Macrocyclic trinuclear gadolinium(iii) complexes: the influence of the linker flexibility on the relaxometric properties

Multimeric systems assembled by linking GdIII complexes to a central scaffold can be Magnetic Resonance Imaging (MRI) contrast agents of improved efficiency at high magnetic fields. Two novel mononuclear GdDO3A-derivatives (DO3A = 1,4,7,10-tetraazacyclododecane-N,N0 ,N00-triacetic acid) featuring a flexible (hexanoic acid, GdL1) or rigid (methyl benzoic acid, GdL2) pendant arm were synthesized and conjugated to a central 1,4,7-triazacyclononane unit through amide coupling to form two novel trinuclear systems. A variable temperature and frequency 1H and 17O NMR relaxometric study on the mononuclear complexes indicated that GdL2 exhibits two water molecules in the inner coordination sphere, as does the parent [Gd(DO3A)(H2O)2] complex (q = 2). However, the flexibility of the alkyl chain of GdL1 allows its folding and coordination to the Gd3+ ion with displacement of one water molecule (q = 1) around neutral pH. In Gd3L4, the linker rigidity results in a compact and rather rigid trinuclear system from the point of view of rotational dynamics, with each GdIII center having q = 2. This favors a considerable degree of coupling between local and overall tumbling motions and hence high relaxivity values (r1 = 13.8 mM-1 s-1; 60 MHz and 298 K). On the other hand, the flexibility of the alkyl chain significantly affects the properties of Gd3L3. The relaxation data suggest the easy folding of one of the chelates with coordination of Gd by an amide group of the central macrocyclic unit (q = 1). The other two complexes (q = 2) exhibit a high degree of rotational mobility around the linker that results in a significant limit on the relaxivity (r1 = 9.8 mM-1 s-1; 60 MHz and 298 K).