Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent

Abstract To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) ( i.e. , small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd 3+ and macromolecules, e.g. , poly(acrylic acid) (PAA). To further decrease the r 2 / r 1 ratio of the reported Gd macrochelates that is an important factor for T 1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd 3+ . The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r 1 value of 16.35 mM −1 s −1 and r 2 / r 1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 ℃ or 1.8 cP at 37 ℃, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications. Graphical Abstract