Development and Evaluation of 18F-TTCO-Cys40-Exendin-4: A PET Probe for Imaging Transplanted Islets

J Nucl Med. 2013 Feb;54(2):244-51. doi: 10.2967/jnumed.112.109694. Epub 2013 Jan 7.

Abstract

Because islet transplantation has become a promising treatment option for patients with type 1 diabetes, a noninvasive imaging method is greatly needed to monitor these islets over time. Here, we developed an (18)F-labeled exendin-4 in high specific activity for islet imaging by targeting the glucagonlike peptide-1 receptor (GLP-1R).

Methods: Tetrazine ligation was used to radiolabel exendin-4 with (18)F. The receptor binding of (19/18)F-tetrazine trans-cyclooctene (TTCO)-Cys(40)-exendin-4 was evaluated in vitro with INS-1 cell and in vivo on INS-1 tumor (GLP-1R positive) and islet transplantation models.

Results: (18)F-TTCO-Cys(40)-exendin-4 was obtained in high specific activity and could specifically bind to GLP-1R in vitro and in vivo. Unlike the radiometal-labeled exendin-4, (18)F-TTCO-Cys(40)-exendin-4 has much lower kidney uptake. (18)F-TTCO-Cys(40)-exendin-4 demonstrated its great potential for transplanted islet imaging: the liver uptake value derived from small-animal PET images correlated well with the transplanted β-cell mass determined by immunostaining. Autoradiography showed that the localizations of radioactive signal indeed corresponded to the distribution of islet grafts in the liver of islet-transplanted mice.

Conclusion: (18)F-TTCO-Cys(40)-exendin-4 demonstrated specific binding to GLP-1R. This PET probe provides a method to noninvasively image intraportally transplanted islets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cyclooctanes*
  • Diagnostic Imaging / methods*
  • Exenatide
  • Fluorine Radioisotopes*
  • Gene Expression Regulation
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulinoma / metabolism
  • Islets of Langerhans Transplantation / methods*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nuclear Medicine / methods*
  • Peptides*
  • Positron-Emission Tomography / methods*
  • Rats
  • Receptors, Glucagon / metabolism
  • Venoms*

Substances

  • Cyclooctanes
  • Fluorine Radioisotopes
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Exenatide