Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the Ln<sup>III</sup> Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

Nicolle, Gaëlle M.; Yerly, Fabrice; Böttger, U.; Bünzli, Jean‐Claude G.; Merbach, André E.

doi:10.1002/chem.200305049

Cited by 23 publications

(23 citation statements)

References 60 publications

(64 reference statements)

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“…Dipole-dipole interactions between electron spins of close Gd III centres have been already observed by EPR or proton relaxometry for dinuclear [46] and trinuclear complexes, [47] micelles [48] and dendrimer complexes. [30] Such intramolecular Gd III -Gd III interactions lead to an increase in the electronic relaxation rate, which is unfavourable for relaxivity.…”

Section: Resultsmentioning

confidence: 92%

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Laus¹,

Sour²,

Ruloff³

et al. 2005

Chemistry A European J

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The EPTPA5) chelate, which ensures fast water exchange in GdIII complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H5EPTPA = ethylenepropylenetriamine-N,N,N',N'',N''-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)111, G7-(GdEPTPA)253 and G9-(GdEPTPA)1157 decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r1 = 20.5, 28.3 and 27.9 mM(-1) s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field 17O NMR and 1H relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)111. The longitudinal 17O and 1H relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)]2- monomer chelate. The longitudinal 17O and 1H relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the GdIII chelates on the surface (tau(lO)), correlated by means of an order parameter S2. The dendrimer complex G5-(GdEPTPA)111 has a considerably higher tau(gO) under acidic than under basic conditions (tau(298)gO = 4040 ps and 2950 ps, respectively), while local motions are less influenced by pH (tau(298)lO = 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)111(k(298)ex = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)]2-. The proton relaxivity of G5-(GdEPTPA)111 is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.

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Section: Resultsmentioning

confidence: 92%

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Laus¹,

Sour²,

Ruloff³

et al. 2005

Chemistry A European J

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115

118

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“…We are confident that the method will be portable enough to allow the simulation of ligand architectures other than only the acyclic-based and the cyclen-based ones. Now that the method has proved its efficiency on well-known complexes, it can be used, as proved by a very recent paper, [37] in parallel with synthetic or analytical studies to target the design of new potential medical MRI contrast agents more efficiently.…”

Section: Resultsmentioning

confidence: 97%

MD Simulations of Acyclic and Macrocyclic Gd³⁺‐Based MRI Contrast Agents: Influence of the Internal Mobility on Water Proton Relaxivity

Yerly

Borel

Helm

et al. 2003

Chemistry A European J

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Classical molecular dynamics simulations with a force field adapted to the family of Gd(3+) polyaminocarboxylate complexes have been successfully applied on two macrocyclic ([Gd(DOTA)(H(2)O)](-) and [Gd(DO3A)(H(2)O)(2)]) and two acyclic ([Gd(DTPA)(H(2)O)](2-) and [Gd(EGTA)(H(2)O)](-)) complexes in aqueous solution (DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane, DO3A=1,4,6-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, DTPA=1,1,4,7,7-pentakis(carboxymethyl)-1,4,7-triazaheptane, EGTA=1,1,10,10-tetrakis(carboxymethyl)-1,10-diaza-4,7-dioxadecane). In both macrocylic complexes the Gd(3+) coordination polyhedron remains close to a monocapped square antiprism (MSA) during the entire simulation time. For the stereolabile acyclic complexes different interconverting sets of geometries are observed: three sets close to tricapped trigonal prisms (TTP) for [Gd(EGTA)(H(2)O)](-) and three sets intermediate between MSA and TTP (distorted C(2v) symmetry) for [Gd(DTPA)(H(2)O)](2-). The fast conformational changes observed in the acyclic complexes might weaken the hydration of the second water shell and therefore disfavour the outer-sphere relaxivity. Moreover, the motions of the chelate observed in both acyclic complexes involve the reorientation of the symmetry elements over time. This reorientation, occurring on a picosecond timescale, can be associated with the correlation time for modulation of the zero field splitting and might participate in the electron spin relaxation mechanisms of the Gd(3+) ion. The internal motion of the inner-sphere water molecule can be quantified by the ratio tau(R)(GD-HW)/tau(R)(GD-OW) which increases slightly from 0.7 for the acyclic to 0.8 for the macrocyclic complexes. This increase for the macrocylic chelates is favourable for a higher relaxivity and can be related to their rigidity. The water exchange rate on the four complexes has been related to the steric constraint of the ligand on the inner-sphere water molecule(s), which is inversely proportional to a geometrical descriptor, the solid angle psi. A range of psi values is given (2<

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“…The N1 atom, which carries the O1 atom, is probably moved by a conformational change of the macrocycle. Simple rotation of the [4] The rate constant is similar to that of DTPA-bis(amides). [18,20] Interaction of this inner-sphere water with the gadolinium() ion and its exchange with bulk water is the basis for the action of MRI contrast agents of such compounds.…”

Section: Coordination Geometry Of the Early To Mid Lanthanide Ions: Imentioning

confidence: 82%

“…Interchange from the major to the minor isomer is accompanied by a III ϭ Eu, Gd, and Tb by means of NMR, UV/Vis, EPR and luminescence spectroscopy. [4] For the europium complex 5 and the gadolinium complex 4 the metal centres change their coordination number from 9 to 8 during isomerisation equilibrium, such as [Ln 2 (OHEC) 2 …”

Section: Coordination Geometry Of the Early To Mid Lanthanide Ions: Imentioning

confidence: 99%

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Structure Comparison of Early and Late Lanthanide(III) Homodinuclear Macrocyclic Complexes with the Polyamine Polycarboxylic Ligand H₈OHEC

et al. 2004

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The solid‐state structures of two new homodinuclear chelate complexes with the late lanthanide(III) ions Yb and Lu, [Na2(Yb2OHEC)].14.5H2O (1), and [Na2(Lu2OHEC)].14.5H2O (2) (H8OHEC = 1,4,7,10,14,17,20,23‐octaazacyclohexacosane‐ 1,4,7,10,14,17,20,23‐octaacetic acid), have been determined by X‐ray crystal structure analysis. Each lanthanide(III) ion is coordinated by eight donor atoms of the ligand and the geometry of the coordination polyhedron approaches a bicapped trigonal prism. These structures are compared with those of the homodinuclear chelate complexes with the same ligand and the mid to early lanthanide(III) ions Gd, Eu, La and also Y. A distinctive structural change occurs across the lanthanide series. The centrosymmetric mid to early lanthanide(III) complexes are all ninefold‐coordinated in a capped square antiprismatic arrangement with a water molecule coordinated in a prismatic position. This structure is maintained in aqueous solution, together with an asymmetric minor isomer. The late lanthanide(III) OHEC complexes not only lack the inner‐sphere water, but the change of coordination sphere also results in a loss of symmetry of the whole complex molecule. The observed change of coordination mode and number of the lanthanide ion may offer a geometric model for the isomerization process in eight‐ and ninefold‐coordinated complex species that are isomers in a possible coordination equilibrium observed by NMR in aqueous solution. This model may also explain the intramolecular rearrangements necessary during water exchange in the inner coordination sphere of the complex [(Gd2OHEC)(H2O)2]2− through a slow dissociative mechanism. Protonation constants of the H8OHEC ligand and complex formation constants of this ligand with GdIII, CaII, CuII and ZnII have been determined by solution thermodynamic studies. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the Ln^III Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

Cited by 23 publications

References 60 publications

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

MD Simulations of Acyclic and Macrocyclic Gd³⁺‐Based MRI Contrast Agents: Influence of the Internal Mobility on Water Proton Relaxivity

Structure Comparison of Early and Late Lanthanide(III) Homodinuclear Macrocyclic Complexes with the Polyamine Polycarboxylic Ligand H₈OHEC

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Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the LnIII Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

Cited by 23 publications

References 60 publications

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

MD Simulations of Acyclic and Macrocyclic Gd3+‐Based MRI Contrast Agents: Influence of the Internal Mobility on Water Proton Relaxivity

Structure Comparison of Early and Late Lanthanide(III) Homodinuclear Macrocyclic Complexes with the Polyamine Polycarboxylic Ligand H8OHEC

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Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the Ln^III Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

MD Simulations of Acyclic and Macrocyclic Gd³⁺‐Based MRI Contrast Agents: Influence of the Internal Mobility on Water Proton Relaxivity

Structure Comparison of Early and Late Lanthanide(III) Homodinuclear Macrocyclic Complexes with the Polyamine Polycarboxylic Ligand H₈OHEC