Mixed-ligand technetium(III) complexes with tetradendate/monodendate NS3/isocyanide coordination: a new nonpolar technetium chelate system for the design of neutral and lipophilic complexes stable in vivo

Starting from the tripodal ligand 2,2',2"-nitrilotris(ethanethiol) (NS3) an d isocyanides (CNR) as coligands, neutral mixed-ligand technetium(III) comp lexes of the general formulation [Tc(NS3)(CNR)] have been synthesized and c haracterized. The Tc-99 complexes can be obtained by a two-step reduction/ substitution procedure starting from [TcO4](-) via the phosphine-containing precursor complex [Tc(NS3)(PMe2Ph)]. As shown by X-ray structural analyses , the complexes adopt a nearly ideal trigonal-bipyramidal geometry with the trigonal plane formed by the three thiolate sulfurs of the tripodal ligand . The central nitrogen atom of the chelate ligand and the monodendate isocy anides occupy the apical positions. The no-carrier-added preparation of the corresponding Tc-99m complexes was performed by a one-step procedure start ing from (99m)[TcO4](-) With stannous chloride as reducing agent. Biodistri bution studies in the rat demonstrated for the nonpolar, lipophilic compoun ds a significant initial brain uptake. In vitro challenge experiments with glutathione clearly indicated that no transchelation reaction occurs. Furth ermore, there were no indications for reoxidation of Tc(III) to Tc(V) speci es or pertechnetate. We propose this type of complexes as a useful tool in the design of lipophilic Tc-99m or Re-186/Re-188 radiopharmaceuticals.