Enhanced MRI Contrast with Gadoquatrane: A Preclinical Evaluation of a Novel Macrocyclic GBCA

This study aimed to evaluate the physicochemical and pharmacokinetic characteristics, as well as the MRI imaging properties of gadoquatrane, a newly developed macrocyclic and tetrameric gadolinium-based contrast agent (GBCA) known for its high relaxivity and stability. The r1-relaxivities were measured in human plasma at different magnetic field strengths, and the stability of the complex was assessed in human serum at physiological conditions. A comparison was made with other GBCAs, including gadodiamide and gadobutrol. Additionally, a zinc transmetallation assay was conducted to determine kinetic inertness, and protein binding and blood-to-plasma ratios were evaluated.

Gadoquatrane demonstrated high solubility and hydrophilicity, with minimal protein binding. It exhibited superior r1-relaxivity in human plasma, exceeding established macrocyclic GBCAs by more than double. The complex showed exceptional stability, with no detectable release of gadolinium after 21 days at 37°C in human serum. No gadolinium release was observed in the presence of zinc, indicating high kinetic inertness. The pharmacokinetic profile of gadoquatrane was found to be similar to that of gadobutrol, with comparable plasma elimination, biodistribution, and recovery.

In MRI studies using a rat glioblastoma model, gadoquatrane significantly improved contrast enhancement compared to gadobutrol at equivalent doses. Furthermore, it achieved similar contrast enhancement as gadoterate meglumine with a significantly reduced Gd dose. Due to its tetrameric structure, gadoquatrane's formulations were iso-osmolar to blood.

In conclusion, gadoquatrane is a promising new macrocyclic GBCA for MRI applications, offering high relaxivity, stability, and negligible protein binding, along with a favorable pharmacokinetic profile. It is a strong candidate for further clinical development.