[Gd-AAZTA]<sup>-</sup>:  A New Structural Entry for an Improved Generation of MRI Contrast Agents

Aime, Silvio; Calabi, Luisella; Cavallotti, Camilla; Gianolio, Eliana; Giovenzana, Giovanni B.; Losi, Pietro; Maiocchi, Alessandro; Palmisano, Giovanni; Sisti, Massimo

doi:10.1021/ic0489692

Cited by 223 publications

(249 citation statements)

References 15 publications

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“…À (which is more than one order of magnitude higher than the previously reported value [11] ) promotes the system into the group of Gd 3 + chelates for in vivo applications in spite of its lower denticity. The rate of the proton-…”

Section: Resultsmentioning

confidence: 72%

“…There are few ligands that provide a good compromise between stability and enhanced hydration of the resulting Gd 3 + complexes; some examples are the hydroxypyridinone (HOPO) family developed by Raymond et al, [6,7,8] the N-alkyldiethylenetri-A C H T U N G T R E N N U N G aminetetraacetic acids reported by the groups of Caravan [9] and Merbach [10] and the AAZTA derivatives (AAZTA = 1,4-bis(hydroxycarbonylmethyl)6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine) prepared by our group. [11] In complexes containing AAZTA, the ligand wraps around the Gd 3 + ion, yielding a system containing two coordinated water molecules in fast exchange with the "bulk water" solvent. This gives [GdA C H T U N G T R E N N U N G (AAZTA)]…”

Section: A C H T U N G T R E N N U N G (Aazta)]mentioning

confidence: 99%

“…(4)], and the stability constant of the dinuclear complex [Eqs. (11) and (8)], the pseudo-first-order rate constant can be expressed by Equation (14):…”

Section: A C H T U N G T R E N N U N G (Aazta)]mentioning

confidence: 99%

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Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Baranyai

Uggeri

Giovenzana

et al. 2009

Chemistry A European J

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127

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The heptadentate ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) and its derivatives were recently reported to give stable complexes with Gd(3+) with superior efficiency as MRI contrast agents. Nevertheless, only preliminary data are available on the coordination behavior of this interesting ligand. In this work, thermodynamic and kinetic stability data are determined for the formation of complexes with AAZTA and the lanthanoid metal ions, and other divalent metal ions of interest for this application. The AAZTA ligand binds the lanthanoid ions with log K(ML) values of 17.53-21.85 with its affinity steadily increasing from La(3+) to Lu(3+), suggesting that the seven-membered skeleton is better suited to accommodate smaller metal ions. Even though the denticity is lower, the stability of the heavier lanthanoid complexes is comparable to those of the classical ligand diethylenetriaminepentaacetic acid (DTPA). The transmetalation reactions of [Gd(AAZTA)](-) with Cu(2+) and Eu(3+) predominantly occur through proton-assisted dissociation of the complex. The role of the direct attack of Cu(2+) or Eu(3+) in the exchange reactions is limited, although the formation of dinuclear complexes decreases the proton-assisted dissociation. Near physiological conditions, [Gd(AAZTA)](-) is significantly more inert than [Gd(DTPA)](2-), allowing its potentially safe use as contrast agent in magnetic resonance imaging.

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Section: Resultsmentioning

confidence: 72%

Section: A C H T U N G T R E N N U N G (Aazta)]mentioning

confidence: 99%

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Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Baranyai

Uggeri

Giovenzana

et al. 2009

Chemistry A European J

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127

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“…[16] Over the last few years, however, a small number of very promising q = 2 gadolinium complexes have been reported. [17][18][19] The introduction of three additional carboxylate groups on the heptadentate do3a 3À ligand suppresses anionic binding to the gadolinium centre by electrostatic repulsion. [17] Recent studies of complexes of the tripodal hydroxypyridone (HOPO)-based ligands show that a high number of inner-sphere water molecules does not necessarily imply their ready displacement by physiological anions, even in neutral or cationic complexes.…”

mentioning

confidence: 99%

Structure, Stability, Dynamics, High‐Field Relaxivity and Ternary‐Complex Formation of a New Tris(aquo) Gadolinium Complex

Nonat

Fries

Pécaut

et al. 2007

Chemistry A European J

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The tripodal hexadentate picolinate ligand dpaa3- (H3dpaa=N,N'-bis[(6-carboxypyridin-2-yl)methyl]glycine) has been synthesised. It can form 1:1 and 1:2 lanthanide/ligand complexes. The crystal structure of the bis(aquo) lutetium complex [Lu(dpaa)(H2O)2] has been determined by X-ray diffraction studies. The number of water molecules was determined by luminescence lifetime studies of the terbium and europium complexes. The tris(aquo) terbium complex shows a fairly high luminescence quantum yield (22 %). The [Gd(dpaa)(H2O)3] complex displays a high water solubility and an increased stability (pGd=12.3) with respect to the analogous bis(aquo) complex [Gd(tpaa)(H2O)2] (pGd=11.2). Potentiometric and relaxometric studies show the formation of a soluble GdIII hydroxo complex at high pH values. A unique aquohydroxo gadolinium complex has been isolated and its crystal structure determined. This complex crystallises as a 1D polymeric chain consisting of square-shaped tetrameric units. In heavy water, the [Gd(dpaa)-(D2O)3] complex shows a quite high HOD proton relaxivity at high field (11.93 s(-1) mM(-1) at 200 MHz and 298 K) because of the three inner-sphere water molecules. The formation of ternary complexes with physiological anions has been monitored by relaxometric studies, which indicate that even under conditions favourable to the formation of adducts with oxyanions, the mean relaxivity remains higher than those of most of the currently used commercial contrast agents except for the citrate. However, the measured relaxivity (r1=7.9 s(-1) mM(-1)) in a solution containing equimolar concentrations of [Gd(dpaa)(D2O)3] and citrate is still high. The interaction with albumin has been investigated by relaxometric and luminescence studies. Finally, a new versatile method to unravel the geometric and dynamic molecular factors that explain the high-field relaxivities has been developed. This approach uses a small, uncharged non-coordinating probe solute, the outer-sphere relaxivity of which mimics that of the water proton. Only a routine NMR spectrometer and simple mathematical analysis are required.

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“…[12] As a consequence, Gd-AAZTA-C17-labeled HDL particles have a four times higher longitudinal relaxivity (the key parameter of MRI contrast-generating potential), making these systems very efficient contrast agents [13]. Once dissolved in water, these amphiphilic Gd-complexes form stable micelles with different critical micellar concentrations (CMC).…”

Section: High Density Lipoproteins (Hdl)mentioning

confidence: 99%

Lipid-Based Nanoparticles in Cardiovascular Molecular Imaging

Crich

Alberti

Orio

et al. 2012

Curr Cardiovasc Imaging Rep

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Abstract.The Gd(III) complexes currently used as MRI contrast agents are hydrophilic agents that distribute in the vascular and extracellular compartments. The visualization of atherosclerotic plaques requires systems endowed with lipophilic characteristics. Several Gd(III) complexes bearing lipophilic substituents have been reported. Among them Gd(III) complexes containing one or two aliphatic chains appears particularly useful for the intended application. These amphiphilic Gd(III) complexes have been incorporated into various type of supramolecular adducts that ensure enough sensibility for their detection in MR images of atherosclerotic plaques. Much attention has been devoted to the use of HDL and LDL Gd-loaded particles. The presence of long aliphatic chain(s) promotes the spontaneous aggregation of these complexes to form micelles that may associate as such to the surface of HDL particles. It has been shown that the transfer of single amphiphilic complexes into the lipidic core of the particles is possible by de-assembling the micelles through the formation of "host-guest" adducts with cyclodextrin. Gd-loaded liposomes have also been successfully tested in plaque detection as well as perfluoronanoparticles loaded with CEST agents. 4Introduction.

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[Gd-AAZTA]^-: A New Structural Entry for an Improved Generation of MRI Contrast Agents

Cited by 223 publications

References 15 publications

Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Structure, Stability, Dynamics, High‐Field Relaxivity and Ternary‐Complex Formation of a New Tris(aquo) Gadolinium Complex

Lipid-Based Nanoparticles in Cardiovascular Molecular Imaging

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[Gd-AAZTA]-: A New Structural Entry for an Improved Generation of MRI Contrast Agents

Cited by 223 publications

References 15 publications

Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Structure, Stability, Dynamics, High‐Field Relaxivity and Ternary‐Complex Formation of a New Tris(aquo) Gadolinium Complex

Lipid-Based Nanoparticles in Cardiovascular Molecular Imaging

Contact Info

Product

Resources

About

[Gd-AAZTA]^-: A New Structural Entry for an Improved Generation of MRI Contrast Agents