European Journal of Nuclear Medicine and Molecular Imaging

, Volume 39, Issue 3, pp 463–473

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

Authors

  • Dale O. Kiesewetter
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • Haokao Gao
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
    • Department of Cardiology, Xijing HospitalThe Fourth Military Medical University
  • Ying Ma
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • Gang Niu
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • Qimeng Quan
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • Ning Guo
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
    • Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
Original Article

DOI: 10.1007/s00259-011-1980-0

Cite this article as:
Kiesewetter, D.O., Gao, H., Ma, Y. et al. Eur J Nucl Med Mol Imaging (2012) 39: 463. doi:10.1007/s00259-011-1980-0

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.

Keywords

Exendin-4 GLP-1R Insulinoma 18F PET

Copyright information

© Springer-Verlag (outside the USA) 2011