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68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-aminohexanoic acid-Lys40-exendin-4

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: April 26, 2012.

Chemical name:68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-aminohexanoic acid-Lys40-exendin-4
Abbreviated name:[Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4
Agent category:Peptide
Target:Glucagon-like peptide-1 receptor (GLP-1R)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:68Ga
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Click on protein, nucleotide (RefSeq), and gene for more information about exendin-4.



Glucagon-like peptide-1 (GLP-1, 30 amino acids) is secreted from enteroendocrine cells of the distal small intestine in response to food ingestion (1). GLP-1 plays an important role in glucose metabolism and homeostasis. It inhibits gastric emptying, glucagon secretion, and glucose production (2). In addition, it induces insulin release from the pancreatic β-cells as well as their proliferation. The GLP-1 receptor has been identified in normal tissues such as the pancreas, stomach, brain, and lung, and it has been shown to be highly overexpressed in human insulinomas and gastrinomas (3). In insulinomas, GLP-1 receptor density is considerably greater, and the GLP-1 receptor is more frequently observed than somatostatin receptors.

Exendin-4 is a GLP-1 analog with 39 amino acids isolated from the venom of the Gila monster (Heloderma suspectum) (4). Exendin-4 and GLP-1 share a 53% amino acid sequence homology. Exendin-4 is a more potent and longer-lasting GLP-1 receptor agonist than GLP-1. Exendin-4 is resistant to cleavage by dipeptidyl peptidase IV, whereas the first two N-terminal amino acids of GLP-1 are rapidly cleaved. Exenatide, a synthetic version of exendin-4, is the first GLP-1 mimetic recently approved by the United States Food and Drug Administration (FDA) for use in select patients with type 2 diabetes (5). 68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-aminohexanoic acid-Lys40-exendin-4 ([Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4) is being developed for positron emission tomography (PET) imaging of the GLP-1 receptor (6).

Related Resource Links:

  • Chapters in MICAD (GLP-1)
  • Gene information in NCBI (GLP-1R)
  • Articles in Online Mendelian Inheritance in Man (OMIM) (GLP-1R)
  • Clinical trials (Exendin)
  • Drug information in FDA (Exendin)



The structure and composition of [Lys40(Ahx-DOTA)NH2]-exendin-4 was verified with high-performance liquid chromatography and matrix-assisted laser desorption-ionization mass spectrometry (6). A mixture of 68GaCl3 and [Lys40(Ahx-DOTA)NH2]-exendin-4 was incubated in HEPES buffer (pH, 3.6) for 5 min at 95°C with a >98% labeling yield of [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 and a specific activity of 13 GBq/µmol (0.35 Ci/µmol). The stability of [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 in solution was not reported.

In Vitro Studies: Testing in Cells and Tissues


Wild et al. (6) reported that [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 was specifically accumulated into β-cell tumors in culture with 2.48 ± 0.29% of incubation dose at 1 h and 10.35 ± 0.43% at 4 h. Most of the accumulated radioactivity was internalized into the cells (>80%).

Animal Studies



Wild et al. (6) performed ex vivo biodistribution studies with the use of Rip1Tag2 mice (n = 6/group) with spontaneous insulinoma β-cell tumors. The organ with the highest uptake was the tumor (205 ± 59% injected dose/g (% ID/g)), followed by the kidneys (202 ± 34% ID/g), lungs (43 ± 5% ID/g), pancreas (14 ± 1% ID/g), spleen (2.3 ± 0.6% ID/g), stomach (2.1 ± 0.8% ID/g), and liver (0.6 ± 0.1% ID/g) at 4 h after injection of [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 (10 pmol/mouse). Excess unlabeled [Lys40(Ahx-DOTA)NH2]-exendin-4 (5 nmol) blocked accumulation by >95% in the tumor and GLP-1R-expressing organs, such as the pancreas and lung, but there was little inhibition in the kidneys. Blood clearance was fast, with 0.3% ID/g remaining in the blood 4 h after injection. In contrast, the tumor washout rate was slow. The tumor/blood ratio was 89 at 0.5 h and 706 at 4 h. The tumor/muscle, tumor/pancreas, and tumor/kidney ratios were 205, 15, and 1 at 4 h, respectively.

PET imaging in one Rip1Tag2 mouse identified high uptake in the kidneys at 1 h after injection of 0.13 MBq (0.0035 mCi) [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4. After bilateral nephrectomy, PET imaging clearly identified two tumors (1.5 mm and 2.3 mm) in the pancreas. No blocking studies were reported.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


Theodorakis M.J., Carlson O., Michopoulos S., Doyle M.E., Juhaszova M., Petraki K., Egan J.M. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 2006;290(3):E550–9. [PubMed: 16219666]
Doyle M.E., Egan J.M. Glucagon-like peptide-1. Recent Prog Horm Res. 2001;56:377–99. [PubMed: 11237222]
Reubi J.C., Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. 2003;30(5):781–93. [PubMed: 12707737]
Meier J.J., Nauck M.A. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev. 2005;21(2):91–117. [PubMed: 15759282]
Nielsen L.L., Young A.A., Parkes D.G. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117(2):77–88. [PubMed: 14700743]
Wild D., Wicki A., Mansi R., Behe M., Keil B., Bernhardt P., Christofori G., Ell P.J., Macke H.R. Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J Nucl Med. 2010;51(7):1059–67. [PubMed: 20595511]
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