Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid–Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent

Abstract

In this study, we designed and synthesized a highly stable manganese (Mn 2+ )-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd 3+ ) chelates and evaluated its usage as a T 1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r 1 relaxivity (2.3 mM −1 s −1 ) than clinically approved Mn 2+ -based hepatobiliary complex Mn-DPDP (1.6 mM −1 s −1 ) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd 3+ -based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn 2+ chelate are comparable to those of Gd 3+ -based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.

Applications for Transition-Metal Chemistry in Contrast-Enhanced Magnetic Resonance Imaging

“…Mn-based alternatives to liver-specific GBCAs have also been explored. Mn-EDTA functionalized with lipophilic ethoxybenzyl (Mn-EOB-DTPA) and benzothiazole aniline moieties (Mn-BTA-EDTA) have been reported, and it was demonstrated that a 0.05 mmol kg –1 dose of either agent provided a delayed phase liver enhancement, which improves visualization of liver tumors in mice. , The transient liver uptake of Mn-PyC3A has also been capitalized on for liver-specific imaging . A more amphiphilic derivative of Mn-PyC3A-3-OBn (log P = 1.15) was recently reported for liver-specific imaging and provides substantially greater liver-to-tumor CNR than Mn-PyC3A …”

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents

“…Molecular docking simulations were run to see if Gd-SucL and Gd-GluL would be good substrates for each transporter. The three-dimensional structure of each transporter was predicted using homology modeling based on the literature . Also, their binding free energies were calculated using the GlideScore (Δ G binding ) (Table ).…”

“…The three-dimensional structure of each transporter was predicted using homology modeling based on the literature. 47 Also, their binding free energies were calculated using the GlideScore (ΔG binding ) (Table 5).…”

A manganese (II)-based coordinative dendrimer with robust efficiency in intracellular peptide delivery

“…Additionally, the coordinative polymer GT/Mn 2+ showed a relatively high relaxation rate (4.39 mM −1 s −1 ) [ [65] , [66] , [67] ], suggesting its potential use as a magnetic resonance imaging (MRI) contrast ( Fig. 2 d-e).…”