Optimizing the Relaxivity of MRI Probes at High Magnetic Field Strengths With Binuclear GdIII Complexes.

Loredana Leone,Giuseppe Ferrauto,Lorenzo Tei,Mauro Botta,Maurizio Cossi

doi:10.3389/fchem.2018.00158

Loredana Leone, Giuseppe Ferrauto + Show 3 more

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https://doi.org/10.3389/fchem.2018.00158

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Abstract

The key criteria to optimize the relaxivity of a Gd(III) contrast agent at high fields (defined as the region ≥ 1.5 T) can be summarized as follows: (i) the occurrence of a rotational correlation time τR in the range of ca. 0.2–0.5 ns; (ii) the rate of water exchange is not critical, but a τM < 100 ns is preferred; (iii) a relevant contribution from water molecules in the second sphere of hydration. In addition, the use of macrocycle-based systems ensures the formation of thermodynamically and kinetically stable Gd(III) complexes. Binuclear Gd(III) complexes could potentially meet these requirements. Their efficiency depends primarily on the degree of flexibility of the linker connecting the two monomeric units, the absence of local motions and the presence of contribution from the second sphere water molecules. With the aim to maximize relaxivity (per Gd) over a wide range of magnetic field strengths, two binuclear Gd(III) chelates derived from the well-known macrocyclic systems DOTA-monopropionamide and HPDO3A (Gd2L1 and Gd2L2, respectively) were synthesized through a multistep synthesis. Chemical Exchange Saturation Transfer (CEST) experiments carried out on Eu2L2 at different pH showed the occurrence of a CEST effect at acidic pH that disappears at neutral pH, associated with the deprotonation of the hydroxyl groups. Then, a complete 1H and 17O NMR relaxometric study was carried out in order to evaluate the parameters that govern the relaxivity associated with these complexes. The relaxivities of Gd2L1 and Gd2L2 (20 MHz, 298 K) are 8.7 and 9.5 mM−1 s−1, respectively, +77% and +106% higher than the relaxivity values of the corresponding mononuclear GdDOTAMAP-En and GdHPDO3A complexes. A significant contribution of second sphere water molecules was accounted for the strong relaxivity enhancement of Gd2L2. MR phantom images of the dinuclear complexes compared to GdHPDO3A, recorded at 7 T, confirmed the superiority of Gd2L2. Finally, ab initio (DFT) calculations were performed to obtain information about the solution structure of the dinuclear complexes.

Highlights

The success of Magnetic Resonance Imaging (MRI) as a clinical diagnostic technique is mainly related to its superb temporal and spatial resolution that allow the clear delineation and differentiation of soft tissues and to its low invasiveness that leads to high patient acceptability
In case of the ligand H2L2, there is a substantial change with respect to HPDO3A: a hydroxypropylamide group replaced the hydroxypropyl group in order to generate electron withdrawing effect on the coordinated hydroxyl group and stronger coordinating ability
In the isolated dimer (Figure 7A), due to the H-bonds between amide groups and coordinated waters, the dihedral angle of the N-C-C-N branch connecting the two GdHPADO3A moieties is close to 180◦, so that the Gd-H2O bond directions are almost opposite to each other. This arrangement changes when the solvent is added, since the amide groups prefer to Dinuclear GdIII and EuIII complexes based on two wellestablished q = 1 monomeric chelates derived from the macrocyclic systems HPDO3A and DOTAMAP were successfully synthesized via a multi-step procedure

Summary

Introduction

The success of Magnetic Resonance Imaging (MRI) as a clinical diagnostic technique is mainly related to its superb temporal and spatial resolution that allow the clear delineation and differentiation of soft tissues and to its low invasiveness that leads to high patient acceptability. MRI contrast agents (CAs) are used for a large fraction of clinical scans (40–50%) to increase tissue contrast on relaxation weighted images by shortening the relaxation times of the water molecules in their proximity. Clinically employed CAs are low molecular weight, nonspecific GdIII complexes with polyaminocarboxylate ligands that are capable to enhance the longitudinal relaxation rate (R1 = 1/T1) of water protons in the extracellular space. The increase in R1 induced by one millimolar concentration of the paramagnetic ion is called relaxivity (r1), a key parameter that depends on several structural and dynamic features of the GdIII complex. Among the most important are the molecular rotation (τR), the electronic relaxation times (T1,2e) and the residence lifetime of the coordinated water molecule(s) (τ M) (Caravan et al, 1999; Botta and Tei, 2012; Merbach et al, 2013)

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