In Vivo Imaging of Transplanted Islets With 64Cu-DO3A-VS-Cys40-Exendin-4 by Targeting GLP-1 Receptor

Bioconjug Chem. 2011 Aug 17;22(8):1587-94. doi: 10.1021/bc200132t. Epub 2011 Jul 14.

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in pancreatic islets, especially on β-cells. Therefore, a properly labeled ligand that binds to GLP-1R could be used for in vivo pancreatic islet imaging. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), a more stable agonist of GLP-1 such as Exendin-4 is a preferred imaging agent. In this study, DO3A-VS-Cys(40)-Exendin-4 was prepared through the conjugation of DO3A-VS with Cys(40)-Exendin-4. The in vitro binding affinity of DO3A-VS-Cys(40)-Exendin-4 was evaluated in INS-1 cells, which overexpress GLP-1R. After (64)Cu labeling, biodistribution studies and microPET imaging of (64)Cu-DO3A-VS-Cys(40)-Exendin-4 were performed on both subcutaneous INS-1 tumors and islet transplantation models. The subcutaneous INS-1 tumor was clearly visualized with microPET imaging after the injection of (64)Cu-DO3A-VS-Cys(40)-Exendin-4. GLP-1R positive organs, such as pancreas and lung, showed high uptake. Tumor uptake was saturable, reduced dramatically by a 20-fold excess of unlabeled Exendin-4. In the intraportal islet transplantation models, (64)Cu-DO3A-VS-Cys(40)-Exendin-4 demonstrated almost two times higher uptake compared with normal mice. (64)Cu-DO3A-VS-Cys(40)-Exendin-4 demonstrated persistent and specific uptake in the mouse pancreas, the subcutaneous insulinoma mouse model, and the intraportal human islet transplantation mouse model. This novel PET probe may be suitable for in vivo pancreatic islets imaging in the human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Tracking / methods*
  • Copper Radioisotopes*
  • Diagnostic Imaging / methods*
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Heterocyclic Compounds, 1-Ring
  • Humans
  • Hypoglycemic Agents
  • Insulinoma / pathology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans Transplantation*
  • Mice
  • Peptides
  • Radiopharmaceuticals
  • Receptors, Glucagon / analysis*
  • Tissue Distribution
  • Venoms
  • Vinyl Compounds

Substances

  • 1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane
  • Copper Radioisotopes
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Heterocyclic Compounds, 1-Ring
  • Hypoglycemic Agents
  • Peptides
  • Radiopharmaceuticals
  • Receptors, Glucagon
  • Venoms
  • Vinyl Compounds
  • Exenatide