title: Glycation methods for bombesin analogs containing the (NalphaHis)Ac chelator for 99mTc(CO)3 radiolabeling.
abstract: The overexpression of peptide receptors in a variety of human carcinomas has generated considerable interest in peptide-based radiopharmaceuticals for peptide receptor imaging and peptide receptor radiotherapy. The gastrin-releasing peptide receptor is overexpressed in human prostate-, breast-, colon- and small cell lung carcinoma cells. We have developed metabolically stable (99m)Tc-radiolabeled bombesin ([Cha(13), Nle(14)]BBS(7-14)) analogs, which bind with high affinity to the gastrin-releasing peptide receptors. However, because of their lipophilicity, they showed unfavorable biodistribution with high hepatic accumulation and hepatobiliary excretion. We now report a study of different glycation methods for [Cha(13), Nle(14)]BBS(7-14) analogs to improve their biodistribution profile. Whereas the glycation using the Maillard reaction was problematic, resulting in low yields, selective introduction of the glycomimetic shikimic acid to the side chain of a Lys residue was possible. A chemoselective ligation of alpha-D-glucose to an amino-oxyacetylated [Cha(13), Nle(14)]BBS(7-14) analog could be achieved, but was complicated by the co-elution of starting peptide and glycopeptide. The best procedure consisted of the [1,3]-cycloaddition of N(3)-beta-D-glucose to a propargylglycine-containing [Cha(13), Nle(14)]BBS(7-14) analog, using a catalytic amount of Cu(I)I. All glycated [Cha(13), Nle(14)]BBS(7-14) analogs showed high affinity for the gastrin-releasing peptide receptor and rapid accumulation into PC-3 tumor cells.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Brans
authors.forename: Veronique
authors.initials: V
authors.lastname: Maes
authors.forename: Elisa
authors.initials: E
authors.lastname: García-Garayoa
authors.forename: Christian
authors.initials: C
authors.lastname: Schweinsberg
authors.forename: Simone
authors.initials: S
authors.lastname: Daepp
authors.forename: Peter
authors.initials: P
authors.lastname: Bläuenstein
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Tourwé
mesh_terms: D001839:Bombesin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D018004:Receptors, Bombesin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002614:Chelating Agents; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin