Rational Design of Gd-DOTA-Type Contrast Agents for Hepatobiliary Magnetic Resonance Imaging

Abstract

The safety risks of gadolinium (Gd 3+ )-based contrast agents (GBCAs) arise from their inevitable leakage of Gd 3+ , and the pursuit of more stable GBCAs for magnetic resonance imaging (MRI) has drawn increasing attention. Yet, Gd-EOB-DTPA and Gd-BOPTA are the only two authorized GBCAs for liver diagnosis in spite of their weak stability. In this study, one of the pendent arms of the most inert commercial Gd-DOTA was decorated with phenyl moieties, in which obvious enhancements of both kinetic and thermodynamic stability were achieved. Gd-L 4 with a para-substituted OBn group was observed with ready hepatocellular uptake, with significant contrast provided in diagnosing orthotopic hepatocellular carcinoma, and its hepatobiliary secretion accounted for more than 50% of the injection dose in mice. In this study, Gd-L 4 was found with comparable performance in liver MRI diagnosis to that of commercial Gd-EOB-DTPA and was thus deemed as an ideal candidate for further clinical applications.

Chiral Gd-DOTA as a Versatile Platform for Hepatobiliary and Tumor Targeting MRI Contrast Agents

“…At 5 min postinjection, around 7 and 17% of Gd-L 2 was detected in the liver and kidney, respectively, in contrast to 28 and 6% of Gd-L 5 in the liver and kidney, respectively. The hepatocyte uptake of Gd-L 5 is only around half the amount of Gd-EOB-DTPA (around 50%), , and this phenomenon is consistent with the lower affinities of Gd-L 5 to transporters including OATP1B1 and OATP1B3 as indicated in molecular docking study. The evacuation of Gd-L 5 from liver took around 2 days, with about 7 and 0.5% of Gd-L 5 detected in hepatic tissue at 24 and 48 h postinjection, respectively.…”

“… a Protonation constants taken from ref ; stability constant taken from ref . b The pGd was defined as −log­[free Gd] when [L] = 10 μM and [Gd] = 1 μM. The pGd of Gd-DOTA was acquired using the data in our previous report …”

“… b The pGd was defined as −log­[free Gd] when [L] = 10 μM and [Gd] = 1 μM. The pGd of Gd-DOTA was acquired using the data in our previous report …”

“…In our recent work, the inertness of Gd-DOTA was highly improved by introducing a phenylic group to one of its pendent arms, while in this research, further improvements on its kinetic inertness and thermodynamic stability were achieved by decorating the macrocycle with extra chiral ethyl groups. The given chiral Gd-L 4 (Figure ) exhibited stability constant and pGd (pH 7.4) as high as 27.08 and 19.25 respectively.…”

Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging

“…Est. log P was measured using RP-HPLC with the conditions described in the RP-HPLC method section following the published literature. ,, Retention times ( t R ) of DMSO, DMF, nitrobenzene, phenol, and pyridine with known log P measured under the same conditions were used to obtain the calibration curve . The calibration curve was subsequently used to estimate the contrast agents in this study.…”