In vivo imaging of transplanted islets with ⁶⁴Cu-DO3A-VS-Cys⁴⁰-Exendin-4 by targeting GLP-1 receptor

Objectives Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in islets, especially on pancreatic beta-cells. Therefore, a properly labeled ligand that binds to GLP-1R could be used for in vivo pancreatic islets imaging. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), a more stable agonist of GLP-1R such as Exendin-4 is preferred. In this study, we developed ⁶⁴Cu-labeled Exendin-4 as a novel PET imaging probe, and tested its targeting ability and binding specificity in vitro and in vivo.

Methods DO3A-VS-Cys40-Exendin-4 was prepared through the conjugation of DO3A-VS with Cys40-Exendin-4. The in vitro binding affinity of DO3A-VS-Cys⁴⁰-Exendin-4 was evaluated in INS-1 cells, which over-express GLP-1R. ⁶⁴Cu-DO3A-VS-Cys⁴⁰-Exendin-4 was obtained with > 95% labeling yield (n=5). The biodistribution studies were performed on subcutaneous INS-1 tumors models with/without excess Exendin4 and microPET imaging was performed on intraportal islet transplantation models.

Results The cell binding assay result demonstrated that the DOTA conjugation had minimal effect on the binding affinity to GLP-1R in vitro. The biodistribution studies showed that the subcutaneous INS-1 tumor had relatively high uptake after the injection of ⁶⁴Cu-DO3A-VS-Cys⁴⁰-Exendin-4. The GLP-1R positive organs such as pancreas and lung also showed high uptake. Tumor uptake was reduced to 19 % by 20-fold excess of unlabeled Exendin-4. The tracer also demonstrated almost two times higher uptake in the human islet portal vein transplantation model compared with normal mice.

Conclusions ⁶⁴Cu-DO3A-VS-Cys⁴⁰-Exendin-4 has demonstrated persistent and specific uptake in the subcutaneous insulinoma mouse model and the intraportal human islet transplantation mouse model by targeting GLP-1R. This novel PET probe holds great potential for in vivo transplanted pancreatic islets imaging in the human.

Research Support This work was supported by a grant from the Juvenile Diabetes Research Foundation International