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: Jens-Uwe Kunstler, Gesine Seidel, Ralf Bergmann, Ewa Gniazdowska, Martin Walther, Eik Schiller, Clemens Decristoforo, Holger Stephan, Roland Haubner, Jorg Steinbach, Hans-Jurgen Pietzsch
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 45 Issue 9 Pg. 3645-55 (Sep 2010) ISSN: 1768-3254 [Electronic] France
• PMID: 20570022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyanides
• Ligands
• Oligopeptides
• Organotechnetium Compounds
• Peptides, Cyclic
• Rhenium
• arginyl-glycyl-aspartic acid

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacokinetics, pharmacology)
• Biological Transport
• Cell Line, Tumor
• Cyanides (chemistry)
• Drug Stability
• Humans
• Hydrophobic and Hydrophilic Interactions
• Ligands
• Mice
• Oligopeptides (chemistry)
• Organotechnetium Compounds (chemistry, metabolism, pharmacokinetics, pharmacology)
• Peptides, Cyclic (chemistry)
• Rats
• Rhenium (chemistry)
• Xenograft Model Antitumor Assays