1. In vivo imaging of GLP-1R with a targeted bimodal PET/fluorescence imaging agent.
- Author
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Brand C, Abdel-Atti D, Zhang Y, Carlin S, Clardy SM, Keliher EJ, Weber WA, Lewis JS, and Reiner T
- Subjects
- Adenoma, Islet Cell diagnostic imaging, Adenoma, Islet Cell drug therapy, Amino Acid Sequence, Animals, Cell Tracking methods, Cells, Cultured, Exenatide, Female, Fluorescent Antibody Technique, Glucagon-Like Peptide-1 Receptor, Humans, Hypoglycemic Agents administration & dosage, Mice, Mice, Nude, Molecular Sequence Data, Pancreas diagnostic imaging, Pancreas drug effects, Peptides administration & dosage, Receptors, Glucagon analysis, Venoms administration & dosage, Xenograft Model Antitumor Assays, Adenoma, Islet Cell metabolism, Copper Radioisotopes, Multimodal Imaging methods, Optical Imaging methods, Pancreas metabolism, Positron-Emission Tomography methods, Radiopharmaceuticals, Receptors, Glucagon metabolism
- Abstract
Accurate visualization and quantification of β-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including (64)Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent (64)Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 μCi/μg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (<2 mm) with PET and pancreatic β-cell mass by phosphor autoradiography. Using the fluorescent properties of the probe, we were able to detect individual pancreatic islets, confirming specific binding to GLP-1R and surpassing the sensitivity of the radioactive label. The use of bimodal PET/fluorescent imaging probes is promising for preoperative imaging and fluorescence-assisted analysis of patient tissues. We believe that our procedure could become relevant as a protocol for the development of bimodal imaging agents.
- Published
- 2014
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