Mixed-ligand complexes of Tc(III) serving as flexible tools for binding the metal to small biomolecules

The most frequently used technetium compounds suitable for coupling the metal to biologically active molecules are square-pyramidal complexes of the oxo ion [Tc=O]³⁺ based on tetradentate N₂S₂ ligands. 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. So there is a considerable interest in alternative chelate systems that offer lower polarity and enhanced in vivo stability. Such systems are based on oxo-free lower oxidation states. Here we offer a new type of Tc(III) chelate 1, formed by the tripodal 2,2‘,2“-nitrilotris(ethanethiol) and a monodentate isocyanide or tertiary phosphine.
The new compounds fulfil the requirements for a non-polar building block stable against ligand exchange reaction in vivo. Belonging to the family of "n+1" mixed-ligand technetium (and rhenium) species, such a "4+1" chelate offers the advantage of high versatility in conjugating biomolecules.
Another type of neutral Tc(III) complexes, [Tc(SCH₂CH₂-E-CH₂CH₂S)(PR₂S)] 2, can be obtained by association of a tridentate HS-E-SH ligand (E = N(CH₃), S) with a bidentate PR₂-SH chelator. This combination enables easy functionalization in order to fine-tune physico-chemical properties of the complexes as well as linking of the chelate unit to biomolecules.
^99mTc analogues can be prepared at no-carrier-added level in high radiochemical yields. The complexes are stable towards ligand exchange in challenge experiments with glutathione. Furthermore, there are no indications for re-oxidation of Tc(III) to Tc(V) species or pertechnetate. There is no tendency of these complexes to bind on plasma components. The substituents at the bidentate P,S chelator significantly influence the biodistribution pattern in rats. Therefore, we propose this new type of Tc(III) complexes as a useful tool in designing of tunable ^99mTc radiopharmaceuticals.