A Highly Stable Gadolinium Complex with a Fast, Associative Mechanism of Water Exchange

The stability and water exchange dynamics of gadolinium (GdIII) complexes are critical characteristics that determine their effectiveness as contrast agents for magnetic resonance imaging (MRI). A new heteropodal GdIII chelate, [Gd-TREN-bis(6-Me-HOPO)-(TAM-TRI)(H2O)2] (Gd-2), is presented which is based on a hydroxypyridinate (HOPO)-terephthalamide (TAM) ligand design. Thermodynamic equilibrium constants for the acid−base properties and the GdIII complexation strength of TREN-bis(6-Me-HOPO)-(TAM-TRI) (2) were measured by potentiometric and spectrophotometric titration techniques, respectively. The pGd of 2 is 20.6 (pH 7.4, 25 °C, I = 0.1 M), indicating that Gd-2 is of more than sufficient thermodynamic stability for in vivo MRI applications. The water exchange rate of Gd-2 (kex = 5.3(±0.6) × 107 s-1) was determined by variable temperature 17O NMR and is in the fast exchange regime − ideal for MRI. Variable pressure 17O NMR was used to determine the volume of activation (ΔV⧧) of Gd-2. ΔV⧧ for Gd-2 is −5 cm...