Iron(III)‐<i>t</i>CDTA derivatives as MRI contrast agents: Increased T<sub>1</sub> relaxivities at higher magnetic field strength and pH sensing
Jing Xie, Akvile Haeckel, Ralf Hauptmann, Iweta Pryjomska Ray, Christian Limberg, Nora Kulak, Bernd Hamm, Eyk Schellenberger
Abstract
Purpose Low molecular weight iron(III) complex‐based contrast agents (IBCA) including iron(III) trans ‐cyclohexane diamine tetraacetic acid [Fe( t CDTA)] − could serve as alternatives to gadolinium‐based contrast agents in MRI. In search for IBCA with enhanced properties, we synthesized derivatives of [Fe( t CDTA)] − and compared their contrast effects. Methods Trans ‐cyclohexane diamine tetraacetic acid ( t CDTA) 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 t CDTA: en‐ t CDTA, en‐ t CDTA‐dimer, trans‐ 1,4‐diaminocyclohexane‐ t CDTA, and trans‐ 1,4‐diaminocyclohexane‐ t CDTA‐dimer. The iron(III) complexes of these derivatives had similarly high stabilities as [Fe( t CDTA)] − . The iron(III) complexes of the trans ‐1,4‐diaminocyclohexane derivatives had higher T 1 relaxivities than [Fe( t CDTA)] − 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‐ t CDTA)] + had a threefold increase from neutral pH toward pH6. Conclusion Four iron(III) complexes with similar stability in comparison to [Fe( t CDTA)] − were synthesized. The relaxivities of trans‐ 1,4‐diaminocyclohexane‐ t CDTA and trans‐ 1,4‐diaminocyclohexane‐ t CDTA‐dimer complexes were in the same range as gadolinium‐based contrast agents at 3 Tesla. The [Fe(en‐ t CDTA)] + complex is a pH sensor at weakly acidic pH levels, which are typical for various cancer types.