title: Double-stabilized neurotensin analogues as potential radiopharmaceuticals for NTR-positive tumors.
abstract: BACKGROUND
  Overexpression of neurotensin (NT) receptors in exocrine pancreatic cancer and other neuroendocrine cancers make them interesting targets for tumor imaging and therapy. Modifications at the cleavage bonds 8-9 and 11-12 led to the synthesis of NT-XII, NT-XIII and NT-XVIII, three new stabilized analogues. (NalphaHis)Ac was coupled to the N-terminus for labeling with [(99m)Tc]-tricarbonyl.
  
  
  METHODS
  Stability was tested in vitro in human plasma and HT-29 cells. Binding to NT1 receptors and internalization/efflux were analyzed in intact HT-29 cells. Biodistribution studies were performed in nude mice bearing HT-29 xenografts.
  
  
  RESULTS
  All analogues were very stable in human plasma, with half-lives of 20-21 days. Degradation in HT-29 cells was more rapid (t(1/2) of 6.5, 5 and 2.5 h for NT-XII, NT-XIII and NT-XVIII, respectively). They also showed high affinity and specificity for NT1 receptors. Bound activity was rapidly internalized at 37 degrees C. The pattern of externalization was different. NT-XII was released more slowly than NT-XIII and NT-XVIII (half of the activity still inside the cells after 24 h). Bigger differences were found in the biodistribution studies. NT-XII showed the highest tumor uptake as well as the best tumor to nontumor ratios.
  
  
  CONCLUSIONS
  The modifications introduced in NT(8-13) increased plasma stability, maintaining unaffected the in vitro binding properties. The best biodistribution corresponded to NT-XII, which shows to be a good candidate for NT1 receptors overexpressing tumors. First clinical trials are ongoing.
authors.affiliation: Center for Radiopharmaceutical Science, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland. elisa.garcia@psi.ch
authors.forename: Elisa
authors.initials: E
authors.lastname: García-Garayoa
authors.forename: Veronique
authors.initials: V
authors.lastname: Maes
authors.forename: Peter
authors.initials: P
authors.lastname: Bläuenstein
authors.forename: Alain
authors.initials: A
authors.lastname: Blanc
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohn
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005240:Feasibility Studies; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009496:Neurotensin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018028:Receptors, Neurotensin / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; D007457:Iodine Radioisotopes; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals; D018028:Receptors, Neurotensin; D009496:Neurotensin