title: Pre-clinical evaluation of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 for imaging of insulinoma.
abstract: BACKGROUND
  Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma.
  
  
  METHODS
  [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5μg/kg (baseline) and 100μg/kg (block). In vivo imaging of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP).
  
  
  RESULTS
  GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p≤0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [(11)C]5-HTP.
  
  
  CONCLUSIONS
  [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.
authors.affiliation: Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden. Electronic address: ramkumar.selvaraju@pet.medchem.uu.se.
authors.forename: Ram Kumar
authors.initials: RK
authors.lastname: Selvaraju
authors.affiliation: Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden; Department of Radiology, Oncology and Radiation Sciences, Uppsala University, SE-751 85 Uppsala, Sweden; PET Centre, Centre for Medical Imaging, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Velikyan
authors.affiliation: Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden.
authors.forename: Veronika
authors.initials: V
authors.lastname: Asplund
authors.affiliation: Department of Radiology, Oncology and Radiation Sciences, Uppsala University, SE-751 85 Uppsala, Sweden; AstraZeneca R&D, SE-431 83 Mölndal, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.affiliation: Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Zhanhong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.affiliation: Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Shively
authors.affiliation: Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.affiliation: Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Eriksson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.affiliation: Preclinical PET Platform (PPP), Department of Medicinal Chemistry, Uppsala University, SE-751 83 Uppsala, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D000077270:Exenatide; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007340:Insulinoma / Q000473:pathology*; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods*; D014688:Venoms / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D014753:Vinyl Compounds / Q000737:chemistry*
chemical_list: C527697:1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; D014688:Venoms; D014753:Vinyl Compounds; D000077270:Exenatide
keywords: Glucagon like peptide-1 receptor (GLP-1R); Insulinoma; Positron emission tomography (PET); [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4