A macrocyclic gadolinium contrast agent bearing an assembly-dissociable feature with albumin for enhanced magnetic resonance imaging and <i>in vivo</i> profiles

Gd-based contrast agents (GBCAs) with high relaxivity and favorable <i>in vivo</i> profiles are greatly desired yet present formidable challenges, especially on the molecular side. Here, we report a macrocyclic GBCA (namely Gd-IN-DO3A) characterized by the presence of an isonicotinate group (IN) tethered asymmetrically to the macrocyclic DO3A scaffold with the pyridine-N coordinated to the Gd³⁺ center. Our studies reveal that it shows an assembly-dissociable feature with human serum albumin (HSA) by moderate non-covalent interactions at Sudlow site II, showing a binding fraction of ∼50%, a binding constant (<i>K</i>_a) of 316 M^-1 and a dissociation constant (<i>K</i>_D) of 5.24 µM. This dynamic GBCA-HSA adduct ensures a high <i>r</i>₁ relaxivity of ∼23.75 mM^-1 s^-1 in 4.5% HSA (∼8.29 mM^-1 s^-1 in water) and enables favorable pharmacokinetic properties, with a blood half-life (<i>t</i>_1/2) of ∼3.2 h, desirable biodistribution and excretion, and superior lesion imaging performance. These results suggest that developing novel GBCAs bearing an assembly-dissociable feature with albumin <i>via</i> moderate non-covalent interactions could serve as a compensation approach for enhanced magnetic resonance imaging and <i>in vivo</i> profiles.