title: Novel 99mTc '4 + 1' peptide conjugates: tuning the biodistribution by variation of coligands.
abstract: A sophisticated coligand strategy is presented for peptide-derived radioconjugates based on (99m)Tc '4 + 1' mixed-ligand complexes. The new pharmacologically active coligands are assessed for (99m)Tc-labeling of the RGD-peptide cyclo(Arg-Gly-Asp-D-Tyr-Lys) which is an established vehicle to target alpha(v)beta(3) integrins playing a crucial part in tumor pathogenesis. Complexes of the general formula [(99m)Tc(NS(3)R)X] were synthesized and evaluated, in which Tc(III) is coordinated by NS(3)R, a derivative of the tetradentate chelator 2,2',2''-nitrilotriethanethiol (NS(3)), and by X, a monodentate binding isocyanide bearing the biomolecule. The novel tetradentate chelators (NS(3)R = NS(3)crown, NS(3)en, NS(3)(COOH)(3)) constitute NS(3) with a crown ether, an amine or a tricarboxylic acid as pharmacological modifiers. The isocyanides (X = L2-RGD, L2-Lys) contained the linker isocyanobutanoic acid (L2) coupled to N(6)-Lys of the RGD-peptide and additionally to a single Lys. The lipophilicity (distribution coefficient log D(O)(/W), pH = 7.4) of the RGD-containing radiotracers decreased in the order of the coligands NS(3)crown (-1.7 +/- 0.1), NS(3)en (-2.7 +/- 0.1) and NS(3)(COOH)(3) (-3.3 +/- 0.1). In the same order of the coligands, the biodistribution of the series [(99m)Tc(NS(3)R)(L2-RGD)] in normal rats showed a decrease of hepatobiliary and an increase of urinary excretion. The ratio of specifically to unspecifically uptaken activity (sum of surface bound and internalized activity) in alpha(v)beta(3) integrin-expressing M21 cells was in the range of approximately 4-5 and comparable for all [(99m)Tc(NS(3)R)(L2-RGD)] tracers. The biodistribution of [(99m)Tc(NS(3)en)(L2-RGD)] in nu/nu mice bearing M21 and M21L (control) tumor xenografts exhibited a specific tumor uptake with a low target-background ratio. The metabolic stability of the [(99m)Tc(NS(3)R)(L2-RGD)] tracers in normal rats was high, since 75-87% of the radioactivity in the plasma extract was assigned to the injected radiotracers 60 min after intravenous application in a rat. The hypothetical metabolites [(99m)Tc(NS(3)R)(L2-Lys)] were not found. These results demonstrate a considerable improvement of in vivo properties of (99m)Tc '4 + 1' peptide conjugates and open up the possibility of applying the labeling approach for further radiodiagnostic peptides.
authors.affiliation: Biotectid GmbH, 04103 Leipzig, Germany.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Kunstler
authors.forename: Gesine
authors.initials: G
authors.lastname: Seidel
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Ewa
authors.initials: E
authors.lastname: Gniazdowska
authors.forename: Martin
authors.initials: M
authors.lastname: Walther
authors.forename: Eik
authors.initials: E
authors.lastname: Schiller
authors.forename: Clemens
authors.initials: C
authors.lastname: Decristoforo
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.forename: Roland
authors.initials: R
authors.lastname: Haubner
authors.forename: Jorg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Hans-Jurgen
authors.initials: HJ
authors.lastname: Pietzsch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D003486:Cyanides / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry*; D051381:Rats; D012211:Rhenium / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003486:Cyanides; D008024:Ligands; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D012211:Rhenium; C047981:arginyl-glycyl-aspartic acid