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

• DOI: 10.1016/j.nucmedbio.2014.03.017
• Publication Date: 2014-03-29T16:03:58Z
• Authors: Ram Kumar Selvaraju; Irina Velikyan; Veronika Asplund; Lars Johansson; Zhanhong Wu; Ivan Todorov; Jack Shively; Fouad Kandeel; Barbro Eriksson; Olle Korsgren; Olof Eriksson
• Keywords: 0303 health sciences; Radiochemistry; Vinyl Compounds; Venoms; Gallium Radioisotopes; Rats; Heterocyclic Compounds, 1-Ring; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Positron-Emission Tomography; Animals; Exenatide; Humans; Insulinoma; Tissue Distribution; Peptides; Tomography, X-Ray Computed

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.[(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).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.[(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.