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Ex Vivo Imaging of Pancreatic Beta Cells using a Radiolabeled GLP-1 Receptor Agonist

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Abstract

Purpose

The purpose of this study was to evaluate the binding specificity of the radiolabeled glucagon-like peptide 1 receptor (GLP-1R) agonist (Lys40(DOTA)NH2)Exendin-4 in the pancreas using a combination of ex vivo autoradiography and immunohistochemistry.

Procedures

Sprague–Dawley rats were administered [64Cu](Lys40(DOTA)NH2)Exendin-4 i.v. with or without unlabeled Exendin (9-39) to determine binding specificity. Similar experiments were performed using Zucker diabetic fatty (ZDF) and Zucker lean (ZLC) rats. Animals were euthanized and the pancreas was extracted, immediately frozen, and sectioned. The sections were apposed to phosphor imaging plates, scanned, and immunostained for insulin.

Results

Co-registration of the autoradiographic and immunohistochemical images revealed that [64Cu] (Lys40(DOTA)NH2)Exendin-4 specific binding was restricted to islet cells. This binding was blocked by the co-administration of Exendin(9-39) indicating that the radiotracer uptake is mediated by GLP-1R. Uptake of [64Cu](Lys40(DOTA)NH2)Exendin-4 was greatly decreased in the pancreas of ZDF rats.

Conclusions

Ex vivo autoradiography results using [64Cu](Lys40(DOTA)NH2)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the in vivo determination of β-cell mass.

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Acknowledgment

The authors would like to thank Lan Zhu for the determination of human GLP-1 receptor potency for (Lys40(DOTA)NH2)Exendin-4 and Karen Schlingmann for the excellent technical assistance.

Conflicts of Interest Statement/Disclosures

Brett Connolly, Amy Vanko, Paul McQuade, Xiangjun Meng, Daniel Rubins, Richard Hargreaves, Cyrille Sur, and Eric Hostetler are employees and shareholders of Merck and Co., Inc.

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Author notes

  1. Ilonka Guenther

    Present address: Maccine Pte Ltd, Singapore, Singapore

  2. Rikki Waterhouse

    Present address: Abbott Laboratories, Abbott Park, North Chicago, IL, USA

Authors and Affiliations

  1. Department of Imaging, Merck Research Laboratories, West Point, PA, 19486, USA

    Brett M. Connolly, Amy Vanko, Paul McQuade, Ilonka Guenther, Xiangjun Meng, Daniel Rubins, Rikki Waterhouse, Cyrille Sur & Eric Hostetler

  2. Department of Neuroscience, Merck Research Laboratories, West Point, PA, 19486, USA

    Richard Hargreaves

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  1. Brett M. Connolly
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Correspondence to Brett M. Connolly.

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Connolly, B.M., Vanko, A., McQuade, P. et al. Ex Vivo Imaging of Pancreatic Beta Cells using a Radiolabeled GLP-1 Receptor Agonist. Mol Imaging Biol 14, 79–87 (2012). https://doi.org/10.1007/s11307-011-0481-7

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  • DOI: https://doi.org/10.1007/s11307-011-0481-7

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