title: Bombesin antagonist-based radioligands for translational nuclear imaging of gastrin-releasing peptide receptor-positive tumors.
abstract: Bombesin receptors are overexpressed on a variety of human tumors. In particular, the gastrin-releasing peptide receptor (GRPr) has been identified on prostate and breast cancers and on gastrointestinal stromal tumors. The current study aims at developing clinically translatable bombesin antagonist-based radioligands for SPECT and PET of GRPr-positive tumors.
  
  
  METHODS
  A potent bombesin antagonist (PEG(4)-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) [AR]) was synthesized; conjugated to the chelators DOTA, 6-carboxy-1,4,7,11-tetraazaundecane (N4), 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A); and radiolabeled with (111)In, (99m)Tc, (68)Ga, and (64)Cu, respectively. The radioconjugates were evaluated in vitro and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was determined by Ca(2+)-flux measurements and immunofluorescence.
  
  
  RESULTS
  All the conjugates showed high binding affinity to GRPr (inhibitory concentration of 50% [IC(50)], 2.5-25 nmol/L). The immunofluorescence and Ca(2+)-flux assays confirmed the antagonist properties of the conjugates. Biodistribution revealed high and specific uptake in PC-3 tumor and in GRPr-positive tissues. Tumor uptake of (64)Cu-CB-TE2A-AR (31.02 ± 3.35 percentage injected activity per gram [%IA/g]) was higher than (99m)Tc-N4-AR (24.98 ± 5.22 %IA/g), (111)In-DOTA-AR (10.56 ± 0.70 %IA/g), and (68)Ga-NODAGA-AR (7.11 ± 3.26 %IA/g) at 1 h after injection. Biodistribution at later time points showed high tumor-to-background ratios because of the fast washout of the radioligand from normal organs, compared with tumor. High tumor-to-background ratios were further illustrated by PET and SPECT images of PC-3 tumor-bearing nude mice acquired at 12 h after injection showing high tumor uptake, clear background, and negligible or no radioactivity in the abdomen.
  
  
  CONCLUSIONS
  The chelators do influence the affinity, antagonistic potency, and pharmacokinetics of the conjugates. The promising preclinical results warrant clinical translation of these probes for SPECT and PET.
authors.affiliation: Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland.
authors.forename: Keelara
authors.initials: K
authors.lastname: Abiraj
authors.forename: Rosalba
authors.initials: R
authors.lastname: Mansi
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Tamma
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Fani
authors.forename: Flavio
authors.initials: F
authors.lastname: Forrer
authors.forename: Guillaume
authors.initials: G
authors.lastname: Nicolas
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000085:Acetates / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001839:Bombesin / Q000037:antagonists & inhibitors*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods*; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D064847:Multimodal Imaging; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism; D011854:Radiochemistry; D018004:Receptors, Bombesin / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D057170:Translational Research, Biomedical
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D009842:Oligopeptides; D018004:Receptors, Bombesin; D011092:Polyethylene Glycols; D001839:Bombesin; D002118:Calcium