Dinuclear, Bishydrated GdIII Polyaminocarboxylates with a Rigid Xylene Core Display Remarkable Proton Relaxivities

Two novel dinuclear GdIII complexes have been synthesized, based on a xylene core substituted with diethylenetriamine-N,N,Nʹ ʹ,Nʹ ʹ-tetraacetate (DTTA) chelators in para or meta position. The complexes [Gd2(pX(DTTA)2)(H2O)4]2- and [Gd2(mX(DTTA)2)(H2O)4]2- both exhibit high complex stability (log KGdL = 19.1 and 17.0, respectively), and a good selectivity for GdIII against ZnII, the most abundant endogenous metal ion (log KZnL = 17.94 and 16.19). The water exchange rate is identical within experimental error for the two isomers: kex298 = (9.0 (plus-minus) 0.4) × 10^6 s^-1 for [Gd2(pX(DTTA)2)(H2O)4]2and (8.9 (plus-minus) 0.5) × 10^6 s^-1 for [Gd2(mX(DTTA)2)(H2O)4]2-. It is very similar to the kex298 of the structural analogue, bishydrated [Gd(TTAHA)(H2O)2]3-, and about twice as high as that of the monohydrated [Gd(DTPA)(H2O)]2- (TTAHA6- = N-tris(2-aminoethyl) amine-Nʹ,Nʹ,N",N",Nʹ",Nʹ"-hexaacetate; DTPA5- = diethylenetriamine-N,N,Nʹ,N",N"-pentaacetate). This relatively fast water exchange can be related to the presence of two inner sphere water molecules which decrease the stereorigidity of the inner sphere thus facilitating the water exchange process. At all frequencies, the water proton relaxivities (r1 = 16.79 and 15.84 mM-1 s-1 for the para and meta isomers, respectively; 25 °C and 20 MHz) are remarkably higher for the two dinuclear chelates than those of mononuclear commercial contrast agents or previously reported dinuclear GdIII complexes. This is mainly the consequence of the two inner-sphere water molecules. In addition, the increased molecular size as compared to monomeric compounds associated with the rigid xylene linker between the two GdIII chelating subunits also contributes to an increased relaxivity. However, proton relaxivity is still limited by fast molecular motions which also hinder any beneficial effect of the increased water exchange rate.