title: 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma.
abstract: OBJECTIVE
  Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging.
  
  
  METHODS
  We prepared (18)F radioligands for GLP-1R by the reaction of [(18)F]FBEM, a maleimide prosthetic group, with [Cys(0)] and [Cys(40)] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice.
  
  
  RESULTS
  The [(18)F]FBEM-[Cys(x)]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [(18)F]FBEM), and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [(18)F]FBEM-[Cys(40)]-exendin-4, had higher affinity for INS-1 tumor cells (IC(50) 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [(18)F]FBEM-[Cys(0)]-exendin-4 (IC(50) 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys(x)]-exendin-4 (p < 0.05).
  
  
  CONCLUSIONS
  [(18)F]FBEM-[Cys(40)]-exendin-4 and [(18)F]FBEM-[Cys(0)]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [(18)F]FBEM-[Cys(40)]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Qimeng
authors.initials: Q
authors.lastname: Quan
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004355:Drug Stability; D000077270:Exenatide; D005260:Female; D005462:Fluorine Radioisotopes; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D007340:Insulinoma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D014688:Venoms / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D005462:Fluorine Radioisotopes; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide