H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of Eu<sup>III</sup> complexes with HP-DO3A-like ligands

Baroni, Simona; Carnovale, Irene Maria; Carrera, Carla; Boccalon, Mariangela; Guidolin, Nicol; Demitri, Nicola; Lattuada, Luciano; Tedoldi, Fabio; Baranyai, Zsolt; Aime, Silvio

doi:10.1039/d1cc00366f

Cited by 5 publications

(6 citation statements)

References 20 publications

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“…In water, the Gd-L1 relaxivity value of 7.1 mM –1 s –1 , measured for 1 mM concentration at 21.5 MHz, 298 K and neutral pH, appears in agreement with the occurrence of an intramolecular catalysis of the prototropic exchange of the coordinated alcoholic group. , The catalysis likely involves the amide proton, as previously shown for similar systems. − Here, the catalytic effect appears even more marked, as the contribution of the OH moiety appears evident already at neutral pH values. Of course, the increased τ R , due to the increased MW (with respect to the parent Gd-HPDO3A), is also important.…”

Section: Discussionsupporting

confidence: 75%

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Stefania,

Palagi,

Di Gregorio

et al. 2023

J. Am. Chem. Soc.

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Gd-L1 is a macrocyclic Gd-HPDO3A derivative functionalized with a short spacer to a trisulfonated pyrene. When compared to Gd-HPDO3A, the increased relaxivity appears to be determined by both the higher molecular weight and the occurrence of an intramolecularly catalyzed prototropic exchange of the coordinated OH moiety. In water, Gd-L1 displayed a relaxivity of 7.1 mM −1 s −1 (at 298 K and 0.5 T), slightly increasing with the concentration likely due to the onset of intermolecular aggregation. A remarkably high and concentration-dependent relaxivity was measured in human serum (up to 26.5 mM −1 s −1 at the lowest tested concentration of 0.005 mM). The acquisition of 1 H-nuclear magnetic relaxation dispersion (NMRD) and 17 O-R 2 vs T profiles allowed to get an in-depth characterization of the system. In vitro experiments in the presence of human serum albumin, γ-globulins, and polylysine, as well as using media mimicking the extracellular matrix, provided strong support to the view that the trisulfonated pyrene fosters binding interactions with the exposed positive groups on the surface of proteins, responsible for a remarkable in vivo hyperintensity in T 1w MR images. The in vivo MR images of the liver, kidneys, and spleen showed a marked contrast enhancement in the first 10 min after the i.v. injection of Gd-L1, which was 2−6-fold higher than that for Gd-HPDO3A, while maintaining a very similar excretion behavior. These findings may pave the way to an improved design of MRI GBCAs, for the first time, based on the setup of weak and dynamic interactions with abundant positive groups on serum and ECM proteins.

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Section: Discussionsupporting

confidence: 75%

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Stefania,

Palagi,

Di Gregorio

et al. 2023

J. Am. Chem. Soc.

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“…and by nearly 40-fold in Eu-An-HP-DO3A. 30 This demonstrates that formation of an intramolecular H-bonding network with an exchanging -OH proton used for CEST activation can substantially increase the sensitivity of a paraCEST agent. This exciting observation could lead to new designs that bring the sensitivity of small molecule paraCEST agents like those described above into competition with existing Gd-based T 1 agents.…”

Section: Some Recent Chemical Insights May Prove Useful In Amplifying...mentioning

confidence: 89%

“…Can we find ways to amplify the sensitivity of paraCEST agents through prototropic exchange mechanisms? A recent report by Baroni et al 30 may provide some useful insights. In that study, Baroni et al demonstrated that the presence of a basic site (carboxyl or amine, see Figure 6) in proximity to the hydroxyl group of Ln (HP‐DO3A) allows for formation of a H‐bond with the coordinated ‐OH group that provides a pathway for intramolecular proton exchange and an enhanced CEST signal.…”

Section: Some Recent Chemical Insights May Prove Useful In Amplifying...mentioning

confidence: 94%

“…In that study, Baroni et al demonstrated that the presence of a basic site (carboxyl or amine, see Figure 6) in proximity to the hydroxyl group of Ln (HP‐DO3A) allows for formation of a H‐bond with the coordinated ‐OH group that provides a pathway for intramolecular proton exchange and an enhanced CEST signal. For example, very little CEST was observed in EuHP‐DO3A because ‐OH proton exchange is too slow, while CEST was increased by ~10‐fold in Eu‐Bz‐HP‐DO3A and by nearly 40‐fold in Eu‐An‐HP‐DO3A 30 . This demonstrates that formation of an intramolecular H‐bonding network with an exchanging ‐OH proton used for CEST activation can substantially increase the sensitivity of a paraCEST agent.…”

Section: Some Recent Chemical Insights May Prove Useful In Amplifying...mentioning

confidence: 98%

“…The chemical structures of two derivatives of Eu (HP‐DO3A) with intramolecular proton donor or acceptor groups situated near the exchanging ‐OH proton (in red) (reproduced from 30 )…”

Section: Some Recent Chemical Insights May Prove Useful In Amplifying...mentioning

confidence: 99%

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Prospects and limitations of paramagnetic chemical exchange saturation transfer agents serving as biological reporters in vivo

2022

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The concept of using paramagnetic metal ion complexes as chemical exchange saturation transfer agents (paraCEST) for molecular imaging of various biological processes first appeared in the literature about 20 years ago. The first paraCEST agent was based on a highly shifted, inner‐sphere, slowly exchanging water molecule that could be activated at a frequency far away from bulk water, a substantial advantage for selective activation of the agent alone. Many other paraCEST agent designs followed that were based on activation of exchanging ‐NH or ‐OH proton on the chelate itself. Both types of paraCEST designs are attractive for molecular imaging because the rates of water molecule or ligand proton exchange can be designed to be sensitive to a biological or physiological property such as pH, enzyme activity, or redox. Hence, the intensity or frequency of the resulting CEST signal provides a direct readout of that property. Many molecular designs have appeared in the literature over the past 20 years, mostly reported as proof‐of‐concept designs but, unfortunately, only a few reports have explored the limitations of paraCEST agents for imaging a biological process in vivo. As a community, we now know that the sensitivity of paraCEST agents is lower than one might anticipate based upon simple chemical exchange principles and, in general, it appears the sensitivity of paraCEST agents is even lower in vivo than in vitro. In this short review, we address some of the factors that contribute to the limited sensitivity of paraCEST agents in vivo, offer some thoughts on approaches that could lead to dramatically improved paraCEST sensitivity, and challenge the scientific community to perform more in vivo experiments designed to test these ideas.

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[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)

Versolatto,

Boccalon,

Guidolin

et al. 2024

Chemistry A European J

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[Gd(HP‐DO3A)] (gadoteridol) as an active compound of ProHance® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long‐term retention of gadolinium‐based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP‐DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP‐DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP‐DO3A)], i.e.: [Gd(HB‐DO3A)], in which (±)‐2‐hydroxy‐1‐propyl pendant arm is replaced by (±)‐2‐hydroxy‐1‐butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB‐DO3A)], compared to the parent [Gd(HP‐DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico‐chemical properties of Gd3+ complexes.

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H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of Eu^III complexes with HP-DO3A-like ligands

Abstract: Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed....

Cited by 5 publications

References 20 publications

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Prospects and limitations of paramagnetic chemical exchange saturation transfer agents serving as biological reporters in vivo

[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)

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H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of EuIII complexes with HP-DO3A-like ligands

Abstract: Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed....

Cited by 5 publications

References 20 publications

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

Prospects and limitations of paramagnetic chemical exchange saturation transfer agents serving as biological reporters in vivo

[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance®)

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Product

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H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of Eu^III complexes with HP-DO3A-like ligands

[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)