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Synthesis and preclinical evaluation of novel 18F-vancomycin-based tracers for the detection of bacterial infections using positron emission tomography

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Název: Synthesis and preclinical evaluation of novel 18F-vancomycin-based tracers for the detection of bacterial infections using positron emission tomography
Autoři: Spoelstra, G. B., Blok, S. N., Reali Nazario, L., Noord, L., Fu, Y., Simeth, N. A., IJpma, F. F. A., van Oosten, M., van Dijl, J. M., Feringa, B. L., Szymanski, W., Elsinga, P. H.
Přispěvatelé: Spoelstra, G. B., Blok, S. N., Reali Nazario, L., Noord, L., Fu, Y., Simeth, N. A., IJpma, F. F. A., van Oosten, M., van Dijl, J. M., Feringa, B. L., Elsinga, P. H.
Zdroj: Eur J Nucl Med Mol Imaging
Informace o vydavateli: Springer Science and Business Media LLC, 2024.
Rok vydání: 2024
Témata: 0301 basic medicine, Fluorine Radioisotopes, Radiochemistry, Bacterial Infections, Chemistry Techniques, Synthetic, 3. Good health, Mice, 03 medical and health sciences, 0302 clinical medicine, Vancomycin, Positron-Emission Tomography, Animals, Original Article, Tissue Distribution, Positron emission tomography, Radioactive Tracers [MeSH], Radiochemistry [MeSH], Radiopharmaceuticals/pharmacokinetics [MeSH], Vancomycin/pharmacology [MeSH], Bacterial infection imaging, Fluorine Radioisotopes/chemistry [MeSH], Animals [MeSH], Bacterial Infections/diagnostic imaging [MeSH], Radiopharmaceuticals/chemical synthesis [MeSH], Gram-positive, Mice [MeSH], Positron-Emission Tomography/methods [MeSH], Biodistribution, Fluorine-18, Tissue Distribution [MeSH], Vancomycin/pharmacokinetics [MeSH], Chemistry Techniques, Synthetic [MeSH], Radioactive Tracers, Radiopharmaceuticals
Popis: Introduction Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three 18F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria. Methods [18F]FB-NHS and [18F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [18F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites. Results [18F]FB-vancomycin, [18F]BODIPY-FL-vancomycin, and [18F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [18F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [18F]PQ-VE1-vancomycin and [18F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones. Conclusion Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1619-7089
1619-7070
DOI: 10.1007/s00259-024-06717-7
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/38644432
https://research.rug.nl/en/publications/c0e030e6-19fb-454c-ad9f-74738c49bb86
https://hdl.handle.net/11370/c0e030e6-19fb-454c-ad9f-74738c49bb86
https://doi.org/10.1007/s00259-024-06717-7
https://resolver.sub.uni-goettingen.de/purl?gro-2/143052
https://repository.publisso.de/resource/frl:6523113
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....284d9d0a54c9f5be49173c0c0bbd7817
Databáze: OpenAIRE
Popis
Abstrakt:Introduction Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three 18F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria. Methods [18F]FB-NHS and [18F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [18F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites. Results [18F]FB-vancomycin, [18F]BODIPY-FL-vancomycin, and [18F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [18F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [18F]PQ-VE1-vancomycin and [18F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones. Conclusion Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.
ISSN:16197089
16197070
DOI:10.1007/s00259-024-06717-7