Developing High Field MRI Contrast Agents by Tuning the Rotational Dynamics: Bisaqua GdAAZTA-based Dendrimers

Monomeric and dimeric AAZTA-based bifunctional chelators (AAZTA=6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) were attached to different generations (G0, G1 and G2) of ethylenediamine-cored PAMAM dendrimers (PAMAM=polyamidoamine) to obtain a series of six dendrimeric systems with 4 to 32 chelates at the periphery. These Gd^III-loaded dendrimers have molecular weight ranging from 3.5 to 25 kDa, thus allowing a systematic investigation on the changes in relaxivity (r₁) with the variation of the rotational dynamics following the increase in molecular size. Variable-temperature ¹⁷O NMR (on the dimeric building block Gd₂L2) and ¹H Nuclear Magnetic Relaxation Dispersion measurements at different temperatures indicate that the water exchange lifetime (τ_M∼90 ns) of the two inner sphere water molecules does not represent a limiting factor to the relaxivity of the systems. The r₁ values at 1.5 T (60 MHz) and 298 K increases from 10.2 mM⁻¹ s⁻¹ for the monomer GdL1 to 31.4 mM⁻¹ s⁻¹ for the dendrimer Gd₃₂G2-32 (+308 %). However, the relaxivity (per Gd) does not show a linear dependence on the molecular mass, but rather the enhancement tends to attenuate markedly for larger systems. This effect has been attributed to the growing decrease in correlation between local rotational motions and global molecular tumbling.