A Gadolinium-Binding Cyclodecapeptide with a Large High-Field Relaxivity Involving Second-Sphere Water

A new cyclodecapeptide incorporating two prolylglycine sequences as beta-turn inducers and bearing four side chains with acidic carboxyl groups for cation complexation has been prepared. Structural analysis in water by H-1 NMR spectroscopy and CD shows that this template adopts a conformation suitable for the complexation of lanthanide ions Ln(3+), with its carboxyl groups oriented on the same face of the peptide scaffold. Luminescence titrations show that mononuclear Ln-PA complexes are formed with apparent stability constants of log beta(110) approximate to 6.5 (pH 7). The high-field water relaxivity values arising from the Gd-PA complex at 200-500 MHz have been interpreted with molecular parameters determined independently. The experimentally determined water relaxivities are undoubtedly 30% higher than the expected values for this complex with two inner-sphere (IS) water molecules and a medium-range rotational correlation time (tau(R)=386 ps (+/-10%)). This led us to propose the existence of a large second-sphere (2S) contribution to the relaxivity caused by the interaction of water molecules with the hydrophilic peptide ligand by hydrogen-bonding.