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Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

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Abstract

Introduction

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated.

Methods

We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer.

Results

In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen.

Discussion

The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

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Abbreviations

AChE:

Acetylcholinesterase

CFU:

Colony forming unit

MRI:

Magnetic Resonance Imaging

PET:

Positron Emission Tomography

PMN:

Polymorph-nuclear cells

ROI:

2D region of interest

SPECT:

Single photon emission computed tomography

SUV:

Standardized uptake value

VAChT:

Vesicular acetylcholine transporter

VOI:

3D volume of interest

WBC:

White blood cells

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Acknowledgments

We acknowledge laboratory technician Mette Simonsen for invaluable help on PET/MRI imaging.

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

    Nis Pedersen Jørgensen & Mariane Høgsberg Schleimann

  2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark

    Aage K. O. Alstrup, Karoline Knudsen, Steen Jakobsen, Dirk Bender, Lars C. Gormsen & Per Borghammer

  3. Department of Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    Frank V. Mortensen

  4. Department of Histopathology, Aarhus University Hospital, Aarhus, Denmark

    Line Bille Madsen

  5. Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark

    Peter Breining

  6. Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark

    Mikkel Steen Petersen

  7. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Frederik Dagnæs-Hansen

Authors
  1. Nis Pedersen Jørgensen
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  13. Per Borghammer
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Corresponding author

Correspondence to Per Borghammer.

Ethics declarations

The study was funded by the Danish Medical Research Council and the Lundbeck foundation. Per Borghammer has served as a consultant for F. Hoffmann – La Roche Ltd. All other co-authors had no conflicts of interest concerning the present study. Permission for the studies of mice and pigs were obtained from the Danish Animal Experiments Inspectorate (j. nr. 2013-15-2934-00878). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All human studies were approved by the Central Denmark Region Committee on Health Research and the Danish Health and Medicines Authority, and followed the ethical standards of the institutional and national research committee and the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from all participants prior to enrollment.

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Jørgensen, N.P., Alstrup, A.K.O., Mortensen, F.V. et al. Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV. Eur J Nucl Med Mol Imaging 44, 449–458 (2017). https://doi.org/10.1007/s00259-016-3555-6

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