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18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

  • Original Article
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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging.

Methods

We prepared 18F radioligands for GLP-1R by the reaction of [18F]FBEM, a maleimide prosthetic group, with [Cys0] and [Cys40] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice.

Results

The [18F]FBEM-[Cysx]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [18F]FBEM), and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [18F]FBEM-[Cys40]-exendin-4, had higher affinity for INS-1 tumor cells (IC50 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [18F]FBEM-[Cys0]-exendin-4 (IC50 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cysx]-exendin-4 (p < 0.05).

Conclusion

[18F]FBEM-[Cys40]-exendin-4 and [18F]FBEM-[Cys0]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [18F]FBEM-[Cys40]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

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Acknowledgments

This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. The authors acknowledge the NIH Clinical Center PET department for radioisotope production. We thank Dr. Henry S. Eden for proof-reading the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), 31 Center Drive, Suite 1 C14, Bethesda, MD, 20892, USA

    Dale O. Kiesewetter, Haokao Gao, Ying Ma, Gang Niu, Qimeng Quan, Ning Guo & Xiaoyuan Chen

  2. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China

    Haokao Gao

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  1. Dale O. Kiesewetter
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  2. Haokao Gao
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  4. Gang Niu
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  5. Qimeng Quan
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  6. Ning Guo
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  7. Xiaoyuan Chen
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Corresponding author

Correspondence to Xiaoyuan Chen.

Additional information

Dale O. Kiesewetter and Haokao Gao contributed equally to this work.

A related editorial commentary can be found at DOI 10.1007/s00259-011-2020-9

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Kiesewetter, D.O., Gao, H., Ma, Y. et al. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging 39, 463–473 (2012). https://doi.org/10.1007/s00259-011-1980-0

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  • DOI: https://doi.org/10.1007/s00259-011-1980-0

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