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

Abstract

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 GdIII‐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 (τM∼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.

Rigid and Compact Binuclear Bis‐hydrated Gd‐complexes as High Relaxivity MRI Agents

“…In particular, [Gd 2 PCTA 2 (H 2 O) 4 ] showed a rotational correlation time more than doubled with respect to the monomeric GdPCTA complex, as a consequence of the zero‐length linker between the two GdPCTA units. In the case of the binuclear AAZTA‐like complex the relaxometric performance are in line with other dimeric AAZTA systems previously reported in the literature [15e, 29] …”

Relaxivity Enhancement of Ditopic Bishydrated Gadolinium(III) Complexes Conjugated to Mesoporous Silica Nanoparticles

“…The relaxivity values of Gd 2 L 2 ‐MSN and Gd 2 L 2 ‐MSN‐PEG measured at 0.47 T and 310 K were 37.1 (ca 5570 m m –1 s –1 per particle) and 36.3 mm –1 s –1 (5450 m m –1 s –1 per particle), respectively. These values are significantly higher than that measured for a related ditopic GdAAZTA complex (Gd 2 L 1 , Figure ) that is structurally similar to Gd 2 L 2 . Moreover, the r 2 / r 1 values measured at 37 °C for the Gd 2 L 2 ‐MSN sample are 1.4 at 0.47 T and 1.9 at 1.5 T. These values are quite typical for nanosized systems.…”

“… 1 H NMRD profiles of Gd 2 L 2 ‐MSN (♦) and Gd 2 L 2 ‐MSN‐PEG (○) in water in the presence of 0.1 wt.‐% xanthan gum at 310 K. The best‐fit curves were calculated with the parameters in Table . The experimental data of the “free” Gd 2 L 1 complex at 310 K (■) are also shown (from ref …”

“…In the best‐fit procedure, the Gd–H w distance r Gd–H was set to 3.0 Å, the distance of the closest approach of the outer‐sphere solvent molecules to the Gd 3+ ions, a , was fixed to 4.0 Å, and the water–solute relative diffusion coefficient, D , was fixed at 3.1 × 10 –5 cm 2 s –1 (37 °C). The number of coordinated water molecules q was fixed to 2, as for related mono‐ and dinuclear complexes , , . The global correlation time was fixed at 1 × 10 3 ns, in accordance with a previously used procedure for Gd‐functionalized mesoporous silicas, whereas the local correlation time τ RL was left to vary along with the order parameter S 2 and τ M .…”

“… 1 H relaxivity values measured at 0.7 (black) and 1.41 T (white) and 310 K for (A) Gd 2 L 1 , (B) GdDOTA‐MSN, (C) Gd 2 L 2 ‐MSN‐PEG and (D) Gd 2 L 2 ‐MSN.…”