Lipophilic Group-Modified Gd-PCTA as a High-Performance MRI Contrast Agent Featuring Kinetic Inertness, Protein Binding, and Enhanced T1 Relaxivity

To address the demands for safer and more effective gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI), we developed Gd-PCTA-Ach, a novel macrocyclic complex featuring a lipophilic cyclohexanol pendant arm. Gd-PCTA-Ach exhibited superior relaxivity (r1 = 13.6 ± 0.2 and r2 = 15.8 ± 0.2 mM–1s–1 at 37 °C, 3.0 T) and kinetic inertness compared to clinically approved agents. Attributed to its enhanced lipophilicity, Gd-PCTA-Ach exhibits moderate albumin affinity (34.8%), resulting in prolonged blood circulation compared to standard extracellular fluid MRI agents. In vivo T1-weighted imaging demonstrated that Gd-PCTA-Ach is primarily cleared via the renal pathway but also exhibits partial hepatobiliary excretion, accounting for approximately 10% of the total elimination. Consequently, Gd-PCTA-Ach successfully visualized tumor lesions in both brain and liver tumor mouse models. These findings position Gd-PCTA-Ach as a highly potent, multipurpose contrast agent with an improved stability profile and broad diagnostic utility.