Xiankai Sun

Pancreatic β-Cell Imaging with High Affinity Peptide Ligands to the GLP-1 Receptor

In both type 1 and type 2 diabetes, early diagnosis and monitoring of the pancreatic beta-cell mass (BCM) change during the disease progression may be highly beneficial. As a specific beta-cell biomarker, glucagon-like peptide-1 receptor (GLP-1R) is found to be highly expressed in the pancreatic beta-cells and can serve as a suitable target for the development of molecular imaging probes [1]. Its natural ligand, glucagon-like peptide-1 (GLP-1), is an incretin and interacts with GLP1R with nanomolar affinity, which makes it an outstanding candidate. There are several GLP-1 based PET imaging probes reported, but high renal uptake of these PET agents has been a concern for developing them for clinical use. As the beta-cells are dispersed throughout the pancreas and constitute less than 2% of the total mass, non-specific uptake by nearby tissues and organs like kidney and liver may decrease contrast of the signal dramatically. In our prior studies, we have demonstrated that strategically positioned lactam bridges at the Nand C-terminus of GLP-1 can increase receptor affinity by stabilizing the helical structures in the peptide and enhance proteolytic stability. Based on the findings, we designed a bicyclic GLP-1 analog EM2198 having two lactam bridges between residues 18-22 and 30-34 [2,3]. D-Ala was also introduced to prevent the degradation by DPP-IV. The resulting bicyclic GLP-1 analog EM2198 was found to be remarkably stable, and a PET imaging agent for the pancreatic uf062-cells was developed by conjugating to DOTA and labeling with Cu [4].