Underlining the Importance of Peripheral Protic Functional Groups to Enhance the Proton Exchange of Gd-Based MRI Contrast Agents

Mariangela Boccalon,Lorenzo Tei,Loredana Leone,Nicola Demitri,Zsolt Baranyai,Giuseppe Marino

doi:10.1021/acs.inorgchem.1c01927

Abstract

In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new GdIII complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange (kH = 1.5 × 1011 M–1 s–1, kOH = 1.7 × 109 M–1 s–1). The determination of the thermodynamic stability and kinetic inertness of the GdIII complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log KGdL = 19.26, t1/2 = 2.14 × 107 hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (r1) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters (r1GdL1 = 4.7 mM–1 s–1 and r1GdL2 = 5.1 mM–1 s–1 at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the GdIII ions.

Highlights

IntroductionThe hydroxyl proton is in fast exchange with bulk water at high pH values (pH > 10) providing a substantial base-catalyzed proton exchange contribution to r1 (Δr1 = 1.2 mM−1 s−1).[5] The fast proton exchange of the OH group has been shown to slightly increase r1 at neutral pH in the presence of the basic component of buffers (e.g., phosphate, carbonate, and HEPES).[5] In addition, the modulation of the chemical groups located in place of the methyl group of HPDO3A has led enhancement due to several peculiar properties.[6−8] to r1 For example, hydroxyl-, amino-, or carboxy-benzyl groups have been shown to favor intramolecular H-bonding with the coordinated hydroxyl moiety, affecting both the pK values of the involved functionalities and the rate of the proton exchange process.[6] An even more remarkable effect has been featured by amide functionalities (GdHPADO3As, Scheme 1) that provide labile protons capable of establishing an acid-catalyzed proton exchange process with the metal-coordinated OH group and second sphere water molecules causing a remarkable relaxivity increase (Δr1 = 5.5 mM−1 s−1 from pH 7.4 to 5 for GdHPADO3A).[7] The importance of introducing functional groups at the periphery of GdIII complexes in the correct position to form hydrogen bonds with the coordinated and/or
Another process effective in enhancing the nuclear relaxation rate of solvent water protons is the exchange with the bulk water of the mobile protons present at a relatively short distance from the GdIII center.[5−8]. This proton exchange has been highlighted in the case of GdHPDO3A (HPDO3A = 10-(2-hydroxypropyl)-1,4,7,10tetraazacyclododecane-1,4,7-triacetic acid, Scheme 1) where a hydroxyl group is coordinated to the metal center
The modulation of the chemical groups located in place of the methyl group of HPDO3A has led enhancement due to several peculiar properties.[6−8] to r1 For example, hydroxyl, amino, or carboxy-benzyl groups have been shown to favor intramolecular H-bonding with the coordinated hydroxyl moiety, affecting both the pK values of the involved functionalities and the rate of the proton exchange process.[6]

Summary

Introduction

The hydroxyl proton is in fast exchange with bulk water at high pH values (pH > 10) providing a substantial base-catalyzed proton exchange contribution to r1 (Δr1 = 1.2 mM−1 s−1).[5] The fast proton exchange of the OH group has been shown to slightly increase r1 at neutral pH in the presence of the basic component of buffers (e.g., phosphate, carbonate, and HEPES).[5] In addition, the modulation of the chemical groups located in place of the methyl group of HPDO3A has led enhancement due to several peculiar properties.[6−8] to r1 For example, hydroxyl-, amino-, or carboxy-benzyl groups have been shown to favor intramolecular H-bonding with the coordinated hydroxyl moiety, affecting both the pK values of the involved functionalities and the rate of the proton exchange process.[6] An even more remarkable effect has been featured by amide functionalities (GdHPADO3As, Scheme 1) that provide labile protons capable of establishing an acid-catalyzed proton exchange process with the metal-coordinated OH group and second sphere water molecules causing a remarkable relaxivity increase (Δr1 = 5.5 mM−1 s−1 from pH 7.4 to 5 for GdHPADO3A).[7] The importance of introducing functional groups at the periphery of GdIII complexes in the correct position to form hydrogen bonds with the coordinated and/or

Objectives

Methods

Conclusion