Abstract
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Objectives The Glucagon-Like Peptide-1 (GLP-1) is a 30 amino acid hormone produced in L-cells in the intestines. GLP-1 has been identified as an important mediator to induce the release of insulin in a glucose-dependent manner. Exenatide is a FDA approved synthetic drug of exendin-4, a known agonist for the GLP-1 receptor. In this study, 64Cu and 68Ga radiolabeled DOTA and NOTA analogues of Exenatide were used for preclinical imaging of pancreatic β-cells via targeting of GLP-1R.
Methods DOTA and NOTA-Exenatide compounds were labeled with 64Cu and 68Ga using standard techniques. In vitro stability studies were conducted in rat serum at 37oC. Biodistribution studies and PET scans were carried out using normal Sprague-Dawley rats and organs of interest were harvested and counted after each time points. In vivo blocking studies were conducted by co-injecting unlabeled Exenatide (agonist) and Exendin-(9-39)-amide (antagonist) to SD rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections from both blocked and unblocked animals.
Results Serum studies indicated that all compounds were highly stable. Biodistribution data indicated a similar uptake in pancreatic islets within the range of 0.1-0.3 %ID/g with 68Ga-NOTA-Exenatide having the highest uptake (0.26 ± 0.03 % ID/g). Both Exenatide and Exendin-(9-39)-amide successfully displaced the radiolabeled DOTA/NOTA-Exenatide with 48 to 88% decrease of the pancreatic uptake compared to the unblocked control.
Conclusions DOTA/NOTA-Exenatide analogues can be used as a PET imaging agent specific for GLP-1R which is expressed on β-cells. Out of the four radiopharmaceuticals compared, 68Ga-NOTA-Exenatide resulted in the best accumulation and specific binding to the GLP-1R.
Research Support This work was supported by US Department of Energy Integrated Research Training Program of Excellence in Radiochemistry (DE-SC00002032).