Digadoglucitol: A New High Relaxivity MRI Contrast Agent Based on the Dimerization of [Gd(HP-DO3A)] and Activated Intramolecular Catalysis of the Prototropic Exchange

Digadoglucitol is an extracellular macrocyclic dinuclear gadolinium-based contrast agent (GBCA) based on the association of two [Gd(HP-DO3A)] units conjugated through a spacer containing the glucamine moiety. It displays a relaxivity per Gd that is 2 to 3 times higher than the most currently used GBCAs, allowing the use of reduced doses while ensuring a noninferior image contrast. Its high relaxivity is the result of a rational design aimed at exploiting the intramolecular catalysis of the prototropic exchange of the coordinated –OH groups as well as the second sphere contribution brought about by the presence of the hydroxyl functionalities on glucamine. Digadoglucitol maintains the excellent kinetic and thermodynamic properties of the parent [Gd(HP-DO3A)] with an SAP/TSAP ratio of 2/3. A HPLC workup yielded three fractions of diastereoisomers based on the chirality of the 2-hydroxypropyl pendants with similar relaxometric and stability properties. From pH 5 to 9, the deprotonated glucamine nitrogen acts as base to catalyze the prototropic exchange of the coordinating –OH group bringing an enhancement of 1.5–2.0 mM–1 s–1 of the observed relaxivity with respect to the expected value for a q = 1 complex of a similar formula weight. Biodistribution and the Magnetic Resonance Imaging pharmacokinetics of digadoglucitol resulted very similarly to those found for [Gd(BT-DO3A)].