title: Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers.
abstract: The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, (125)I-Bolton-Hunter-Exendin(9-39)NH2 ((125)I-BH-Ex(9-39)NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas.
  
  
  
  The affinity and biodistribution of Ex(9-39)NH2-based antagonists, modified with DOTA or NODAGA chelators at positions Lys(27) and Lys(40) and labeled with (68)Ga and (125)I-BH-Ex(9-39)NH2, were compared with the reference GLP-1 receptor agonist [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]Ex-4. The inhibitory concentration of 50% (IC50) values were determined using autoradiography on human tissues with (125)I-GLP-1(7-36)NH2 as a radioligand. Pharmacokinetics and PET imaging were studied in nude mice bearing rat Ins-1E tumors.
  
  
  
  Conjugation of DOTA and NODAGA chelators at positions Lys(27) and Lys(40) of Ex(9-39)NH2 resulted in a distinct loss of affinity toward GLP-1 receptor in vitro. Among the studied antagonists, [Lys(40)(NODAGA-(nat)Ga)NH2]Ex(9-39) showed the lowest IC50 value (46.7 ± 16.3 nM). The reference agonist [Nle(14),Lys(40)(Ahx-DOTA)NH2]Ex-4 demonstrated the highest affinity (IC50 = 0.9 ± 0.3 nM). Biodistribution of [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]Ex-4 at 1 h after injection demonstrated 40.2 ± 8.2 percentage injected activity per gram (%IA/g) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys(40)(NODAGA-(68)Ga)NH2]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, (125)I-BH-Ex(9-39)NH2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of (125)I-BH-Ex(9-39)NH2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of (125)I-BH-Ex(9-39)NH2 was improved 20-fold.
  
  
  
  Our results suggest that iodinated Ex(9-39)NH2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumor-to-kidney ratio (125)I-BH-Ex(9-39)NH2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with (124)I-BH-Ex(9-39)NH2 are warranted.
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany; and svetlana.rylova@uniklinik-freiburg.de.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Rylova
authors.affiliation: Institute of Pathology, University of Berne, Berne, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany; and.
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Pozzo
authors.affiliation: Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Tönnesmann
authors.affiliation: Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Mansi
authors.affiliation: Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.affiliation: Institute of Pathology, University of Berne, Berne, Switzerland.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.affiliation: Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D004357:Drug Synergism; D005260:Female; D000067756:Glucagon-Like Peptide Receptors; D007553:Isotope Labeling / Q000379:methods*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009928:Organ Specificity; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals; D014018:Tissue Distribution
chemical_list: C000594972:125I-Bolton-Hunter-exendin(9-39); D000067756:Glucagon-Like Peptide Receptors; D010446:Peptide Fragments; D019275:Radiopharmaceuticals
keywords: GLP-1 receptor; antagonist; insulinoma; β-cell mass