title: Novel glycated [99mTc(CO)3]-labeled bombesin analogues for improved targeting of gastrin-releasing peptide receptor-positive tumors.
abstract: Radiolabeled bombesin (BBS) analogues are promising pharmaceuticals for imaging of cancer cells expressing gastrin-releasing peptide receptors (GRPR). However, most of the radiolabeled BBS derivatives show a high accumulation of activity in the liver and a strong hepatobiliary excretion, both unfavorable for imaging and therapy of abdominal lesions. For this reason, we introduced hydrophilic carbohydrated linker moieties into our BBS analogues to reduce the abdominal accumulation and to improve the tumor-to-background ratios. A stabilized BBS(7-14) sequence bearing the (NalphaHis)Ac-chelator was modified with amino acid linkers containing a lysine or propargylglycine residue. The epsilon-amino group of a lysine was either coupled to shikimic acid or reacted with glucose to form the Amadori conjugate. Alternatively, a glucose was attached to the peptide via "click" chemistry with the propargylglycine side chain. The peptides were synthesized on Rink amide resin using solid-phase peptide synthesis and labeled with 99mTc using the tricarbonyl technique. Binding and degradation were tested in Vitro in GRPR-expressing PC-3 cells. Biodistribution and SPECT/CT imaging studies were performed in nude mice bearing PC-3 tumor xenografts. The new peptides showed a log D between -0.2 and -0.5 and kept the high affinity for GRPR with Kd values of <0.5 nM. In Vitro, they were rapidly internalized into the tumor cells and showed an increased cellular retention and stability (t(1/2 )>35 min). In ViVo, all new compounds exhibited higher tumor-to-background ratios compared to the nonglycated reference. Thus, the best results were obtained with the triazole coupled glucose with a 4-fold increased uptake and retention in tumor tissue (3.6 and 2.5%ID/g at 1.5 h and 5 h p.i, respectively) and a significantly reduced accumulation in the liver (0.6 vs 2.4%ID/g, 1.5 h p.i., respectively). Apart from higher tumor-to-liver ratios (17-fold, 1.5 h p.i.), both tumor-to-kidney and tumor-to-blood ratios could be significantly improved by a factor of 1.5 and 2.7, respectively (1.5 h p.i., P<0.05). The imaging studies proved the reduction of abdominal background, and tumor xenografts could clearly be visualized. In conclusion, the introduction of a carbohydrated linker substantially improved the biodistribution properties of BBS analogues labeled with the 99mTc-tricarbonyl core.
authors.affiliation: Paul Scherrer Institute, Centre for Radiopharmaceutical Science, CH-5232 Villigen PSI, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schweinsberg
authors.forename: Veronique
authors.initials: V
authors.lastname: Maes
authors.forename: Luc
authors.initials: L
authors.lastname: Brans
authors.forename: Peter
authors.initials: P
authors.lastname: Bläuenstein
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Tourwé
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Elisa
authors.initials: E
authors.lastname: García Garayoa
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D002417:Cattle; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003365:Costs and Cost Analysis; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D015609:Organotechnetium Compounds / Q000737:chemistry*; D011485:Protein Binding; D011874:Radiometry; D018004:Receptors, Bombesin / Q000032:analysis / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013194:Staining and Labeling; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D002614:Chelating Agents; D015609:Organotechnetium Compounds; D018004:Receptors, Bombesin; D001839:Bombesin