Development of ¹²³I labeled Exendin derivatives for the imaging of GLP-1 receptors on pancreatic β-cell with SPECT

Objectives Pancreatic β-cell mass (BCM) decreases in the pathogenic mechanism of type 2 diabetes mellitus (T2DM). Some novel drugs are expected to suppress the decrease of BCM. We focused on glucagon-like peptide-1 (GLP-1) receptors, which are selectively expressed on pancreatic β-cells. Moreover, GLP-1 performs antidiabetic actions. Thus, the noninvasive detection of pancreatic GLP-1 receptors is hoped not only for the elucidation of the pathogenesis and the early diagnosis of T2DM but also for developing ideal treatment for T2DM. Then, noting that Exendin-4 can bind to GLP-1 receptors and is more stable than GLP-1 in vivo, we designed and evaluated 3-[¹²³I]iodobenzoyl Exendin-4 ([¹²³I]IB-Ex4)) as imaging probe for the detection of pancreatic GLP-1 receptors with SPECT.

Methods The binding affinity of IB-Ex4 to the pancreatic islets from normal mice was evaluated in competition binding assays with ¹²⁵I-labeled Exendin(9-39). The biodistribution after injection of [¹²³I]IB-Ex4 was measured in normal mice. Using MIP-GFP mice, expressing GFP in pancreatic β-cells, the pancreas was harvested and cut in several pieces after injection of [¹²⁵I]IB-Ex4, signals of fluorescence and radioactivity from sections of pancreas were compared. Moreover, SPECT was performed after injection of [¹²³I]IB-Ex4 to normal mice.

Results IB-Ex4 has high affinity to the pancreatic islets. In biodistribution study, accumulation in pancreas was 43.7±2.3 ID%/g at 30min after injection and the ratio of accumulation in pancreas to that in nearby organs were over 6. The comparison of signals of pancreas from MIP-GFP mice indicates specific binding of IB-Ex4 to β-cells. Moreover, in SPECT images, pancreas was distinctly visualized.

Conclusions We demonstrated that newly synthesized [¹²³I]IB-Ex4 derivatives have a potential as imaging probe detecting pancreatic GLP-1 receptors. [¹²³I]IB-Ex4 will give the information for effective countermeasures for T2DM