title: In vivo imaging of GLP-1R with a targeted bimodal PET/fluorescence imaging agent.
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.
authors.affiliation: Radiochemistry and Imaging Sciences Service and §Molecular Imaging and Therapy Service, Department of Radiology, ∥Molecular Pharmacology and Chemistry Program, and ⊥Center for Molecular Imaging and Nanotechnology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Brand
authors.forename: Dalya
authors.initials: D
authors.lastname: Abdel-Atti
authors.forename: Yachao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sean
authors.initials: S
authors.lastname: Carlin
authors.forename: Susan M
authors.initials: SM
authors.lastname: Clardy
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Keliher
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiner
mesh_terms: D007516:Adenoma, Islet Cell / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D058948:Cell Tracking / Q000379:methods; D002478:Cells, Cultured; D003301:Copper Radioisotopes; D000077270:Exenatide; D005260:Female; D005455:Fluorescent Antibody Technique; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D064847:Multimodal Imaging / Q000379:methods*; D061848:Optical Imaging / Q000379:methods*; D010179:Pancreas / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon / Q000032:analysis / Q000378:metabolism*; D014688:Venoms / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D003301:Copper Radioisotopes; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide