Comparison of Iron(III)-Trans-1,4-Diaminocyclohexane-tCDTA and Iron(III)-Trans-1,4-Diaminocyclohexane-tCDTA-Dimer With Gadobutrol for T1 Contrast Enhancement in DCE-MRI.

Abstract

Purpose: This study evaluated the T1 enhancement of the 2 iron-based contrast agents (IBCAs), [Fe(trans-tCDTA)]+ and [Fe(trans-Di-tCDTA)], in blood and other organs compared with a gadolinium-based contrast agent (GBCA) in DCE-MRI, as well as their in vitro toxicity and the stability of the IBCAs compared to [Fe-(tCDTA)]-.

Methods: Iron(III) chelates of trans-tCDTA and trans-Di-tCDTA were synthesized and characterized. The T1 relaxivity of IBCAs and gadobutrol was measured at 3T using human whole blood samples. In vitro toxicity was assessed by cytotoxicity of IBCAs and gadobutrol against BRL-3A using MTT viability assays. Kinetic stability was evaluated spectrophotometrically using a zinc stress test (2.5 mM ZnCl2). The T1 contrast in mice was measured using a dynamic T1-weighted gradient-echo sequence. DCE-MRI was performed with 0.17 mmol/kg or 0.35 mmol/kg [Fe(trans-tCDTA)]+, 0.1 mmol/kg [Fe(trans-Di-tCDTA)], and 0.1 mmol/kg gadobutrol. DCE time curves in different organs were evaluated using a 2-phase exponential decay function.

Results: [Fe(trans-tCDTA)]+ and [Fe(trans-Di-tCDTA)] showed T1 relaxivities in human whole blood at 3T comparable to gadobutrol. No significant differences in short-term cytotoxicity were found between gadobutrol and iron chelates. [Fe(trans-Di-tCDTA)] had a higher kinetic stability than [Fe-(tCDTA)]-, and [Fe(trans-tCDTA)]+ had a lower stability in the presence of zinc chloride and phosphate. [Fe(trans-tCDTA)]+ showed lower relative blood enhancement at 0.17 mmol/kg (P = 0.0025) but comparable at 0.35 mmol/kg (P = 0.4739) versus gadobutrol at 0.1 mmol/kg. [Fe(trans-Di-tCDTA)] showed a similar enhancement to gadobutrol at 0.1 mmol/kg (P = 0.5238). Max relative enhancement (RE%) were 131.0 ± 18.0, 93.6 ± 9.4, 144.0 ± 15.4, and 143.2 ± 12.3; blood half-lives (rapid phase/slow phase) were 2.3/15.0 minutes, 1.5/59.7 minutes, 1.9/177.1 minutes, and 1.5/27.5 minutes for gadobutrol, [Fe(trans-tCDTA)]+ at 0.17 mmol/kg or 0.35 mmol/kg, and [Fe(trans-Di-tCDTA)].

Conclusion: [Fe(trans-Di-tCDTA)] provided comparable contrast enhancement and kinetics to gadobutrol at the same molecular dose (double the metal dose), is very stable, and could serve as an alternative to nonspecific GBCA, thereby avoiding potential long-term gadolinium toxicity and retention concerns as well as environmental gadolinium deposition. [Fe(trans-tCDTA)]+ required a higher dose and showed delayed clearance in blood and other organs.