Binuclear DOTA-based Gd(III) chelates: revisiting a straightforward strategy for relaxivity improvement

Abstract

The need for MRI contrast agents with improved relaxivity maintains the development of new Gd(III) chelates an intensive and demanding field of research. In this work we introduce the new dimeric chelators bis(DOTA-AHA)adipate and bis(DOTA-AHA)1,3-phenyldiacetate (L2 = bis(1,4,7,10-tetraazacyclododecane-1-((6-amino)hexanoic)-4,7,10-triacetic acid)adipate and L3 = bis(1,4,7,10-tetraazacyclododecane-1-((6-amino)hexanoic)-4,7,10-triacetic acid)1,3-phenyldiacetate, respectively), based on the bifunctional ligand DOTA-AHA (L1 = 1,4,7,10-tetraazacyclododecane-1-((6-amino)hexanoic)-4,7,10-triacetic acid). Their Gd(III) chelates were studied by variable temperature 1H NMRD and 17O NMR spectroscopy in order to measure the relaxivity and the parameters that govern it. The exchange of inner-sphere water from the monomer GdL1 and from the two binuclear chelates Gd2L2 and Gd2L3 is very similar (298kex ≈ 6.5 x106 s-1) and slightly faster than on [Gd(DOTA)H2O]- (298kex = 4.1 x 106 s-1). All three compounds form weakly bound aggregates with equilibrium constants 298K of 2.9, 15.6 and 14.6 for GdL1, Gd2L2 and Gd2L3, respectively. Even if the aggregates contain only 10 to 15% of the total amount of Gd(III) ions a marked increase in relaxivity between 30 and 100 MHz is observed. Furthermore the distance between the two Gd(III) centers in the binuclear compounds has been determined by double electron-electron resonance (DEER) experiments and by molecular modelling studies affording comparable distances. The linkers between the chelating moieties allow Gd(III)-Gd(III) distances of circa 3.0 nm for completely stretched linker conformation and ≤ 1.9 nm for the conformation with the metal centers at closer distance. These metal to metal distances by themselves cannot explain the considerably long tumbling times of chelates in solution. Only a model consistent with some level of aggregation for the binuclear chelates in aqueous solution could satisfactorily explain our results.