title: Species differences of bombesin analog interactions with GRP-R define the choice of animal models in the development of GRP-R-targeting drugs.
abstract: The biologic profiles of [(99m)Tc]Demobesin 1 ([(99m)Tc-N(4)(0-1),bzlg(0),d-Phe(6),Leu-NHEt(13),des-Met(14)]BB(6-14)) and [(111)In]Z-070 were compared using various gastrin-releasing peptide receptor GRP-R)-expressing tissues of human and animal origin.
  
  
  METHODS
  The binding affinities of Demobesin 1, Z-070, and its metallated analogs were determined by receptor autoradiography on human cancer biopsy and mouse pancreas samples and by binding assays in rat AR4-2J and human PC-3 cell membranes. Biodistribution of [(99m)Tc]Demobesin 1 and [(111)In]Z-070 was compared in nude mice bearing AR4-2J and PC-3 xenografts.
  
  
  RESULTS
  Demobesin 1, Z-070, and metallated Z-070 showed high affinity for the rat GRP-R in AR4-2J cell membranes (50% inhibitory concentration values = 0.17-0.45 nmol/L). In human PC-3 cell membranes, Demobesin 1 showed 11- to 15-fold higher affinity than the Z-070 peptides. These data were corroborated by results from human cancers and mouse pancreas. In AR4-2J and PC-3 tumor-bearing mice, [(99m)Tc]Demobesin 1 and [(111)In]Z-070 displayed similar uptake in the rat tumor. However, in the human PC-3 xenografts, [(99m)Tc]Demobesin 1 showed a 2- to 3-fold higher uptake than [(111)In]Z-070.
  
  
  CONCLUSIONS
  Considerable differences between rat or mouse and human GRP-R-expressing tissues were found for the in vitro and in vivo characteristics of 2 radiolabeled bombesin analogs. This finding may have a significant impact in the selection of experimental tools in the development of bombesin analogs for GRP-R-targeting applications in humans.
authors.affiliation: Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, 152 10 Ag. Paraskevi Arrikis, Athens, Greece. mainathe@rrp.demokritos.gr
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D018004:Receptors, Bombesin / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013045:Species Specificity; D013667:Technetium / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D013667:Technetium; D001839:Bombesin