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Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals

  • Original Article
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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers.

Methods and Results

Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers.

Conclusions

The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

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Abbreviations

11C-MET:

11C-methionine

18F-FDG:

18F-fluorodeoxyglucose

18F-FET:

18F-fluoroethyltyrosine

CXCR4:

Chemokine (CXC motif) receptor type 4

LPS:

Lipopolysaccharide

NRCF:

Neonatal rat cardiac fibroblast

NRCM:

Neonatal rat cardiomyocyte

PET:

Positron emission tomography

SSTR2:

Somatostatin receptor type 2

TSPO:

Translocator protein

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Acknowledgments

This study was supported by the German Research Foundation (DFG, Clinical Research Group KFO311, Excellence Cluster REBIRTH-2, and research Grant TH-2161/1-1 (JT)). The authors thank the Preclinical Molecular Imaging Core Facility, Radiochemistry Laboratory, and the Molecular Cardiology Laboratory for skilled assistance.

Disclosure

All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg-Str. 1, 30625, Hannover, Germany

    Tobias Borchert MSc, Laura Beitar, Laura B. N. Langer MSc, Andras Polyak PhD, Tobias L. Ross PhD, Frank M. Bengel MD & James T. Thackeray PhD

  2. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

    Denise Hilfiker-Kleiner PhD

  3. Department of Radiopharmaceutical Chemistry, Technical University of Munich, Munich, Germany

    Hans-Jürgen Wester PhD

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  1. Tobias Borchert MSc
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Correspondence to James T. Thackeray PhD.

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Borchert, T., Beitar, L., Langer, L.B.N. et al. Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals. J. Nucl. Cardiol. 28, 1636–1645 (2021). https://doi.org/10.1007/s12350-019-01929-z

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  • DOI: https://doi.org/10.1007/s12350-019-01929-z

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