Synthesis and NMRD studies of gadolinium(3+) complexes of macrocyclic polyamino polycarboxylic ligands bearing .beta.-benzyloxy-.alpha.-propionic residues

Aime, Silvio; Botta, Maurizio; Ermondi, Giuseppe; Fedeli, Franco; Uggeri, Fulvio

doi:10.1021/ic00032a035

Cited by 67 publications

(39 citation statements)

References 7 publications

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“…However, an opposite result is seen in Figure 2. Such a result was also obtained at low frequencies (e0.4 MHz) by Aime (27) who observed a greater relaxivity for a complex of Gd 3+ with monoamidified DOTA than for GdDOTA -. The conclusion was that the increase in the ligand molecular mass, resulting from the amidification of one of the four carboxylic functions, compensated for the lost of symmetry provoked by DOTA amidification.…”

Section: Resultssupporting

confidence: 66%

Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

1998

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Macromolecular conjugates of dextran 40 (Mn = 38 kg/mol, Mw = 43 kg/mol) and diethylenetriaminepentaacetic acid (DTPA), capable of complexing Gd3+, were synthesized in order to obtain contrast agents for nuclear magnetic resonance imaging, with long intravascular persistence. As already reported, relaxivity of these macromolecular complexes was greater than that of molecular complexes (2-2.5 times). On the other hand, as relaxivity of paramagnetic agents partially depends on their rotation speed, the influence of the length of the spacer arm inserted between DTPA and dextran was investigated. Various conjugates with spacer arms comprised of methylenic chains (-(CH2)n-) with varying lengths (2 < or = n < or = 6) were prepared. The result was that, whatever the distance between DTPA and dextran, all of the Gd(3+)-complexed polymeric conjugates with similar DTPA content (0.6-0.8 mmol/g) exhibited, at 20 MHz, about the same relaxivity values. On the other hand, in the same way, no significant effect of the molecular masses (Mn between 166 and 224 kg/mol and Mw between 332 and 865 kg/mol) of the polymeric conjugates on relaxivity were observed. Toxicity studies carried out on mice, showed very similar LD50 values whatever the spacer arm and molecular mass of the macromolecular conjugates. Finally the urinary excretion studied on rats (after 4 h) and on rabbits (after 24 h) was relatively low (15-20% of the administered dose), and, as expected, the lower values were obtained with the higher molecular mass conjugates.

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Section: Resultssupporting

confidence: 66%

Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

1998

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“…the mean values 3.0 f 0.11 (M) and 3.2 f 0.10 (m) in excellent agreement with the value of 3.16 f 0.01 obtained from the fitting of NMR D profiles[33].…”

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confidence: 87%

Modelling studies in aqueous solution of lanthanide (III) chelates designed for nuclear magnetic resonance biomedical applications

2003

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Molecular dynamics simulations and complementary modelling studies have been carried out for the [Gd(DOTA).(H20)]-and [Tm(DOTP)]'-chelates in aqueous media, to provide a better understanding of several structural and dynamical properties of these versatile nuclear magnetic resonance (NMR) probes, including coordination shells and corresponding water exchange mechanisms, and interactions of these complexes with alkali metal ions. This knowledge is of key importance in the areas of 'H relaxation and shift reagents for NMR applications in medical diagnosis. A new refinement of our own previously developed set of parameters for these Ln(II1) chelates has been used, and is reported here. Calculations of water mean residence times suggest a reassessment of the characterization of the chelates' second coordination shell, one where the simple spherical distribution model is discarded in favour of a more detailed approach. Nat probe interaction maps are in good agreement with the available site location predictions derived from 23Na NMR shifts. Molecular Physics ISSN

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“…Synthesis of the DTPA(CyM) 3 , DOTA(BOM) 3 , and DO3A(BOM) 3 ligands and of the corresponding Gd III complexes: DOTA(BOM) 3 and DO3A(BOM) 3 ligands were synthesized according to previously reported procedures, [36] and the corresponding Gd III complexes were prepared following the General Procedure described in the same paper. The DTPA(CyM) 3 ligand was prepared according to a modification of the Rapoport synthesis of DTPA.…”

Section: Methodsmentioning

confidence: 99%

High-Relaxivity Contrast Agents for Magnetic Resonance Imaging Based on Multisite Interactions between aβ-Cyclodextrin Oligomer and Suitably Functionalized GdIII Chelates

Aime

Botta

Fedeli³

et al. 2001

Chem. Eur. J.

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The results reported in this work show that tightly assembled adducts formed by trisubstituted GdIII complexes and a beta-CD multimer (Poly-beta-CD, d.p. ca. 12) may represent very interesting candidates for novel MRI applications wherein a high number of paramagnetic ions endowed with high relaxivity (per GdIII ion) are necessary. The relaxivities found for the paramagnetic adducts represent a remarkable step forward on the relaxivity scale. However, a detailed investigation of the determinants of the relaxation enhancement in these systems shows that their relaxivities are still limited by a nonoptimal tauR and a relatively long exchange lifetime of the coordinated water(s). Moreover, the exchange rate of the water molecule(s) coordinated to the GdIII ion further decreases upon binding to the Poly-beta-CD. It is suggested that this finding is related to the structural properties of the supramolecule, which brings a high density of hydroxyl groups into the proximity of the "guest" complexes, and this yields an overall reinforcement of the hydrogen-bonding network involving the coordinated water(s). On the other hand, such a tight arrangement appears responsible for an enhanced contribution to the observed relaxivity arising from water molecules in the second coordination sphere of the metal center.

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Synthesis and NMRD studies of gadolinium(3+) complexes of macrocyclic polyamino polycarboxylic ligands bearing .beta.-benzyloxy-.alpha.-propionic residues

Cited by 67 publications

References 7 publications

Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Modelling studies in aqueous solution of lanthanide (III) chelates designed for nuclear magnetic resonance biomedical applications

High-Relaxivity Contrast Agents for Magnetic Resonance Imaging Based on Multisite Interactions between aβ-Cyclodextrin Oligomer and Suitably Functionalized GdIII Chelates

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Synthesis and NMRD studies of gadolinium(3+) complexes of macrocyclic polyamino polycarboxylic ligands bearing .beta.-benzyloxy-.alpha.-propionic residues

Cited by 67 publications

References 7 publications

Polymeric Conjugates of Gd3+−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Polymeric Conjugates of Gd3+−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Modelling studies in aqueous solution of lanthanide (III) chelates designed for nuclear magnetic resonance biomedical applications

High-Relaxivity Contrast Agents for Magnetic Resonance Imaging Based on Multisite Interactions between aβ-Cyclodextrin Oligomer and Suitably Functionalized GdIII Chelates

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Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters

Polymeric Conjugates of Gd³⁺−Diethylenetriaminepentaacetic Acid and Dextran. 2. Influence of Spacer Arm Length and Conjugate Molecular Mass on the Paramagnetic Properties and Some Biological Parameters