Approaching the kinetic inertness of macrocyclic gadolinium(III)-based MRI contrast agents with highly rigid open-chain derivatives

A highly rigid open-chain octadentate ligand (H₄cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6^'-[(ethane-1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H₄octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd³⁺ complex slightly (log K_GdL=20.68 vs. 20.23 for [Gd(octapa)]^-) while other MRI-relevant parameters remain unaffected (one coordinated water molecule; relaxivity r₁=5.73 mm^-1 s^-1 at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton half-life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)]^- (t_1/2=1.49 x 10⁵ h) than for [Gd(octapa)]^-. The kinetic inertness of this novel chelate is superior by 2-3 orders of magnitude compared to non-macrocyclic MRI contrast agents approved for clinical use. (copyright 2016 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)