title: Glycated99mTc-Tricarbonyl-Labeled Peptide Conjugates for Tumor Targeting by "Click-to-Chelate".
abstract: Attaching polar pharmacological modifiers to molecular imaging probes is a common strategy to modulate their pharmacokinetic profiles to improve such parameters as the clearance rate of radiotracers and/or metabolites, and to enhance signal-to-background ratios. We combined the tumor-targeting peptide sequence of bombesin (BBN) with glucuronic acid and the single-photon emission computed tomography (SPECT) radionuclide99mTc by the "click-to-chelate" methodology. The99mTc-tricarbonyl-labeled glucuronated BBN conjugate was compared with a reference compound lacking the carbohydrate. The radiolabeled conjugates displayed similar characteristics in vitro (cell internalization, receptor affinity), but the hydrophilicity of the glycated version was significantly increased. While the tumor uptake of the two radioconjugates in xenografted mice was similar, the glycated peptide exhibited unexpected higher uptake in organs of the hepatobiliary excretion pathway than the more lipophilic reference compound. Control experiments suggest that this may be the result of unspecific accumulation of metabolites in which the glucuronic acid moiety does not act as an innocent pharmacological modifier.
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Karolin
authors.initials: K
authors.lastname: Römhild
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Fischer
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.|Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.|Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Mindt
mesh_terms: D000818:Animals; D001839:Bombesin / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured
chemical_list: D002614:Chelating Agents; D015335:Molecular Probes; D015609:Organotechnetium Compounds; D010455:Peptides; D001839:Bombesin
keywords: 99mTc-tricarbonyl; SPECT; glycopeptides; pharmacokinetics; radiopharmaceuticals