exenatide and Cell-Transformation--Neoplastic

Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad-spectrum and high-absorbance near-infrared optoacoustic contrast agent, E4

Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Infrared Rays; Insulinoma; Mice; Photoacoustic Techniques; Tissue Distribution

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.

Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Exenatide; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Humans; Insulinoma; Mice; Peptides; Positron-Emission Tomography; Radiochemistry; Rats; Tissue Distribution; Tomography, X-Ray Computed; Venoms; Vinyl Compounds

Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging.. We prepared (18)F radioligands for GLP-1R by the reaction of [(18)F]FBEM, a maleimide prosthetic group, with [Cys(0)] and [Cys(40)] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice.. The [(18)F]FBEM-[Cys(x)]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [(18)F]FBEM), and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [(18)F]FBEM-[Cys(40)]-exendin-4, had higher affinity for INS-1 tumor cells (IC(50) 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [(18)F]FBEM-[Cys(0)]-exendin-4 (IC(50) 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys(x)]-exendin-4 (p < 0.05).. [(18)F]FBEM-[Cys(40)]-exendin-4 and [(18)F]FBEM-[Cys(0)]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [(18)F]FBEM-[Cys(40)]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Stability; Exenatide; Female; Fluorine Radioisotopes; Glucagon-Like Peptide 1; Humans; Insulinoma; Mice; Molecular Sequence Data; Peptides; Positron-Emission Tomography; Rats; Venoms