Objective Iron-based contrast agents (IBCAs) have potential as alternatives to Gd-based contrast agents (GBCAs), intending to address the long-term safety concerns associated with gadolinium. We investigated [Fe-EOB-tCDTA] as a potential alternative to [Gd-EOB-DTPA]2- for liver magnetic resonance imaging (MRI). Materials and methods [Fe-EOB-tCDTA] was synthesized by reacting the monoanhydride of tCDTA with 4-ethoxybenzylamine followed by iron chelation. Its kinetic stability was spectrophotometrically evaluated using a zinc stress test. The T1 relaxivity was measured in water and serum at 1.41 T, 37 °C and 3 T, 23 °C. Cellular cytotoxicity against liver-derived BRL-3A cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The uptake of [Fe-EOB-tCDTA] by liver cells was investigated using LA-ICP-MS, in competition with [Gd-EOB-DTPA]2-. T1 contrast effects in BALB/c mice were evaluated by DCE-MRI. Results [Fe-EOB-tCDTA] exhibited higher kinetic stability than [Fe-(tCDTA)]- and demonstrated a r1 of 1.94 and 2.45 mM-1s-1 at 1.4 and 3 T in serum. No significant differences in the short-term cytotoxicity were observed between [Gd-EOB-DTPA]2- and [Fe-EOB-tCDTA]. [Fe-EOB-tCDTA] inhibited [Gd-EOB-DTPA]2- uptake in BRL-3A liver cells. [Fe-EOB-tCDTA] (0.2 mmol/kg) demonstrated a comparable blood peak RE% compared to [Gd-DO3A-butrol] (0.1 mmol/kg). However, RE of [Gd-EOB-DTPA]2- in liver at a clinical dose was significantly higher than that of [Fe-EOB-tCDTA] at both injection doses. Conclusion [Fe-EOB-tCDTA] provides comparable blood enhancement to [Gd-DO3A-butrol] and exhibits hepatobiliary excretion like [Gd-EOB-DTPA]2- but without a comparable liver contrast. [Fe-EOB-tCDTA] may serve as an alternative to nonspecific GBCAs, particularly for patients with renal insufficiency and a contraindication to GBCAs. Relevance statement This study reports on the synthesis and in vitro and in vivo characterization of the iron complex [Fe-EOB-tCDTA]. This complex demonstrates strong blood contrast and liver excretion, though it lacks strong liver contrast. This complex could serve as an extracellular contrast agent, particularly for patients with reduced kidney clearance. Key Points <UnorderedList Mark="Bullet"> <ItemContent> [Fe-EOB-tCDTA] was synthesized as a novel iron-based MRI T1 contrast agent with liver excretion. </ItemContent> <ItemContent> [Fe-EOB-tCDTA] generated a strong blood enhancement effect and exhibited hepatobiliary excretion. </ItemContent> <ItemContent> Negative charge is crucial to the hepatic uptake and long-lasting liver enhancement. </ItemContent> </UnorderedList> Graphical Abstract

[Fe-EOB-tCDTA] generates strong contrast in the blood but not in the liver, despite inhibiting cellular [Gd-EOB-DTPA]^2- uptake and partial liver excretion

期刊论文
出版模式：

开放获取
发表日期：

2026年5月13日

查看全文

Fei Ni,
Akvile Haeckel,
Hamidreza Hojjat,
Mathias Schannor,
Heike Traub,
Eyk Schellenberger

摘要

Objective

Iron-based contrast agents (IBCAs) have potential as alternatives to Gd-based contrast agents (GBCAs), intending to address the long-term safety concerns associated with gadolinium. We investigated [Fe-EOB-tCDTA] as a potential alternative to [Gd-EOB-DTPA]²^- for liver magnetic resonance imaging (MRI).

Materials and methods

[Fe-EOB-tCDTA] was synthesized by reacting the monoanhydride of tCDTA with 4-ethoxybenzylamine followed by iron chelation. Its kinetic stability was spectrophotometrically evaluated using a zinc stress test. The T1 relaxivity was measured in water and serum at 1.41 T, 37 °C and 3 T, 23 °C. Cellular cytotoxicity against liver-derived BRL-3A cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The uptake of [Fe-EOB-tCDTA] by liver cells was investigated using LA-ICP-MS, in competition with [Gd-EOB-DTPA]²^-. T1 contrast effects in BALB/c mice were evaluated by DCE-MRI.

Results

[Fe-EOB-tCDTA] exhibited higher kinetic stability than [Fe-(tCDTA)]^- and demonstrated a r1 of 1.94 and 2.45 mM^-1s^-1 at 1.4 and 3 T in serum. No significant differences in the short-term cytotoxicity were observed between [Gd-EOB-DTPA]²^- and [Fe-EOB-tCDTA]. [Fe-EOB-tCDTA] inhibited [Gd-EOB-DTPA]²^- uptake in BRL-3A liver cells. [Fe-EOB-tCDTA] (0.2 mmol/kg) demonstrated a comparable blood peak RE% compared to [Gd-DO3A-butrol] (0.1 mmol/kg). However, RE of [Gd-EOB-DTPA]^2- in liver at a clinical dose was significantly higher than that of [Fe-EOB-tCDTA] at both injection doses.

Conclusion

[Fe-EOB-tCDTA] provides comparable blood enhancement to [Gd-DO3A-butrol] and exhibits hepatobiliary excretion like [Gd-EOB-DTPA]²^- but without a comparable liver contrast. [Fe-EOB-tCDTA] may serve as an alternative to nonspecific GBCAs, particularly for patients with renal insufficiency and a contraindication to GBCAs.

Relevance statement

This study reports on the synthesis and in vitro and in vivo characterization of the iron complex [Fe-EOB-tCDTA]. This complex demonstrates strong blood contrast and liver excretion, though it lacks strong liver contrast. This complex could serve as an extracellular contrast agent, particularly for patients with reduced kidney clearance.

Key Points

[Fe-EOB-tCDTA] was synthesized as a novel iron-based MRI T1 contrast agent with liver excretion.

[Fe-EOB-tCDTA] generated a strong blood enhancement effect and exhibited hepatobiliary excretion.

Negative charge is crucial to the hepatic uptake and long-lasting liver enhancement.

Graphical Abstract

[Fe-EOB-tCDTA] generates strong contrast in the blood but not in the liver, despite inhibiting cellular [Gd-EOB-DTPA]2- uptake and partial liver excretion

摘要

[Fe-EOB-tCDTA] generates strong contrast in the blood but not in the liver, despite inhibiting cellular [Gd-EOB-DTPA]^2- uptake and partial liver excretion