Original Article

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

  • Dale O. KiesewetterAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • , Haokao GaoAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)Department of Cardiology, Xijing Hospital, The Fourth Military Medical University
  • , Ying MaAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • , Gang NiuAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • , Qimeng QuanAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • , Ning GuoAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)
  • , Xiaoyuan ChenAffiliated withLaboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) Email author 

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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