Dataset Information

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

ABSTRACT: The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C-C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd-complexes. Thus, the ¹ H relaxometric study on [Gd₂ PCTA₂ (H₂ O)₄ ] and on [Gd₂ AAZTA₂ (H₂ O)₄ ]^2- highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12-12.6 mM^-1 s^-1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes.

SUBMITTER: Leone L

PROVIDER: S-EPMC8456821 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Leone Loredana L Guarnieri Luca L Martinelli Jonathan J Sisti Massimo M Penoni Andrea A Botta Mauro M Tei Lorenzo L

Chemistry (Weinheim an der Bergstrasse, Germany) 20210702 46

The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C-C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd-complexes. Thus, the 1 H relaxometric study on [Gd2 PCTA2 (H2 O)4 ] and on [Gd2 AAZTA2 (H2</s ...[more]

PMID: 34114699

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Project description: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 ?R in the range of ca. 0.2-0.5 ns; (ii) the rate of water exchange is not critical, but a ?M < 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.

Project description:The correct parametrization of lanthanide complexes is of the utmost importance for their characterization using computational tools such as molecular dynamics simulations. This allows the optimization of their properties for a wide range of applications, including medical imaging. Here we present a systematic study to establish the best strategies for the correct parametrization of lanthanide complexes using [Gd(DOTA)]- as a reference, which is used as a contrast agent in MRI. We chose the bonded model to parametrize the lanthanide complexes, which is especially important when considering the study of the complex as a whole (e.g., for the study of the dynamics of its interaction with proteins or membranes). We followed two strategies: a so-called heuristic approach employing strategies already published by other authors and another based on the more recent MCPB.py tool. Adjustment of the Lennard-Jones parameters of the metal was required. The final topologies obtained with both strategies were able to reproduce the experimental ion to oxygen distance, vibrational frequencies, and other structural properties. We report a new strategy to adjust the Lennard-Jones parameters of the metal ion in order to capture dynamic properties such as the residence time of the capping water (τm). For the first time, the correct assessment of the τm value for Gd-based complexes was possible by recording the dissociative events over up to 10 μs all-atom simulations. The MCPB.py tool allowed the accurate parametrization of [Gd(DOTA)]- in a simpler procedure, and in this case, the dynamics of the water molecules in the outer hydration sphere was also characterized. This sphere was divided into the first hydration layer, an intermediate region, and an outer hydration layer, with a residence time of 18, 10 and 19 ps, respectively, independent of the nonbonded parameters chosen for Gd3+. The Lennard-Jones parameters of Gd3+ obtained here for [Gd(DOTA)]- may be used with similarly structured gadolinium MRI contrast agents. This allows the use of molecular dynamics simulations to characterize and optimize the contrast agent properties. The characterization of their interaction with membranes and proteins will permit the design of new targeted contrast agents with improved pharmacokinetics.

Dataset Information

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

Publications

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

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