The efficacy and clinical utility of gadolinium-based contrast agents (GBCAs) in contrast-enhanced magnetic resonance imaging (CE-MRI) is well established in clinical routine [1]. In the last decades more that >700 million procedures with GBCAs have been performed. It has been shown that these compounds are generally well-tolerated and exhibit an excellent safety profile [2-4].

The discovery of nephrogenic systemic fibrosis (NSF) in 2006 [5] and the association between repeated use of GBCAs and MRI signal hyperintensities in certain brain regions in 2014 [6, 7] have prompted a thorough evaluation of the clinical use of GBCAs. This eventually led to regulatory restrictions on labelling, particularly for multipurpose linear contrast agents which are not marketed in the EU anymore. Consequently, there has been a shift from linear to macrocyclic contrast agents, as these have a higher kinetic stability compared to linear GBCAs and are therefore less prone to release Gd3+ in vivo [8-10]. It has been shown that the degree of Gd presence in organs and tissues corresponds to the complex stability of GBCAs [11-13]. To additionally reduce the probability of such a presence in the body the development of high relaxivity macrocyclic Gd chelates for clinical MRI has been advocated [14]. Next-generation high relaxivity GBCAs allow a significant reduction of the Gd dose due to an increased relaxivity per Gd atom. Such an increase can be achieved using different strategies. Gadoquatrane (currently in clinical phase 3) has a tetrameric structure with four Gd containing macrocycles while in gadopiclenol (recently approved in the US and the EU) one of the chelating ligand arms was replaced by a second inner sphere water molecule. Both contrast agents allow a >2-fold dose reduction compared to conventional GBCAs [15-18].

In the current study a first direct comparative assessment of the physico-chemical properties of gadoquatrane and gadopiclenol, regarding r1-relaxivity and complex stability, is presented.