title: Preclinical evaluation of a new bombesin analog for imaging of gastrin-releasing peptide receptors.
abstract: Bombesin (BBN) is a peptide showing high affinity for the gastrin-releasing peptide receptor. Tumors such as prostate, small cell lung cancer, breast, gastric, and colon cancer are known to over express receptors to BBN and gastrin-releasing peptide (GRP). The goal of this study was to evaluate a new (67)Ga radiolabeled BBN analog based on the bifunctional chelating ligand DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), which could be used as a tool for diagnosis of GRP receptor-positive tumors. DOTA-GABA-BBN (7-14) NH(2) was synthesized using a standard Fmoc strategy. Labeling with (67)Ga was performed at 95°C for 30 minutes in ammonium acetate buffer (pH = 4.8). Radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was examined in the presence of human serum at 37°C up to 24 hours. The receptor-bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >90% was obtained corresponding to a specific activity of approximatrly 2.6 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed a good and specific internalization into PC-3 cells (16.13% ± 0.71% at 4 hours). After 4 hours, a considerable amount of activity (52.42% ± 1.86%) was externalized. In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in GRP-receptor-positive organs. After 4 hours, the uptake in mouse tumor and pancreas was 1.30% ± 0.18% ID/g (percentage of injected dose per gram of tissue) and 1.21% ± 0.13% ID/g, respectively. These data show that [(67)Ga]-DOTA-GABA-BBN (7-14) NH₂ is a specific radioligand for GRP receptor positive tumors and is a suitable candidate for clinical studies.
authors.affiliation: Faculty of Nuclear engineering and Physics, Amirkabir University of Technology, Tehran, Iran.
authors.forename: Seyed Pezhman
authors.initials: SP
authors.lastname: Shirmardi
authors.forename: Mostafa
authors.initials: M
authors.lastname: Gandomkar
authors.forename: Mohammad Ghannadi
authors.initials: MG
authors.lastname: Maragheh
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Shamsaei
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D019886:Gastrin-Releasing Peptide / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D018004:Receptors, Bombesin / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; D018004:Receptors, Bombesin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005680:gamma-Aminobutyric Acid; D019886:Gastrin-Releasing Peptide; D001839:Bombesin