Zwitterionic MRI contrast agents with enhanced relaxivity, stability and reduced renal retention

Concerns over <i>in vivo</i> Gd(III) retention have recently prompted the development of Gd(III)-based contrast agents (GBCAs) with high-relaxivity and stability. This work describes the synthesis of a novel modular and enantiomerically pure chelator, (<i>R</i>,<i>R</i>,<i>R</i>)-Bn₃-PCTAZA 8 allowing modification <i>via</i> Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Two zwitterionic GBCAs, Gd-SB₃-PCTA 11a and Gd-NOx₃-PCTA 12a, were prepared by CuAAC and analysed for important physicochemical properties and complex stability. Both zwitterionic complexes have improved kinetic inertness compared to the clinically relevant GBCA gadopiclenol 3. In addition, Gd-SB₃-PCTA 11a revealed an 18% increase in relaxivity (<i>r</i>₁) compared to gadopiclenol 3. Gd-NOx₃-PCTA 12a, has a slightly lower relaxivity but the highest kinetic stability among all complexes tested. Both agents maintain high relaxivity at clinically relevant magnetic field strengths (1.4 T and 7 T) and have high inertness under transmetallation conditions, acidic conditions and in human serum. These favourable characteristics are due to enhanced second-sphere hydration of the kosmotropic periphery of the complexes. Gd-SB₃-PCTA 11a revealed a significantly reduced retention in mice kidneys compared to gadopiclenol 3. The zwitterionic GBCAs Gd-SB₃-PCTA 11a and Gd-NOx₃-PCTA 12a are thus promising candidates for the development of next-generation contrast agents for magnetic resonance imaging (MRI).