Unprecedented Kinetic Inertness for a Mn<sup>2+</sup>‐Bispidine Chelate: A Novel Structural Entry for Mn<sup>2+</sup>‐Based Imaging Agents

Ndiaye, Daouda; Sy, Maryame; Pallier, Agnès; Même, Sandra; Silva, Isidro; Lacerda, Sara; Nonat, Aline; Charbonnière, Loı̈c J.; Tóth, Éva

doi:10.1002/ange.202003685

Cited by 8 publications

(2 citation statements)

References 35 publications

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“…The dissociation of Gd(III) from its complex in vivo may occur by competition with protons or endogenous divalent cations such as Cu 2+ and Zn 2+ . , The toxicity of free Gd(III) from the dissociation of its complex may cause serious side effects such as nephrogenic systemic fibrosis (NSF) in patients with kidney dysfunctions. , Therefore, the high kinetic stability (the low rate of Gd(III) dissociation) of the Gd(III) complex plays important roles in designing safer Gd(III)-based MRI contrast agents.…”

Section: Resultsmentioning

confidence: 99%

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Cai

Liu

et al. 2023

ACS Appl. Mater. Interfaces

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Compared to traditional branched polymers with Gd(III) chelates conjugated on their surface, branched polymers with Gd(III) chelates as the internal skeleton are considered to be a reasonable strategy for preparing efficient magnetic resonance imaging contrast agents. Herein, the Gd(III) ligand DOTA was chosen as the internal skeleton; four different molecular weights (3.5, 5.3, 8.6, and 13.1 kDa) and degrees of branching poly-DOTA branched polymers (P1, P2, P3, and P4) were synthesized by a simple “A2 + B4”-type one-pot polymerization. The Gd(III) chelates of these poly-DOTA branched polymers (P1-Gd, P2-Gd, P3-Gd, and P4-Gd) display excellent kinetic stability, which is significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol and slightly lower than that of cyclic Gd-DOTA. The T 1 relaxivities of P1-Gd, P2-Gd, P3-Gd, and P4-Gd are 29.4, 38.7, 44.0, and 47.9 Gd mM–1 s–1, respectively, at 0.5 T, which are about 6–11 times higher than that of Gd-DOTA (4.4 Gd mM–1 s–1). P4-Gd was selected for in vivo magnetic resonance angiography (MRA) because of its high kinetic stability, T 1 relaxivity, and good biosafety. The results showed excellent MRA effect, sensitive detection of vascular stenosis, and prolonged observation window as compared to Gd-DOTA. Overall, Gd(III) chelates of poly-DOTA branched polymers are good candidates of MRI probes, providing a unique design strategy in which Gd chelation can occur at both the interior and surface of the poly-DOTA branched polymers, resulting in excellent relaxivity enhancement. In vivo animal MRA studies of the probe provide possibilities in discovering small vascular pathologies.

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Section: Resultsmentioning

confidence: 99%

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Cai

Liu

et al. 2023

ACS Appl. Mater. Interfaces

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“…Complexation of Mn 2+ with R,iPr L was slow, requiring a batch titration approach to study the equilibrium (Figures S46—S48). Despite the lability of Mn 2+ in general, slow complex formation with chelating ligands has been observed in a number of cases, and has in at least one case been shown to result from the pre‐equilibrium formation of an unstable “pre‐complex” that more slowly converts to the stable complexed product [7,49] . This may also be the case in our system, but we have not attempted to probe this process further.…”

Section: Resultsmentioning

confidence: 90%

Steric Effects on the Chelation of Mn²⁺and Zn²⁺by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2

Gaynor

McIntyre

Lindsey

et al. 2023

Chemistry A European J

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Recently, there has been increasing interest in the design of ligands that bind Mn 2 + with high affinity and selectivity, but this remains a difficult challenge. It has been proposed that the cavity size of the binding pocket is a critical factor in most synthetic and biological examples of selective Mn 2 + binding. Here, we use a bioinspired approach adapted from the hexahistidine binding site of the manganese-sequestering protein calprotectin to systematically study the effect of cavity size on Mn 2 + and Zn 2 + binding. We have designed a hexadentate, trisimidazole ligand whose cavity size can be tuned through peripheral modification of the steric bulk of the imidazole substituents. Conformational dynamics and redox potentials of the complexes are dependent on ligand steric bulk. Stability constants are consistent with the hypothesis that larger ligand cavities are relatively favorable for Mn 2 + over Zn 2 + , but this effect alone may not be sufficient to achieve Mn 2 + selectivity.

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Exceptional Manganese(II) Stability and Manganese(II)/Zinc(II) Selectivity with Rigid Polydentate Ligands**

et al. 2022

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While MnII complexes meet increasing interest in biomedical applications, ligands are lacking that enable high MnII complex stability and selectivity vs. ZnII, the most relevant biological competitor. We report here two new bispidine derivatives, which provide rigid and large coordination cavities that perfectly match the size of MnII, yielding eight‐coordinate MnII complexes with record stabilities. In contrast, the smaller ZnII ion cannot accommodate all ligand donors, resulting in highly strained and less stable six‐coordinate complexes. Combined theoretical and experimental data (X‐ray crystallography, potentiometry, relaxometry and 1H NMR spectroscopy) demonstrate unprecedented selectivity for MnII vs. ZnII (KMnL/KZnL of 108–1010), in sharp contrast to the usual Irving–Williams behavior, and record MnII complex stabilities and inertness with logKMnL close to 25.

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Unprecedented Kinetic Inertness for a Mn²⁺‐Bispidine Chelate: A Novel Structural Entry for Mn²⁺‐Based Imaging Agents

Cited by 8 publications

References 35 publications

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Steric Effects on the Chelation of Mn²⁺and Zn²⁺by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2

Exceptional Manganese(II) Stability and Manganese(II)/Zinc(II) Selectivity with Rigid Polydentate Ligands**

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Unprecedented Kinetic Inertness for a Mn2+‐Bispidine Chelate: A Novel Structural Entry for Mn2+‐Based Imaging Agents

Cited by 8 publications

References 35 publications

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Gadolinium(III) Complex-Backboned Branched Polymers as Imaging Probes for Contrast-Enhanced Magnetic Resonance Angiography

Steric Effects on the Chelation of Mn2+and Zn2+by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2

Exceptional Manganese(II) Stability and Manganese(II)/Zinc(II) Selectivity with Rigid Polydentate Ligands**

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Unprecedented Kinetic Inertness for a Mn²⁺‐Bispidine Chelate: A Novel Structural Entry for Mn²⁺‐Based Imaging Agents

Steric Effects on the Chelation of Mn²⁺and Zn²⁺by Hexadentate Polyimidazole Ligands: Modeling Metal Binding by Calprotectin Site 2