) PET 68 Ge/ 68 Ga generator Total chemical synthesis, followed by manual radiolabelling None Specific uptake in E. coli ATCC25922 strain Margeta et al ( 2024 ) [ 68 Ga]Ga-ferrirubin PET 68 Ge/ 68 Ga generator Simple manual synthesis None High uptake in S. aureus, P. aeruginosa and K. pneumoniae , with negligible uptake in E. coli Krasulova et al ( 2024 ) [ 64 Cu]Cu-YbT PET Cyclotron— 64 Ni(p,n) 64 Cu Manual labelling None Ferric Ybt uptake A receptor-expressing bacteria— E. coli UTI89, E. coli Nissle WT and Klebsiella pneumoniae Siddiqui et al ( 2021 ) Antimicrobial peptides [ 68 Ga]Ga-NOTA/DOTA-UBI29-41 PET 68 Ge/ 68 Ga generator Automated synthesis and in-house production reported Low uptake in sterile inflammation, with rapid washout Broad-spectrum bacterial uptake (including P. aeruginosa ...…”

Section: Main Textmentioning

confidence: 99%

“…In vitro uptake studies of [ 68 Ga]Ga-ORNB-C6 in different BCC cultures illustrated significantly high uptake in B. multivorans species and comparative uptake studies with Margeta et al (Margeta et al 2024) utilised salmochelin, an enterobactin-based siderophore, to radiolabel the salmochelin-derivate, RMA693, with 68 Ga with the aim of targeting E. coli-induced infections. The synthesis of the precursor seems quite complicated, but subsequent [ 68 Ga]Ga-RMA693 (see Fig.…”

Section: Radiolabelled Bacterial Siderophoresmentioning

confidence: 99%

“…Conventional infection imaging agents (such as [ 67 Ga]Ga-citrate, [ 111 In]In-oxine- or [ 99m Tc]Tc-HMPAO-labelled leukocytes, and [ 18 F]FDG) do not target bacteria, but rather the host immune response to the bacterial infection, and will therefore also localise in sterile inflammatory foci. The nonspecificity of these tracers can result in delayed or even inaccurate diagnosis, localisation, and treatment of infection, which may increase the cost-related burden, antimicrobial resistance, morbidity and even mortality of patients (Jiang et al 2024 ; Margeta et al 2024 ; Santos et al 2024 ; Spoelstra et al 2024 ; Li et al 2020 ). The development and investigation of new radiopharmaceuticals focuses on the differentiation of infection from sterile inflammation and the imaging of specific infectious microbes and processes (Palestro 2019 ; Signore et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Recently developed radiopharmaceuticals for bacterial infection imaging

Kahts,

Summers,

Gutta

et al. 2024

EJNMMI radiopharm. chem.

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Background Infection remains a major cause of morbidity and mortality, regardless of advances in antimicrobial therapy and improved knowledge of microorganisms. With the major global threat posed by antimicrobial resistance, fast and accurate diagnosis of infections, and the reliable identification of intractable infection, are becoming more crucial for effective treatment and the application of antibiotic stewardship. Molecular imaging with the use of nuclear medicine allows early detection and localisation of infection and inflammatory processes, as well as accurate monitoring of treatment response. There has been a continuous search for more specific radiopharmaceuticals to be utilised for infection imaging. This review summarises the most prominent discoveries in specifically bacterial infection imaging agents over the last five years, since 2019. Main body Some promising new radiopharmaceuticals evaluated in patient studies are reported here, including radiolabelled bacterial siderophores like [68Ga]Ga-DFO-B, radiolabelled antimicrobial peptide/peptide fragments like [68Ga]Ga-NOTA-UBI29-41, and agents that target bacterial synthesis pathways (folic acid and peptidoglycan) like [11C]para-aminobenzoic acid and D-methyl-[11C]-methionine, with clinical trials underway for [18F]fluorodeoxy-sorbitol, as well as for 11C- and 18F-labelled trimethoprim. Conclusion It is evident that a great deal of effort has gone into the development of new radiopharmaceuticals for infection imaging over the last few years, with remarkable progress in preclinical investigations. However, translation to clinical trials, and eventually clinical Nuclear Medicine practice, is apparently slow. It is the authors’ opinion that a more structured and harmonised preclinical setting and well-designed clinical investigations are the key to reliably evaluate the true potential of the newly proposed infection imaging agents.

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18F-labelled gentiobiose as potential PET-radiotracer for specific bacterial imaging: precursor synthesis, radiolabelling and in vitro evaluation

Landau,

Hermann,

Schelhaas

et al. 2024

Nuklearmedizin

Self Cite

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Aim Bacterial infections are a clinical challenge, requiring fast and specific diagnosis to ensure effective treatment. Therefore, this project is dedicated to development of positron emission tomography (PET) radiotracers specifically targeting bacteria. Unlike previously developed bacteria-specific radiotracers, which are successful in detecting Gram-negative bacteria, tracers capable of imaging Gram-positive infections are still lacking. Methods The disaccharide gentiobiose as abundant part of the cell wall of Gram-positive bacteria could fill this gap. Herein, the synthesis and evaluation of 2‘-deoxy-2‘-[18F]fluorogentiobiose ([18F]FLA280) is reported. The precursor for radiolabelling was obtained from a convergent synthesis under application of a benzylidene/benzyl group protecting strategy. Results The first catalytic hydrogenation in 18F-radiochemistry is reported as proof of concept. The deprotection was carried out without any side product formation, giving the final radiotracer [18F]FLA280 in good radiochemical yield and excellent radiochemical purity. [18F]FLA280 was proven to be stable in murine and human blood serum for 120 minutes and was subjected to in vitro bacterial uptake studies towards S. aureus and E. coli resulting in a low bacterial uptake. Conclusion The observed bacterial uptake indicates that [18F]FLA280 may be not a promising tracer candidate for in vivo translation and alternative candidates particularly for Gram-positive bacteria are required. However, further development on the concept of labelled carbohydrates and cell wall building blocks might be promising.

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A novel radiolabelled salmochelin derivative for bacteria-specific PET imaging: synthesis, radiolabelling and evaluation

Abstract: For specific imaging of bacterial infections we aimed at targeting the exclusive bacterial iron transport system via siderophore-based radiotracers. De novo synthesis and radiolabeling yielded the salmochelin-based PET radiotracer [68Ga]Ga-RMA693,...

Cited by 3 publications

References 32 publications

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography

Recently developed radiopharmaceuticals for bacterial infection imaging

18F-labelled gentiobiose as potential PET-radiotracer for specific bacterial imaging: precursor synthesis, radiolabelling and in vitro evaluation

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