UNLABELLED: The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on β-cells in the islets of Langerhans and is therefore an attractive target for imaging of the β-cell mass. In the present study, (68)Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. METHODS: Dose escalation studies of (68)Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. RESULTS: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 μg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 μg/kg ranged from 49% to 97%, as estimated by compartment modeling. CONCLUSION: These results strongly support the notion that (68)Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of β-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native β-cells.
UNLABELLED: The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on β-cells in the islets of Langerhans and is therefore an attractive target for imaging of the β-cell mass. In the present study, (68)Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. METHODS: Dose escalation studies of (68)Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabeticrats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. RESULTS: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 μg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 μg/kg ranged from 49% to 97%, as estimated by compartment modeling. CONCLUSION: These results strongly support the notion that (68)Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of β-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native β-cells.
Authors: Ram Kumar Selvaraju; Thomas N Bulenga; Daniel Espes; Mark Lubberink; Jens Sörensen; Barbro Eriksson; Sergio Estrada; Irina Velikyan; Olof Eriksson Journal: Am J Nucl Med Mol Imaging Date: 2015-02-15
Authors: Irina Velikyan; Thomas N Bulenga; Ramkumar Selvaraju; Mark Lubberink; Daniel Espes; Ulrika Rosenström; Olof Eriksson Journal: Am J Nucl Med Mol Imaging Date: 2015-01-15
Authors: Lisa Bodei; Mark Kidd; Vikas Prasad; Richard P Baum; Ignat Drozdov; Irvin M Modlin Journal: Eur J Nucl Med Mol Imaging Date: 2014-12 Impact factor: 9.236
Authors: Amy C Kelly; Leah V Steyn; Jenna P Kitzmann; Miranda J Anderson; Kate R Mueller; Nathaniel J Hart; Ronald M Lynch; Klearchos K Papas; Sean W Limesand Journal: Xenotransplantation Date: 2014-05-07 Impact factor: 3.907