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Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

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Abstract

Purpose

Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice.

Procedures

Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified.

Results

Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively.

Conclusions

Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.

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Acknowledgments

Funding was provided by NIH grant 1K01DK093766 (GMT). We thank Dr. Tim Scott and Tao Wei for assistance with NMR data, and Dr. Allen Liu for use of the spinning disk confocal microscope.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA

    Liang Zhang & Greg M. Thurber

  2. Department of Biomedical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI, 48109, USA

    Greg M. Thurber

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  1. Liang Zhang
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Correspondence to Greg M. Thurber.

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Zhang, L., Thurber, G.M. Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging. Mol Imaging Biol 18, 79–89 (2016). https://doi.org/10.1007/s11307-015-0880-2

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