Synthesis, complexation and NMR relaxation properties of Gd3+ complexes of Mes(DO3A)3

Medium sized molecules endowed with multiple Gd3+ complexes are efficient high magnetic field MRI contrast agents. The novel ligand Mes(DO3A)3, presenting three DO3A (1,4,7,10-tetraazacyclododecane-N,N′,N′′-triacetatic acid) units grafted on the methyl positions of a central mesitylene (1,3,5-trimethylbenzene), has been synthesized. Designed as an MRI contrast agent, this ligand is complexed with Gd3+ and its efficiency is characterized by variable field 1H-NMR and variable temperature 17O-NMR. The evaluation of the relaxation and paramagnetic chemical shift data allowed the identification of an undesired binuclear complex which is obtained by using the classical procedure for complexation as described in the literature. An intramolecular capping mechanism appears to be responsible for the failure to introduce a third Gd3+ ion into the ligand. A new alternative method, based on pre-complexation with Mg2+ followed by transmetallation is described here and leads to the expected trinuclear Gd3+ complex [Mes{Gd(DO3A)(H2O)2}3]. The rate constants for the water exchange (kex298 = 32 × 106 s−1) for the bi- and trinuclear complex appeared to be the same, which is surprising in relation to the difference in the charge of the complex and to the difference in the number of coordinated water molecules, one and two per Gd3+ for the binuclear and trinuclear complex, respectively.

Mécanismes d'isomérisation et d'échange de ligand de complexes octaédriques labiles de cobalt (II)

Fabrice Riblet

There are only few structural thermodynamic and kinetic studies on labile octahedral complexes available today. Octahedral paramagnetic compounds of cobalt(II) have an optimum electronic relaxation leading to NMR spectra with good resolution. Therefore, they are excellent candidates to follow substitution and isomerisation processes by multinuclear NMR at variable pressure and temperature. This work groups the study of nine labile complexes (three families of compounds with three examples each) which can exist in different isomeric forms. The first part of the work concerns octahedral complexes with bis-chelating ligands of the general formula [Co(LA)2Rpy2] with LA being a bidentate acetylacetonate ligand and Rpy a monodentate ligand of the γ-substituted pyridine type. The second part of the work concerns octahedral complexes with tris-chelating ligands of the general [Co(LA)2(LB)] with LA being a bidentate acetylacetonate ligand and LB a bidentate ligand of the γ-substituted bipyridine type. The third part of the work concerns trinuclear heterometallic complexes with the general formula [Fe2M(μ3-O)(μ2-Ac)6(Rpy)3] with M = CoII, NiII and Rpy a monodentate ligand of the γ-substituted pyridine type. Each type of the metal centres has an octahedral geometry. For each example chosen, the different species present in equilibrium in solution have been identified and the thermodynamic and kinetic parameters measured are discussed. Mechanisms for isomerisation and ligand exchange are proposed on the basis of variable temperature and pressure kinetics data. It has been shown that the bis-chelate compounds isomerise via a dissociative mechanism (with an intermediate of bipyramid geometry). The monodentate ligand participates more or less depending on its donor character. In the case of complexes with γ-methylpyridine, the mechanism consists essentially of an opening of one arm of the bidentate ligand (with little exchange of the pyridine). However, in the case of complexes with γ-trifluoromethylpyridine, a more frequent exchange of the monodentate ligand is observed competing with the opening of the arm of the bidentate ligand. In the case of tris-chelate compounds the isomerisation mechanism proposed on the bases of the exchange matrix used for spectral simulations is a twist with an intermediate of prismatic geometry. This observed rates (faster) and the obtained activation parameters (smaller) are very different of those found for complexes with bis-chelating ligands. The trinuclear heterometallic complexes maintain their structure in dichloromethane solution. Variable pressure experiments allowed assigning a dissociative mechanism (D) for the exchange of pyridine on both the divalent and the trivalent centres. Experiments at variable temperature indicated an increase of lability for the trivalent metals and a decrease in lability for the divalent metals compared to the homoleptic octahedral mononuclear complexes. The activation parameters for the trinuclear heterometallic complexes are bigger than those found for the bis- and tris-chelate compounds.

EPFL2007

A Mesoionic Diselenolene Anion and the Corresponding Radical Dianion

Cesare Berton, Zhaowen Dong, Farzaneh Fadaei Tirani, Rosario Scopelliti, Kay Severin, Andrzej Sienkiewicz, Abdusalom Suleymanov

Dichalcogenolenes are archetypal redox non-innocent ligands with numerous applications. Herein, we describe a diselenolene ligand with fundamentally different electronic properties. By selenation of a C2-protected imidazolium salt, we have prepared a mesoionic diselenolene. This ligand is diamagnetic, which is in contrast to the paramagnetic nature of standard dichalcogenolene monoanions. The new ligand is also redox-active, as demonstrated by isolation of a stable diselenolene radical dianion. The unique electronic properties of the new ligand give rise to unusual coordination chemistry. Thus, we were able to prepare a hexa-coordinate aluminum tris(diselenolene) complex, and a Lewis acidic aluminate complex with two ligand-centered unpaired electrons.

2022

New strategies for highly efficient medical MRI contrast agents

Sabrina Laus

During the last two decades, magnetic resonance imaging (MRI) has evolved into one of the most powerful techniques in medical diagnosis. Among the various medical diagnostic modalities, such as X-ray or ultra-sound imaging, MRI is the technique of choice especially because of its non-invasive character, the absence of ionizing radiations and its high spatial resolution. The principle of an MRI examination relies on the relaxation of water protons in the human body placed in a magnetic field after radiofrequency excitations. MRI is sensitive to the nature of the soft tissues, to the proton density and to the relaxation rate of protons to produce a contrast. The development of MRI is closely related to the successful use of paramagnetic contrast agents, essentially gadolinium(III) complexes. Unlike contrast agents used in other clinical imaging techniques, the MRI contrast agents are not themselves imaged but rather enhance the nuclear relaxation rate of water protons in their vicinity. The use of MRI contrast agents induces not only a better image contrast and a better delineating of diseased tissues but also a shortening of the examination time. Since the discovery of GdIII chelates as MRI contrast agents, a lot of effort has been made to increase their relaxivity, i.e. the gauge of efficiency of the contrast agent. In the work presented in this thesis, two groups of paramagnetic compounds have been studied: GdIII poly(amino carboxylates) and GdIII trapped in carbon cage compounds. For traditional monohydrated GdIII poly(amino carboxylate) complexes, the Solomon- Bloembergen-Morgan equations predict maximum proton relaxivities of 100 mM-1 s-1, instead of 4-5 mM-1 s-1 for commercial agents, when the three most important influencing factors, the rotation, the electron spin relaxation and the water exchange rate are simultaneously optimized. On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated GdIII poly(amino carboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA5- ligand by replacing one ethylene bridge of the amine backbone by a propylene one (EPTPA5--based ligand), leading to a water exchange rate two orders of magnitude higher than that for the commercial [Gd(DTPA)(H2O)]2-. The replacement of two ethylene bridges (DPTPA5-) results in the elimination of the water molecule from the inner sphere. Although the thermodynamic stability of [Gd(EPTPA-bz-NO2)(H2O)]2- is reduced to a slight extent in comparison to [Gd(DTPA)(H2O)]2-, it is stable enough to be used in medical diagnosis. The next step to obtain high relaxivity contrast agents is the covalent coupling of GdIII EPTPA complexes to three generations (5, 7 and 9) of PAMAM dendrimers to ensure fast water exchange rate and slow rotation. These macromolecular GdIII complexes allow high relaxivities with maximum values at magnetic fields presently used in clinical applications thanks to slow molecular tumbling. The relaxivities show a strong and reversible pH dependency for all three dendrimer generations. This smart behaviour originates from the pHdependent rotational dynamics of the dendrimer skeleton. From the studies on the monomeric and dendrimeric GdIII EPTPA complexes, general considerations have been proposed about the crucial need of more rigid macromolecular assemblies to obtain the highest relaxivity values predicted by the Solomon-Bloembergen-Morgan equations. Water-soluble fullerenes and carbon nanotubes have shown a great potential for various biological and medical applications. Gadofullerenes have been proposed not only as high relaxivity contrast agents thanks to the high number of water molecules close to the paramagnetic centre and their slow tumbling arising from aggregation phenomena but also as smart pH-responsive drugs. Proton relaxivity was proposed as an ideal aggregation-state sensor for the disruption of the water-soluble Gd@C60(OH)x (x ≈ 27) and Gd@C60[C(COOH)2]10 aggregates upon salt addition. This phenomenon has important implications for biological or biomedical applications of fullerene-based materials, since real biological fluids present a rather high salt concentration. With the aim of gaining more insight into the paramagnetic relaxation mechanism induced by water-soluble gadofullerenes, an NMR analysis with the common techniques used for GdIII MRI contrast agents allowed a comparison between the aggregated and the disaggregated systems. In analogy to C60 buckyballs, ultra-short single-walled nanotubes have been loaded with Gd3+ aqua-ions clusters. These Gdn3+@US-tubes, which self-organise into bundles-like structures, exhibit relaxivities up to 90 times higher (depending on the magnetic field) than that of any GdIII-based MRI contrast agent in current clinical use.