A computer-aided radiopharmaceutical drug design study using ab initio and molecular mechanics methods

This is an investigation of technetium ligands and their complexes with [TcO](3+) using ab initio population analysis and molecular mechanics conformational searching methods. Calculated atomic electronic populations on the technetium atom in complexes with a number of ligands gauge the degree of covalent bonding between technetium and these ligands. Here a reduction in the positive charge on the [TcO](3+) moiety by complexation with a given ligand is correlated with covalent bonding. Our ab initio results suggest that ligands with more sulphur atoms have better covalent bonding to technetium than do other ligands. A conformational analysis of the uncomplexed ligands indicates that conformational reorganization before complexation correlates inversely with stable complex formation. This conformational analysis shows that ligands with ethylene carbonyl bridges have low energy conformations closer to the final complexation geometries than do ligands with ethylene, propylene or propylene carbonyl bridges. The presence of these low energy conformations facilitates a faster complexation of the ethylene carbonyl [TcO](3+) moiety. This result produces a kinetic explaination why ethylene carbonyl bridged ligands form stable complexes while many other ligands do not [1]. The conclusion is that kinetic and thermodynamic considerations play a role in stable complex formation between these ligands and technetium.