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Specific PET imaging of xC- transporter activity using a 18F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism

Koglin, Norman, Mueller, Andre, Berndt, Mathias, Schmitt-Willich, Heribert, Toschi, Luisella, Stephens, Andrew W., Gekeler, Volker, Friebe, Matthias, Dinkelborg, Ludger M.·2011·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-11-0687

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Abstract

PURPOSE: (18)F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable ¹⁸F-labeled glutamate analogue for PET imaging of tumors. EXPERIMENTAL DESIGN: Derivatives of l-glutamate were investigated in cell competition assays to characterize the responsible transporter. An automated radiosynthesis was established for the most promising candidate. The resulting ¹⁸F-labeled PET tracer was characterized in a panel of in vitro and in vivo tumor models. Tumor specificity was investigated in the turpentine oil-induced inflammation model in rats. RESULTS: A fluoropropyl substituted glutamate derivative showed strong inhibition in cell uptake assays. The radiosynthesis was established for (4S)-4-(3-[¹⁸F]fluoropropyl)-l-glutamate (BAY 94-9392). Tracer uptake studies and analysis of knockdown cells showed specific transport of BAY 94-9392 via the cystine/glutamate exchanger designated as system x(C)(-). No metabolites were observed in mouse blood and tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in preclinical tumor models. In addition, BAY 94-9392 did not accumulate in inflammatory lesions in contrast to FDG. CONCLUSIONS: BAY 94-9392 is a new tumor-specific PET tracer which could be useful to examine system x(C)(-) activity in vivo as a possible hallmark of tumor oxidative stress. Both preclinical and clinical studies are in progress for further characterization.

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Authors: Koglin, N., Mueller, A., Berndt, M., Schmitt-Willich, H., Toschi, L., Stephens, A. W., Gekeler, V., Friebe, M., & Dinkelborg, L. M.
Affiliations: Bayer (Germany) (DE)
Authors' Affiliation: Global Drug Discovery, Bayer HealthCare, Berlin, Germany
ORCID: Koglin, Norman
Berndt, Mathias
Stephens, Andrew W.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-09-14
Volume: 17
Issue: 18
Pages: 6000-6011
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-11-0687
OpenAlex: W2142880945
Cited by: 120
References: 51
Citations by year: 2026: 5 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 8 · 2021: 7 · 2020: 14 · 2019: 9 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 11 · 2014: 9 · 2013: 8 · 2012: 8
FWCI: 6.11
Type: journal article
Language: en
Open access: closed
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: Bayer HealthCare
Topics: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: system xc-, cystine/glutamate exchanger, cancer metabolism, radiotracer synthesis, tumor-specific imaging, tumor-to-background ratio
MeSH terms: Animals, Female, Glutamates, Humans, Mice, Nude, Neoplasms, Rats, Nude, Tomography, X-Ray Computed, Signal Transduction, Radiopharmaceuticals, Xenograft Model Antitumor Assays, Amino Acid Transport System y+, Cell Line, Tumor, Positron-Emission Tomography, Mice, Rats, Multimodal Imaging

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Specific PET imaging of xC- transporter activity using a 18F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism

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