Ram Kumar Selvaraju1, Irina Velikyan2, Veronika Asplund3, Lars Johansson4, Zhanhong Wu5, Ivan Todorov5, Jack Shively5, Fouad Kandeel5, Barbro Eriksson6, Olle Korsgren7, Olof Eriksson3. 1. Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden. Electronic address: ramkumar.selvaraju@pet.medchem.uu.se. 2. Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; Department of Radiology, Oncology and Radiation Sciences, Uppsala University, SE-751 85 Uppsala, Sweden; PET Centre, Centre for Medical Imaging, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. 3. Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden. 4. Department of Radiology, Oncology and Radiation Sciences, Uppsala University, SE-751 85 Uppsala, Sweden; AstraZeneca R&D, SE-431 83 Mölndal, Sweden. 5. Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. 6. Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. 7. Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
Abstract
INTRODUCTION: Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma. METHODS: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5μg/kg (baseline) and 100μg/kg (block). In vivo imaging of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). RESULTS: GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p≤0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [(11)C]5-HTP. CONCLUSION: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.
INTRODUCTION:Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma. METHODS: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficientmice at two different doses of peptide: 2.5μg/kg (baseline) and 100μg/kg (block). In vivo imaging of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). RESULTS:GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p≤0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [(11)C]5-HTP. CONCLUSION: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.
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: Tom J P Jansen; Sanne A M van Lith; Marti Boss; Maarten Brom; Lieke Joosten; Martin Béhé; Mijke Buitinga; Martin Gotthardt Journal: J Labelled Comp Radiopharm Date: 2019-08 Impact factor: 1.921