Novel Procedures for Preparing 99mTc(III) Complexes with Tetradentate/Monodentate Coordination of Varying Lipophilicity and Adaptation to 188Re Analogues

• Published in: Bioconjugate chemistry 2004-07, Vol.15 (4), p.856-863
• Main Authors: Seifert, S, Künstler, J.-U, Schiller, E, Pietzsch, H.-J, Pawelke, B, Bergmann, R, Spies, H
• Format: Article
• Language: English
• Subjects: Animals; Chemistry; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Ligands; Lipids - chemistry; Male; Metals; Methods; Molecular Structure; Radioisotopes; Rats; Rats, Wistar; Rhenium - chemistry; Technetium Compounds - administration & dosage; Technetium Compounds - chemical synthesis; Technetium Compounds - chemistry; Technetium Compounds - pharmacokinetics; Tissue Distribution
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc0300798

Improved methods are presented for the preparation of 99mTc and 188Re mixed-ligand complexes with tetradentate and monodentate ligands of the general formula [MIII(Lm)(Ln)] (M = Tc, Re; Lm = NS3 or NS3COOH; Ln = isocyanide or phosphine). To avoid the undesired formation of reduced-hydrolyzed species of both metals, the preparation of complexes is performed in a two-step procedure. At first the Tc(III)− or Re(III)−EDTA complex is formed which reacts in a second step with the tripodal ligand 2,2‘,2‘ ‘-nitrilotris(ethanethiol) (NS3) or its carboxyl derivative NS3COOH (a) and the monodentate phosphine ligands (triphenylphosphine L 1 , dimethylphenylphosphine L 2 ) or isocyanides (tert-butyl isonitrile L 3 , methoxyisobutyl isonitrile L 4 , 4-isocyanomethylbenzoic acid-l-arginine L 5 , 4-isocyanomethylbenzoic acid-l-arginyl-l-arginine L 6 , 4-isocyanomethylbenzoic acid-neurotensin(8−13) L 7 ) to the so-called ‘4+1' complex. Copper(I) isocyanide complexes are used for preparing the ‘4+1' complexes. That facilitates storage stability and allows kit formulations, and, moreover, enables the formation of 188Re complexes in acidic solution. Only micromolar amounts of the monodentate ligand are needed, and that results in high specific activity labeling of interesting molecules. The lipophilicity of complexes can be controlled by introducing a carboxyl group into the tetradentate ligand and/or derivatization of the monodentate ligands. Furthermore, the carboxyl group enables the conjugation of biomolecules. As an example, the neurotensin derivative CN-NT(8−13) was prepared and labeled with 99mTc according to the ‘4+1' approach, and its behavior in vivo was studied.