title: (64)Cu labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression.
abstract: The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of BarMalSar-exendin-4 and Mal2Sar-(exendin-4)2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal2Sar-(exendin-4)2 demonstrated around 3 times higher binding affinity compared with BaMalSar-exendin-4. After (64)Cu labeling, microPET imaging of (64)Cu-BaMalSar-exendin-4 and (64)Cu-Mal2Sar-(exendin-4)2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of (64)Cu-Mal2Sar-(exendin-4)2 was significantly higher than that of (64)Cu-BaMaSarl-exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both (64)Cu-BaMalSar-exendin-4 and (64)Cu-Mal2Sar-(exendin-4)2 hold a great potential for GLP-1R targeted imaging.
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Zhanhong
authors: Z
authors: Wu
authors: 2. Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA.
authors: Shuanglong
authors: S
authors: Liu
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Indu
authors: I
authors: Nair
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Keiko
authors: K
authors: Omori
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Stephen
authors: S
authors: Scott
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Ivan
authors: I
authors: Todorov
authors: 3. Department of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: John E
authors: JE
authors: Shively
authors: 2. Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA.
authors: Peter S
authors: PS
authors: Conti
authors: 2. Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA.
authors: Zibo
authors: Z
authors: Li
authors: 1. Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors: Fouad
authors: F
authors: Kandeel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D004151:Dipeptides / Q000737:chemistry; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D049268:Positron-Emission Tomography; D051381:Rats; D018027:Receptors, Glucagon / Q000032:analysis / Q000378:metabolism*; D014688:Venoms / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D003301:Copper Radioisotopes; D004151:Dipeptides; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C016968:alanyltyrosine; D000077270:Exenatide
keywords: 64Cu; PET; Sarcophagine; exendin-4 dimer; insulinoma