Skip to main content


Log in

64Cu- and 68Ga-Labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

An Erratum to this article was published on 14 November 2013



Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle14,Lys40(Ahx-NODAGA-64Cu)NH2]-exendin-4 ([64Cu]NODAGA-exendin-4) and [Nle14,Lys40(Ahx-NODAGA-68Ga)NH2]-exendin-4 ([68Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents.


The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated.


We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [64Cu]NODAGA-exendin-4 and [68Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively.


[64Cu]NODAGA-exendin-4 might be more effective for labelling islets than [68Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [68Ga]NODAGA-exendin-4 compared to [64Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [64Cu]NODAGA-exendin-4 as a clinical tracer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others


  1. Mukai E, Toyoda K, Kimura H et al (2009) GLP-1 receptor antagonist as a potential probe for pancreatic beta-cell imaging. Biochem Biophys Res Commun 389:523–526

    Article  CAS  PubMed  Google Scholar 

  2. Wu Z, Kandeel F (2010) Radionuclide probes for molecular imaging of pancreatic beta-cells. Adv Drug Deliv Rev 62:1125–1138

    Article  CAS  PubMed  Google Scholar 

  3. Holst JJ, Deacon CF, Vilsbøll T et al (2008) Glucagon like peptide-1, glucose homeostasis and diabetes. Trends Mol Med 14:161–168

    Article  CAS  PubMed  Google Scholar 

  4. Nielsen LL, Young AA, Parkes DG (2004) Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 117:77–88

    Article  CAS  PubMed  Google Scholar 

  5. Tornehave D, Kristensen P, Rømer J et al (2008) Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem 56:841–851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Xu G, Doris A, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276

    Article  CAS  PubMed  Google Scholar 

  7. Reubi JC, Waser B (2003) Concominant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 30:781–793

    Article  CAS  PubMed  Google Scholar 

  8. Körner M, Stöckli M, Waser B, Reubi JC (2007) GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 48:736–743

    Article  PubMed  Google Scholar 

  9. Wild D, Christ E, Caplin ME et al (2011) Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med 52:1073–1078

    Article  PubMed  Google Scholar 

  10. Gotthardt M, Lalyko G, van Eerd-Vismale J et al (2006) A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents. Regul Pept 137:162–167

    Article  CAS  PubMed  Google Scholar 

  11. Wild D, Béhé M, Wicki A et al (2006) [Lys40(Ahx-DTPA-111In)NH2]Exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 47:2025–2033

    CAS  PubMed  Google Scholar 

  12. Brom M, Oyen WJ, Joosten L et al (2010) 68Ga-labeled exendin-3, a new agent for the detection of insulinomas with PET. Eur J Nucl Med Mol Imaging 37:1345–1355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Wu Z, Todorov I, Li L et al (2011) In vivo imaging of transplanted islets with 64Cu-DO3A-VS-Cys40-exendin-4 by targeting GLP-1 receptor. Bioconjug Chem 22:1587–1594

    Article  CAS  PubMed  Google Scholar 

  14. Connolly BM, Vanko A, McQuade P et al (2011) Ex vivo imaging of pancreatic beta cells using a radiolabeled GLP-1 receptor agonist. Mol Imaging Biol 14:79–87

    Article  Google Scholar 

  15. Gao H, Niu G, Yang M et al (2011) PET of insulinoma using 18F-FBEM-EM3106B, a new GLP-1 analogue. Mol Pharm 8:1775–1782

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kiesewetter DO, Gao H, Ma Y et al (2012) 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging 39:463–473

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Fani M, Del Pozzo L, Abiraj K et al (2011) PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med 52:1110–1118

    Article  CAS  PubMed  Google Scholar 

  18. McCarthy DW, Shefer RE, Klinkowstein RE et al (1997) Efficient production of high specific activity 64Cu using a biomedical cyclotron. Nucl Med Biol 24:35–43

    Article  CAS  PubMed  Google Scholar 

  19. Avila-Rodriguez MA, Nye JA, Nickles RJ (2007) Simultaneous production of high specific activity 64Cu and 61Co with 11.4 MeV protons on enriched 64Ni nuclei. Appl Radiat Isot 65:1115–1120

    Article  CAS  PubMed  Google Scholar 

  20. Rajander J, Schlesinger J, Avila-Rodriguez MA, Solin O (2009) Increasing specific activity in Cu-64 production by reprocessing the Ni-64 target material. J Labelled Comp Radiopharm 52:234

    Google Scholar 

  21. Någren K, Halldin C (1998) Methylation of amide and thiol functions with [11C]methyl triflate, as exemplified by [11C]NMSP, [11C]Flumazenil and [11C]Methionine. J Labelled Comp Radiopharm 41:831–841

    Article  Google Scholar 

  22. Howell RW, Wessels BW, Lovinger R (1999) The MIRD perspective 1999. J Nucl Med 40:3–10

    Google Scholar 

  23. Stabin MG, Sparks R, Crowe E (2005) OLINDA/EXM: the second generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027

    PubMed  Google Scholar 

  24. Wild D, Mäcke H, Christ E et al (2008) Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med 359:766–768

    Article  CAS  PubMed  Google Scholar 

  25. Christ E, Wild D, Forrer F et al (2009) Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab 94:4398–4405

    Article  CAS  PubMed  Google Scholar 

  26. Pattou F, Kerr-Conte J, Wild D (2010) GLP-1-receptor scanning for imaging of human beta cells transplanted in muscle. N Engl J Med 363:1289–1290

    Article  PubMed  Google Scholar 

  27. Andralojc K, Srinivas M, Brom M et al (2012) Obstacles on the way to the clinical visualisation of beta cells: looking for the Aeneas of molecular imaging to navigate between Scylla and Charybdis. Diabetologia 55:1247–1257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Blomberg BA, Moghbel MC, Alavi A (2012) PET imaging of β-cell mass: is it feasible? Diabetes Metab Res Rev 28:601–602

    Article  PubMed  Google Scholar 

  29. Sweet IR, Cook DL, Lernmark A et al (2004) Non-invasive imaging of beta cell mass: a quantitative analysis. Diabetes Technol Ther 6:652–659

    Article  PubMed  Google Scholar 

  30. Selvaraju RK, Velikyan I, Johansson L et al (2013) In vivo imaging of the glucagon like peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4. J Nucl Med 54:1–6

    Article  Google Scholar 

  31. Schmidtler J, Dehne K, Allescher HD et al (1994) Rat parietal cell receptors for GLP-1-(7-36) amide: Northern blot, cross-linking, and radioligand binding. Am J Physiol 267:G423–432

    CAS  PubMed  Google Scholar 

  32. Schmidtler J, Schepp W, Janczewska I et al (1991) GLP-1-(7-36) amide, -(1-37), and (1-36) amide: potent cAMP-dependent stimuli of rat parietal cell function. Am J Physiol 260:G940–950

    CAS  PubMed  Google Scholar 

  33. Holst JJ (2000) Gut hormones as pharmaceuticals from enteroglucagon to GLP-1 and GLP-2. Regul Pept 93:45–51

    Article  CAS  PubMed  Google Scholar 

  34. Vegt E, Melis M, Eek A et al (2011) Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice. Eur J Nucl Med Mol Imaging 38:623–632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Wessels BW, Konijnenberg MW, Dale RG et al (2008) MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response—implications for radionuclide therapy. J Nucl Med 49:1884–1899

    Article  PubMed  Google Scholar 

Download references


The authors thank Dr. Jörn Schlesinger for technical expertise and scientific discussions and Vesa Oikonen MSc for helping with PET/CT data analysis. Aake Honkaniemi, Elisa Riuttala, Merja Tuomas and Marko Vehmanen are acknowledged for their technical assistance. The study was conducted within the Finnish Centre of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research, financially supported by the Academy of Finland, the University of Turku, Turku University Hospital and Åbo Akademi University. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 222980 and from the Diabetes Research Foundation, Finland.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Nuutila Pirjo.

Additional information

Mikkola Kirsi and Yim Cheng-Bin contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.


(PDF 280 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kirsi, M., Cheng-Bin, Y., Veronica, F. et al. 64Cu- and 68Ga-Labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats. Mol Imaging Biol 16, 255–263 (2014).

Download citation

  • Published:

  • Issue Date:

  • DOI:

Key words