Recent advances in bioresponsive macrocyclic gadolinium(III) complexes for MR imaging and therapy

Magnetic resonance (MR) imaging is a non-invasive clinical diagnostic modality that provides anatomical and physiological information with sub-millimetre spatial resolution at the organ and tissue levels. It utilizes the relaxation times (T₁ and T₂) of protons in water to generate MR images. However, the intrinsic MR contrast produced by water relaxation in organs and tissues is limited. To enhance the sensitivity and specificity of MR imaging, about 30%-45% of all clinical MR diagnoses need to use contrast media. Currently, all clinically approved MR contrast agents are linear or macrocyclic gadolinium(III) (Gd(III)) complexes, which are not specific to particular biological events. Due to the relatively high potential for releasing toxic free Gd(III), linear Gd(III) complexes raise safety concerns, making macrocyclic Gd(III) probes the preferred choice for clinical MR imaging without acute safety issues. To enhance the capability of MR imaging for detecting dynamic biological processes and conditions, many bioresponsive macrocyclic Gd(III) complexes capable of targeting diverse biomarkers have been developed. This review provides a concise and timely summary of bioresponsive macrocyclic Gd(III) contrast agents, particularly those developed between 2019 and 2024. We focus on three major types of Gd(III) agent that respond specifically to changes in pH, chemicals, and enzymes, highlighting their molecular design strategies, proton-relaxivity responses, and applications in in vitro and in vivo MR imaging for monitoring specific biomedical conditions and therapies.