Iron(III)‐tCDTA derivatives as MRI contrast agents: Increased T 1 relaxivities at higher magnetic field strength and pH sensing

Abstract

Purpose: Low molecular weight iron(III) complex-based contrast agents (IBCA) including iron(III) trans-cyclohexane diamine tetraacetic acid [Fe(tCDTA)](-) could serve as alternatives to gadolinium-based contrast agents in MRI. In search for IBCA with enhanced properties, we synthesized derivatives of [Fe(tCDTA)](-) and compared their contrast effects.

Methods: Trans-cyclohexane diamine tetraacetic acid (tCDTA) was chemically modified in 2 steps: first the monoanhydride of Trans-cyclohexane diamine tetraacetic acid was generated, and then it was coupled to amines in the second step. After purification, the chelators were analyzed by high-performance liquid chromatography, mass spectrometry, and NMR spectrometry. The chelators were complexed with iron(III), and the relaxivities of the complexes were measured at 0.94, 1.5, 3, and 7 Tesla. Kinetic stabilities of the complexes were analyzed spectrophotometrically and the redox properties by cyclic voltammetry.

Results: Using ethylenediamine (en) and trans-1,4-diaminocyclohexane, we generated monomers and dimers of tCDTA: en-tCDTA, en-tCDTA-dimer, trans-1,4-diaminocyclohexane-tCDTA, and trans-1,4-diaminocyclohexane-tCDTA-dimer. The iron(III) complexes of these derivatives had similarly high stabilities as [Fe(tCDTA)](-). The iron(III) complexes of the trans-1,4-diaminocyclohexane derivatives had higher T-1 relaxivities than [Fe(tCDTA)](-) that increased with increasing magnetic field strengths and were highest at 6.8 L.mmol(-1).s(-1) per molecule for the dimer. Remarkably, the relaxivity of [Fe(en-tCDTA)](+) had a threefold increase from neutral pH toward pH6.

Conclusion: Four iron(III) complexes with similar stability in comparison to [Fe(tCDTA)](-) were synthesized. The relaxivities of trans-1,4-diaminocyclohexane-tCDTA and trans-1,4-diaminocyclohexane-tCDTA-dimer complexes were in the same range as gadolinium-based contrast agents at 3 Tesla. The [Fe(en-tCDTA)](+) complex is a pH sensor at weakly acidic pH levels, which are typical for various cancer types.