Acid-catalyzed proton exchange as a novel approach for relaxivity enhancement in Gd-HPDO3A-like complexes

Abstract

<p>A current challenge in medical diagnostics is how to obtain high MRI relaxation enhancement using Gd^III-based contrast agents (CAs) containing the minimum concentration of GdIII ion. We report that in...</p>

Defining the conditions for the development of the emerging class of FeIII-based MRI contrast agents

“…16 The residence lifetime of water protons obtained from 1 H NMRD measurements is much shorter ( 298 s H M ¼ 0.76 ms, Table 1), which indicates that 1 H exchange receives an important contribution from prototropic exchange under highly acidic conditions, as recently shown for Gdcomplexes bearing amide ancillary groups. 21 Therefore, the observed exchange rate k can be expressed as M value calculated by Jordan is very inaccurate. Finally, it is worth noting that the calculated k H value is 3-4 times larger than that calculated through a pH-dependent study for a cationic GdDOTA-tetraamide derivative.…”

“… 16 The residence lifetime of water protons obtained from 1 H NMRD measurements is much shorter ( 298 τ H M = 0.76 μs, Table 1 ), which indicates that 1 H exchange receives an important contribution from prototropic exchange under highly acidic conditions, as recently shown for Gd-complexes bearing amide ancillary groups. 21 Therefore, the observed exchange rate k can be expressed as , where and k H are the rate constants characterizing the exchange of the whole water molecule and the prototropic mechanism, respectively. Since = 4.0 × 10 4 s −1 and k H = 9.06 × 10 6 s −1 M −1 , the prototropic exchange is expected to provide the main contribution at the acidic pH values required to avoid the hydrolysis of [Fe(H 2 O) 6 ] 3+ .…”

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

“…Paramagnetic gadolinium chelates were introduced several decades ago as medical magnetic resonance imaging (MRI) contrast agents (GBCAs) to enhance the differences between normal and diseased tissues by markedly accelerating the relaxation rates of the hydrogen atoms of the body fluids. , During the past two decades, the great relevance of MRI in modern diagnostic medicine has driven the search for GBCA optimization by modulation of the main parameters governing paramagnetic relaxation, i.e., the number ( q ) and residence lifetime (τ M = 1/ k ex ) of the metal-coordinated water molecule(s) and the rotational motion of the paramagnetic system, described by the correlation time τ R . , Another process effective in enhancing the nuclear relaxation rate of solvent water protons (relaxivity, r 1 ) is the exchange with the bulk water of the mobile protons present at a relatively short distance from the Gd III center. − …”

“…The fast proton exchange of the OH group has also been shown to slightly increase r 1 at neutral pH in the presence of the basic component of buffers (e.g., phosphate, carbonate, and HEPES) . In addition, the modulation of the chemical groups located in place of the methyl group of HPDO3A has led to r 1 enhancement due to several peculiar properties. − For example, hydroxyl-, amino-, or carboxy-benzyl groups have been shown to favor intramolecular H-bonding with the coordinated hydroxyl moiety, affecting both the p K values of the involved functionalities and the rate of the proton exchange process . An even more remarkable effect has been featured by amide functionalities (GdHPADO3As, Scheme ) 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 ( Δr 1 = 5.5 mM –1 s –1 from pH 7.4 to 5 for GdHPADO3A) .…”

“…In addition, the modulation of the chemical groups located in place of the methyl group of HPDO3A has led to r 1 enhancement due to several peculiar properties. − For example, hydroxyl-, amino-, or carboxy-benzyl groups have been shown to favor intramolecular H-bonding with the coordinated hydroxyl moiety, affecting both the p K values of the involved functionalities and the rate of the proton exchange process . An even more remarkable effect has been featured by amide functionalities (GdHPADO3As, Scheme ) 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 ( Δr 1 = 5.5 mM –1 s –1 from pH 7.4 to 5 for GdHPADO3A) . The importance of introducing functional groups at the periphery of Gd III complexes in the correct position to form hydrogen bonds with the coordinated and/or second sphere water molecules has also been recently demonstrated providing either a relaxivity increase or modulation of the water exchange rate. − …”