Pre-clinical evaluation of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 for imaging of insulinoma

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, [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma. Methods: [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-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: 2.5 μg/kg (baseline) and 100 μg/kg (block). In vivo imaging of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [¹¹C]5-hydroxy-tryptophan ([¹¹C]5-HTP). Results: GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-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 [¹¹C]5-HTP. Conclusion: [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo