Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)‐Based MRI Contrast Agents with Highly Rigid Open‐Chain Derivatives

Tircsó, Gyula and Regueiro‐Figueroa, Martín and Nagy, Viktória and Garda, Zoltán and Garai, Tamás and Kálmán, Ferenc K. and Esteban‐Gómez, David and Tóth, Éva and Platas‐Iglesias, Carlos (2016) Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)‐Based MRI Contrast Agents with Highly Rigid Open‐Chain Derivatives. CHEMISTRY-A EUROPEAN JOURNAL, 22. pp. 896-901. ISSN 0947-6539

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Abstract

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 KGdL=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)]− (t1/2=1.49×105 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.

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