TOWARDS MRI CONTRAST AGENTS OF IMPROVED EFFICACY - NMR RELAXOMETRIC INVESTIGATIONS OF THE BINDING INTERACTION TO HSA OF A NOVEL HEPTADENTATE MACROCYCLIC TRIPHOSPHONATE GD(III)-COMPLEX

A novel heptacoordinating ligand consisting of a thirteen-membered tet raazamacrocycle containing the pyridine ring and bearing three methyle nephosphonate groups (PCTP-[13]) has been synthesized. Its Gd(III) com plex displays a remarkably high longitudinal water proton relaxivity ( 7.7 mM(-1) s(-1) at 25 degrees C, 20 MHz and pH 7.5) which has been ac counted for in terms of contributions arising from (1) one water molec ule bound to the metal ion, (2) hydrogen-bonded water molecules in the second coordination sphere, or (3) water molecules diffusing near the paramagnetic chelate. Variable-temperature O-17-NMR transverse relaxa tion data indicate that the residence lifetime of the metal-bound wate r molecule is very short (8.0 ns at 25 degrees C) with respect to the Gd(III) complexes currently considered as contrast agents for magnetic resonance imaging. Furthermore, GdPCTP-[13] interacts with human seru m albumin (HSA), likely through electrostatic forces. By comparing wat er proton relaxivity data for the GdPCTP-[13]-HSA adduct, measured as a function of temperature and magnetic field strength, with those for the analogous add;ct with GdDOTP (a twelve-membered tetraaza macrocycl ic tetramethylene-phosphonate complex lacking a metal-bound water mole cule), it has been possible to propose a general picture accounting fo r the main determinants of the relaxation enhancement observed when a paramagnetic Gd(III) complex is bound to HSA. Basically, the relaxatio n enhancement in these systems arises from (1) water molecules in the hydration shell of the macromolecule and protein exchangeable protons which lie close to the interaction site of the paramagnetic complex an d (2) the metal bound water molecule(s). As far as the latter contribu tion is concerned, the interaction with the protein causes an elongati on of the residence lifetime of the metal-bound water molecule, which limits, to some extent, the potential relaxivity enhancement expected upon the binding of the paramagnetic complex to HSA.