Background

[PubMed]

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). It 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 US Food and Drug Administration (FDA) for use in select patients with type 2 diabetes (5). ¹¹¹In-Diethylenetriaminepentaacetic acid-aminohexanoic acid-Lys⁴⁰-exendin-4 (¹¹¹In-DTPA-Ahx-Lys⁴⁰-exendin-4) is being developed for single-photon emission computed tomography (SPECT) imaging of the GLP-1 receptor (6).

Synthesis

[PubMed]

A mixture of 100 MBq (2.7 mCi) ¹¹¹InCl₃ and diethylenetriaminepentaacetic acid-aminohexanoic acid-Lys⁴⁰-exendin-4 (20 nmol) was incubated in sodium acetate buffer (pH 5.0) for 30 min at room temperature (6). ¹¹¹In-DTPA-Ahx-Lys⁴⁰-exendin-4 was identified with high-performance liquid chromatography and matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS) to have a radiochemical purity of >90%. The specific activity was 90 GBq/µmol (2.5 Ci/µmol). The labeling yield was >99%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Wild et al. (7) reported that ¹¹¹In-DTPA-Ahx-Lys⁴⁰-exendin-4 was 82% and 74% intact after 4.5 and 24 h of incubation in human serum at 37°C, respectively. DTPA-Ahx-Lys⁴⁰-exendin-4 exhibited an inhibition constant (IC₅₀) value of 2.1 ± 1.1 nM compared with 0.65 ± 0.1 nM for exendin-4 and 2.4 ± 0.1 nM for GLP-1 using ¹²⁵I-labeled GLP-1 as a radioligand on mouse insulinoma β-cell tumors. ¹¹¹In-DTPA-Ahx-Lys⁴⁰-exendin-4 was specifically accumulated into β-cell tumors in culture with 2.4% of administered dose at 1 h and 9.8% at 4 h. Most of the accumulated radioactivity was internalized into the cells (85–97%).

Animal Studies

Human Studies

[PubMed]

Christ et al. (8) performed whole-body SPECT scans in six patients with proven endogenous hyperinsulinemic hypoglycemia after injection of 90 MBq (2.4 mCi, 30 µg) of ¹¹¹In-DTPA-Ahx-Lys⁴⁰-exendin-4. The detection rate of insulinomas was 100% allowing successful surgical removal of the tumors in all patients.

References

1.

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]

2.

Doyle M.E., Egan J.M. Glucagon-like peptide-1. Recent Prog Horm Res. 2001;56:377–99. [PubMed: 11237222]

3.

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]

4.

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]

5.

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]

6.

Gotthardt M., Lalyko G., van Eerd-Vismale J., Keil B., Schurrat T., Hower M., Laverman P., Behr T.M., Boerman O.C., Goke B., Behe M. A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents. Regul Pept. 2006;137(3):162–7. [PubMed: 16930741]

7.

Wild D., Behe M., Wicki A., Storch D., Waser B., Gotthardt M., Keil B., Christofori G., Reubi J.C., Macke H.R. [Lys40(Ahx-DTPA-111In)NH2]Exendin-4, a Very Promising Ligand for Glucagon-like Peptide-1 (GLP-1) Receptor Targeting. J Nucl Med. 2006;47(12):2025–2033. [PubMed: 17138746]

8.

Christ E., Wild D., Forrer F., Brandle M., Sahli R., Clerici T., Gloor B., Martius F., Maecke H., Reubi J.C. Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab. 2009;94(11):4398–405. [PubMed: 19820010]