title: Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging.
abstract: OBJECTIVE
  Copper-64 (Cu-64) and Galium-68 (Ga-68) radiolabeled DO3A and NODA conjugates of exendin-4 were used for preclinical imaging of pancreatic β cells via targeting of glucagon-like peptide-1 receptor (GLP-1R).
  
  
  METHODS
  DO3A-VS- and NODA-VS-tagged Cys(40)exendin-4 (DO3A-VS-Cys(40)-exendin-4 and NODA-VS-Cys(40)-exendin-4, respectively) were labeled with Cu-64 and Ga-68 using standard techniques. Biodistribution and dynamic positron emission tomography (PET) were carried out in normal Sprague-Dawley (SD) rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections.
  
  
  RESULTS
  DO3A-VS- and NODA-VS-Cys(40)-exendin-4 analogues were labeled with Cu-64 and Ga-68 to a specific activity of 518.7 ± 3.7 Ci/mmol (19.19 ± 0.14 TBq/mmol) and radiochemical yield above 98 %. Biodistribution data demonstrated pancreatic uptake of 0.11 ± 0.02 %ID/g for [(64)Cu]DO3A-VS-, 0.14 ± 0.02 %ID/g for [(64)Cu]NODA-VS-, 0.11 ± 0.03 for [(68)Ga]DO3A-VS-, and 0.26 ± 0.03 for [(68)Ga]NODA-VS-Cys(40)-exendin-4. Excess exendin-4 and exendin-(9-39)-amide displaced all four Cu-64 and Ga-68 labeled exendin-4 derivatives in blocking studies.
  
  
  CONCLUSIONS
  [(64)Cu]/[(68)Ga]DO3A-VS-Cys(40)- and [(64)Cu]/[(68)Ga]NODA-VS-Cys(40)-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Nilantha
authors.initials: N
authors.lastname: Bandara
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Zheleznyak
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
authors.forename: Kaavya
authors.initials: K
authors.lastname: Cherukuri
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.affiliation: Clinical and Translational Imaging, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Jianqing
authors.affiliation: Clinical and Translational Imaging, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
authors.forename: Rikki
authors.initials: R
authors.lastname: Waterhouse
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. lapis@mir.wustl.edu.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
mesh_terms: D000818:Animals; D001345:Autoradiography; D003301:Copper Radioisotopes / Q000378:metabolism*; D000077270:Exenatide; D005710:Gallium Radioisotopes / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D050417:Insulin-Secreting Cells / Q000000981:diagnostic imaging*; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012815:Signal Processing, Computer-Assisted; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D014688:Venoms / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C527697:1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane; D003301:Copper Radioisotopes; D005710:Gallium Radioisotopes; D000067757:Glucagon-Like Peptide-1 Receptor; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; D019275:Radiopharmaceuticals; D014688:Venoms; D014753:Vinyl Compounds; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Cu-64; Exendin-4; GLP-1; GLP-1R; Ga-68; PET; Pancreatic β cells; β cell mass