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

  • Dale O. Kiesewetter
  • Haokao Gao
  • Ying Ma
  • Gang Niu
  • Qimeng Quan
  • Ning Guo
  • Xiaoyuan ChenEmail author
Original Article



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.


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.


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).


[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.


Exendin-4 GLP-1R Insulinoma 18PET 



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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Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Dale O. Kiesewetter
    • 1
  • Haokao Gao
    • 1
    • 2
  • Ying Ma
    • 1
  • Gang Niu
    • 1
  • Qimeng Quan
    • 1
  • Ning Guo
    • 1
  • Xiaoyuan Chen
    • 1
    Email author
  1. 1.Laboratory of Molecular Imaging and Nanomedicine (LOMIN)National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH)BethesdaUSA
  2. 2.Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina

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