The Discovery of Gadopiclenol: An Example of Rational Drug Design?

Abstract Gadopiclenol was initially developed as a high-relaxivity, nonspecific magnetic resonance imaging contrast agent to enhance image quality and thereby improve diagnostics. This design required a highly demanding Drug Target Profile, addressing not only relaxivity but also factors such as physicochemical properties of the injectable solution (viscosity, osmolality, heat sterilization compatibility), pharmacokinetics and toxicity, particularly related to the stability of the complex. These considerations led to a multiparametric molecular design based on a gadolinium complex characterized by the following features: (1) a macrocyclic, nonionic structure based on the PCTA framework with 2 water molecules in the inner sphere; (2) the introduction of steric constraints around the gadolinium to enhance stability and reduce relaxivity quenching by endogenous ions; (3) slowed rotational diffusion due to gadolinium's position at the center of the complex; and (4) the incorporation of 3 hydrophilic amino polyol pendant arms to ensure aqueous solubility, reduce binding with endogenous proteins, and enhance product safety. This rational design led to the creation of a first prototype, P03277V1. However, the occurrence of nephrogenic systemic fibrosis necessitated modifications to the Drug Target Profile, aimed at improving the complex's stability and reducing production costs. This was achieved through the discovery of an isomerization process for P03277V1, resulting in gadopiclenol, which demonstrated excellent kinetic stability. The rational design of gadopiclenol thus exemplifies the concept of Property-Based Drug Design used in medicinal chemistry. It also highlights that the complexity of designing a diagnostic agent is comparable to that of a therapeutic agent. Furthermore, the case of gadopiclenol illustrates that the medical positioning of a drug candidate can evolve during clinical development. Gadopiclenol's medical positioning shifted from being a product with high relaxivity to improve signal strength, to one intended for use at a half dose to limit gadolinium injection and minimize risks to patients, such as nephrogenic systemic fibrosis or accumulation in specific areas of the brain. Currently, gadopiclenol is approved for clinical use at a dose of 0.05 mmol/kg to minimize gadolinium exposure to patients. Whether the 0.1 mmol/kg dose can be used to enhance clinical diagnostics and improve patient management in the future remains to be seen.