Lanthanide complexes of triethylenetetramine tetra-, penta-, and hexaacetamide ligands as paramagnetic chemical exchange-dependent saturation transfer contrast agents for magnetic resonance imaging: Nona- versus decadentate coordination

The solid state and solution structure of a series of lanthanide complexes of the decadentate ligand triethyienetetramine-N,N, N′,N″,N‴, N‴-hexaacetamide, (ttham), its two decadentate derivatives di-terf-butyl N,N, N‴,N‴-tetra(carbamoylmethyl)triethylenetetramine-N′, N″-diacetate (Bu₂ttha-tm) and N,N,N‴,N‴- tetra(carbamoylmethyl)-triethylenetetramine-N′,N″diacetic acid (H₂ttha-tm), and its two nonadentate derivatives N-benzyl- triethylenetetramine-N,N′,N″,N‴,N‴-pentaacetamide (1bttpam) and N′-benzyl-triethylenetetramine-N,N,N″,N‴, N‴-pentaacetamide (4bttpam) have been investigated by infrared and Raman spectroscopy, X-ray crystallography, cyciovoitammetry, and NMR spectroscopy. In these mononuclear lanthanide complexes, the first coordination sphere Is generally saturated by four amine nitrogens of the triethylenetetramine ligand backbone and five or six carbonyl oxygen atoms of the pendent amide or acetate donor groups. In the [Ln(ttham)]³⁺ complex series, a switch from a decadentate to a nonadentate coordination occurs between [Er(ttham)] ³⁺ and [Tm(ttham)]³⁺. This switch In coordination mode, which Is caused by decreasing metal ion radii going from lanthanum to lutetium (lanthanide contraction), has no significant effect on the T₁- relaxivity of these complexes. it Is shown that the T₁-relaxlvity is dominated by second coordination sphere interactions, with an ascendant contribution of the classical dipolar relaxation mechanism for the earlier (Ce - Sm) and very late (Tm, Yb) lanthanides, and a prevailing Curie relaxation mechanism for most of the remaining paramagnetic lanthanide Ions. In chemical exchange-dependent saturation transfer (CEST) ¹H NMR experiments, most of the above complexes exhibit multiple strong CEST peaks of the paramagnetically shifted amide protons spread over a >100 ppm chemical shift range. The effective CEST effect of the studied thulium complexes strongly depends on temperature and pH. The pH at which the CEST effect maximizes (generally between pH 7 and 8) Is determined by the overall charge of the complex. Depending on the used saturation frequency offset, the temperature-dependence varies between the extremes of strongly linearly dependent and fully Independent in the case of [Tm(ttham)]³⁺. In combination with the strong pH-dependence of the CEST effect at the latter frequency offset, this complex Is highly suitable for simultaneous temperature and pH mapping using magnetic resonance Imaging.