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

The stability and water exchange dynamics of gadolinium (Gd^III) 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 Gd^III 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 (k_ex = 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 cm³ mol^-1, indicative of an interchange associative (I_a) water exchange mechanism. The results reported herein are important as they provide insight into the factors influencing high stability and fast water exchange in the HOPO series of complexes, potentially future clinical contrast agents.