The Synthesis and Evaluation of Macrocyclic Gadolinium-DTPA-bis (amide) Complexes as Magnetic Resonance Imaging Contrast Agents

Ja, Varadarajan; Sp, Crofts; Jf, Carvalho; Jd, Fellmann; Sh, Kim; Chang, C. Allen; Aj, Watson

doi:10.1097/00004424-199406001-00007

Cited by 19 publications

(9 citation statements)

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“…The dissociation of these macrocyclic chelates, which is much less important than that of linear open-chain chelates (Varadarajan et al 1994), is also a proton-assisted process and the observed linear dependence of the exchange rate (k obs ) on the H + concentration has been interpreted in the same way for the three macrocyclic chelates. In weakly acidic solutions (3.2 \ pH \ 5), the exchange rate is linearly proportional to the concentration of a monoprotonated species.…”

Section: Kinetic Stability: In Vitro Studiesmentioning

confidence: 87%

Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

et al. 2008

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Gadolinium-based contrast agents are widely used to enhance image contrast in magnetic resonance imaging (MRI) procedures. Over recent years, there has been a renewed interest in the physicochemical properties of gadolinium chelates used as contrast agents for MRI procedures, as it has been suggested that dechelation of these molecules could be involved in the mechanism of a recently described disease, namely nephrogenic systemic fibrosis (NSF). The aim of this paper is to discuss the structure-physicochemical properties relationships of marketed gadolinium chelates in regards to their biological consequences. Marketed gadolinium chelates can be classified according to key molecular design parameters: (a) nature of the chelating moiety: macrocyclic molecules in which Gd3+ is caged in the pre-organized cavity of the ligand, or linear open-chain molecules, (b) ionicity: the ionicity of the complex varies from neutral to tri-anionic agents, and (c) the presence or absence of an aromatic lipophilic residue responsible for protein binding. All these molecular characteristics have a profound impact on the physicochemical characteristics of the pharmaceutical solution such as osmolality, viscosity but also on their efficiency in relaxing water protons (relaxivity) and their biodistribution. These key molecular parameters can also explain why gadolinium chelates differ in terms of their thermodynamic stability constants and kinetic stability, as demonstrated by numerous in vitro and in vivo studies, resulting in various formulations of pharmaceutical solutions of marketed contrast agents. The concept of kinetic and thermodynamic stability is critically discussed as it remains a somewhat controversial topic, especially in predicting the amount of free gadolinium which may result from dechelation of chelates in physiological or pathological situations. A high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) will minimize the amount of free gadolinium released in tissue parenchymas.

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Section: Kinetic Stability: In Vitro Studiesmentioning

confidence: 87%

Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

et al. 2008

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“…As noted in the previous section, electronic relaxation can influence low field (<1 MHz) relaxivities; however, the similarity in relaxivity at 20 MHz for [Gd- Tables 20 and 21, relaxivities are collected for a variety of gadolinium(III) chelates. 23,28,[33][34][35]40,49,51,64,65,85,87,144,150,152,159,160,162,185,204,[225][226][227]231,239, Tweedle and co-workers 265 have shown that relaxivity per gadolinium(III) correlates well with molecular weight for a series of monomeric and multimeric gadolinium(III) chelates (Charts 17-19) and this is shown in Figure 38 (data in Table 21). For spheroidal molecules, increases in relaxivity increase approxi- mately with increasing molecular weight.…”

Section: Relaxivitymentioning

confidence: 99%

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

et al. 1999

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“…For instance Varadarajan et al (25) described five macrocyclic versions of GdDTPA-BMA, but four of these have lower stability constants than GdDTPA-BMA itself. Another example is the effect of adding one or two CH 2 groups to the DOTA macrocycle to give the compounds TRITA and TETA, respectively (Figure 6).…”

Section: Are All Macrocyclic Complexes Stable and Inert?mentioning

confidence: 99%

Primer on gadolinium chemistry

Sherry

Caravan

Lenkinski

2009

Magnetic Resonance Imaging

355

318

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Gadolinium is widely known by all practitioners of magnetic resonance imaging (MRI) but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA-tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence, forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity.

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The Synthesis and Evaluation of Macrocyclic Gadolinium-DTPA-bis (amide) Complexes as Magnetic Resonance Imaging Contrast Agents

Cited by 19 publications

References 0 publications

Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

Primer on gadolinium chemistry

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