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

Improved methods are presented for the preparation of ^99mTc and ¹⁸⁸Re mixed-ligand complexes with tetradentate and monodentate ligands of the general formula [M^III(L₁)(L₂)] (M = Tc, Re; L₁ = NS₃ or NS₃-COOH; L₂ = isocyanide or phosphine). To avoid the unrequested 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 NS₃ ligand and the monodentate isocyanide or phosphine ligand 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. Moreover, using that stabilized form of isocyanides 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.