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

Abstract

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, 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 (Gd₃L3 and Gd₃L4). 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 Gd^III 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).