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

Multimeric systems assembled by linking Gd III 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 , N ′, N ′′-triacetic acid) featuring a flexible (hexanoic acid, Gd L1 ) or rigid (methyl benzoic acid, Gd L2 ) pendant arm were synthesized and conjugated to a central 1,4,7-triazacyclononane unit through amide coupling to form two novel trinuclear systems (Gd 3 L3 and Gd 3 L4 ). A variable temperature and frequency 1 H and 17 O NMR relaxometric study on the mononuclear complexes indicated that Gd L2 exhibits two water molecules in the inner coordination sphere, as does the parent [Gd(DO3A)(H 2 O) 2 ] complex ( q = 2). However, the flexibility of the alkyl chain of Gd L1 allows its folding and coordination to the Gd 3+ ion with displacement of one water molecule ( q = 1) around neutral pH. In Gd 3 L4 , the linker rigidity results in a compact and rather rigid trinuclear system from the point of view of rotational dynamics, with each Gd III center having q = 2. This favors a considerable degree of coupling between local and overall tumbling motions and hence high relaxivity values ( r 1 = 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 Gd 3 L3 . 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 ( r 1 = 9.8 mM −1 s −1 ; 60 MHz and 298 K).