[GdPCP2A(H2O)(2)](-): A paramagnetic contrast agent designed for improved applications in magnetic resonance imaging

A novel ligand based on a pyridine-containing macrocycle bearing two acetic and one methylenephosphonic arms (PCP2A) has been synthesized. An efficien t synthesis of PCP2A is based on the macrocyclization reaction between 2,6- bis(chloromethyl)pyridine and a 1,4,7-triazaheptane derivative bearing a me thylenephosphonate group on N-4. The Gd(III) complex of PCP2A displays char acteristic properties which make it a very promising contrast agent for imp roved applications in magnetic resonance imaging. In fact it shows (i) a ve ry high stability constant (log K-GdPCP2A = 23.4) which should guarantee ag ainst the in vivo release of toxic free Gd(III) ions and free ligand molecu les and (ii) a relaxivity that is about 2 times higher than the values repo rted for contrast agents currently used in the clinical practice. Its high relaxivity is the result of the presence of two water molecules in the inne r coordination sphere and a significant contribution from water molecule(s) hydrogen bonded to the phosphonate group. Moreover, the inner sphere water molecules are involved in an exchange with the bulk water which is relativ ely fast. This property is important for the attainment of an even higher r elaxivity once the molecular reorientation rate of the [GdPCP2A(H2O)(2)](-) moiety is lengthened by means of conjugation to a macromolecular substrate .