Manganese (II) Complex of 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid (NOTA) as a Hepatobiliary MRI Contrast Agent
Md. Kamrul Islam, Ahrum Baek, Byeong Woo Yang, Soyeon Kim, Dong Wook Hwang, Sung‐Wook Nam, Gang Ho Lee, Yongmin Chang
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, Mn-NOTA-NP, was designed and synthesized as a non-gadolinium alternative for liver-specific MRI. Mn-NOTA-NP exhibits an r1 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 Mn-NOTA-NP were similar to those of the Gd3+-based hepatobiliary agent, Gd-DTPA-EOB. Additionally, a 0.05 mmol/kg dose of Mn-NOTA-NP facilitated high-sensitivity tumor detection with tumor signal enhancement in a liver tumor model. Ligand-docking simulations further indicated that Mn-NOTA-NP differed from other hepatobiliary agents in their interactions with several transporter systems. Collectively, we demonstrated that Mn-NOTA-NP could be a new liver-specific MRI contrast agent.