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Purpose: The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [Ga]Ga-DO3A-VS-Cys-Exendin-4 in non-diabetic and streptozotocin (STZ)-induced diabetic pigs treated with insulin was investigated. Methods: Non-diabetic ( n = 4) and STZ-induced diabetic pig s (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [Ga]Ga-DO3A-VS-Cys-Exendin-4 was assessed by administration of either tracer alone or by competition with 3-6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model. Results: [O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [Ga]Ga-DO3A-VS-Cys-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [Ga]Ga-DO3A-VS-Cys-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR). Conclusion: Pancreatic uptake of [Ga]Ga-DO3A-VS-Cys-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs. [ABSTRACT FROM AUTHOR]