title: In vivo imaging of the glucagonlike peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4.
abstract: The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on β-cells in the islets of Langerhans and is therefore an attractive target for imaging of the β-cell mass. In the present study, (68)Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas.
  
  
  METHODS
  Dose escalation studies of (68)Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model.
  
  
  RESULTS
  In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 μg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 μg/kg ranged from 49% to 97%, as estimated by compartment modeling.
  
  
  CONCLUSIONS
  These results strongly support the notion that (68)Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of β-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native β-cells.
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Ram K
authors.initials: RK
authors.lastname: Selvaraju
authors.forename: Irina
authors.initials: I
authors.lastname: Velikyan
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.forename: Zhanhong
authors.initials: Z
authors.lastname: Wu
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Jack
authors.initials: J
authors.lastname: Shively
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.forename: Olof
authors.initials: O
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D000077270:Exenatide; D005710:Gallium Radioisotopes; D000067757:Glucagon-Like Peptide-1 Receptor; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D008252:Macaca fascicularis; D064847:Multimodal Imaging / Q000379:methods*; D010179:Pancreas / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011829:Radiation Dosage; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D014688:Venoms / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C520644:1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; D005710:Gallium Radioisotopes; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide
keywords: GLP-1R; β-cell imaging; β-cell mass