Manganese (II) Complex of 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid (NOTA) as a Hepatobiliary MRI Contrast Agent

Abstract

Magnetic resonance imaging (MRI) is increasingly used to diagnose focal and diffuse liver disorders. Despite their enhanced efficacy, liver-targeted gadolinium-based contrast agents (GBCAs) raise safety concerns owing to the release of toxic Gd³⁺ ions. A π-conjugated macrocyclic chelate, <b>Mn-NOTA-NP</b>, was designed and synthesized as a non-gadolinium alternative for liver-specific MRI. <b>Mn-NOTA-NP</b> exhibits an <i>r</i>₁ relaxivity of 3.57 mM^-1 s^-1 in water and 9.01 mM^-1 s^-1 in saline containing human serum albumin at 3 T, which is significantly greater than the clinically utilized Mn²⁺-based hepatobiliary drug, Mn-DPDP (1.50 mM^-1 s^-1), and comparable with that of GBCAs. Furthermore, the in vivo biodistribution and MRI enhancement patterns of <b>Mn-NOTA-NP</b> were similar to those of the Gd³⁺-based hepatobiliary agent, Gd-DTPA-EOB. Additionally, a 0.05 mmol/kg dose of <b>Mn-NOTA-NP</b> facilitated high-sensitivity tumor detection with tumor signal enhancement in a liver tumor model. Ligand-docking simulations further indicated that <b>Mn-NOTA-NP</b> differed from other hepatobiliary agents in their interactions with several transporter systems. Collectively, we demonstrated that <b>Mn-NOTA-NP</b> could be a new liver-specific MRI contrast agent.