Novel technetium(III) mixed-ligand chelates for the design of lipophilic complexes stable in vivo

The most frequently used technetium compounds suitable for coupling the metal to biologically active molecules are square-pyramidal oxo complexes based on tetradentate N₂S₂ ligands (1). Properties and thus the in vivo behaviour of such complexes are strongly influenced by the presence of the quite polar [Tc=O]³⁺ unit. Whether such a polarity is beneficial or not is not obvious and depends on the requirements for specific radiotracers, e.g. for receptor-targeting agents or for metabolic tracers. Another crucial point in tracer design is the stability of the respective Tc chelate towards ligand exchange in vivo. Recently it was shown that the applicability of the "3+1" mixed-ligand Tc(V) chelates is limited because of their reaction with glutathione in vivo (2,3). So there is a considerable interest in alter-native chelate systems that combine lower polarity with enhanced in vivo stability. Such systems are based on oxo-free Tc cores at lower oxidation state.
Here we describe novel types of Tc(III) mixed-ligand complexes. Both chelate systems fulfil the requirements for a lipophilic, non-polar building block stable against ligand exchange reaction in vivo. They offer the advantage of high versatility in conjugating biomolecules as described for the "3+1"-series (4).