Lipophilic Group-Modified Gd-PCTA as a High-Performance MRI Contrast Agent Featuring Kinetic Inertness, Protein Binding, and Enhanced <i>T</i> ₁ Relaxivity

To address the demands for safer and more effective gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI), we developed <b>Gd-PCTA-Ach</b>, a novel macrocyclic complex featuring a lipophilic cyclohexanol pendant arm. <b>Gd-PCTA-Ach</b> exhibited superior relaxivity (<i>r</i>₁ = 13.6 ± 0.2 and <i>r</i>₂ = 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, <b>Gd-PCTA-Ach</b> exhibits moderate albumin affinity (34.8%), resulting in prolonged blood circulation compared to standard extracellular fluid MRI agents. <i>In vivo</i> <i>T</i>₁-weighted imaging demonstrated that <b>Gd-PCTA-Ach</b> is primarily cleared via the renal pathway but also exhibits partial hepatobiliary excretion, accounting for approximately 10% of the total elimination. Consequently, <b>Gd-PCTA-Ach</b> successfully visualized tumor lesions in both brain and liver tumor mouse models. These findings position <b>Gd-PCTA-Ach</b> as a highly potent, multipurpose contrast agent with an improved stability profile and broad diagnostic utility.