Supramolecular assemblies based on amphiphilic Mn²⁺-complexes as high relaxivity MRI probes

In the research field of MRI contrast agents (CAs), amphiphilic paramagnetic complexes are typically sought for the increased plasmatic half-life and high relaxivity values, but limited examples of amphiphilic Mn²⁺-based CAs have been reported to date. In this work the Mn²⁺-complexes of six original amphiphilic ligands (three EDTA-like ligands and three 1,4-DO2A derivatives) embodying one or two aliphatic chains were evaluated as potential MRI contrast agents and compared. Strong self-association into micelles resulted in a relaxivity (r₁) enhancement (ca. 80% with respect to MnEDTA) as a consequence of the increased molecular tumbling rate of the supramolecular aggregate. In the case of bis-substituted systems the r₁ gain is much higher due to the restricted local rotation of the chelates about the pendant aliphatic chains (r₁ in the range 12.6-18.4 mM^-1 s^-1, 2-3 times higher than for the micelles obtained with single-chain EDTA systems). Furthermore, these amphiphilic chelates tightly bind to human serum albumin (HSA) with association constants K_A in the range 10⁴-10⁵ M^-1. The resulting supramolecular adducts achieve remarkable relaxivity values, in the range 50-60 mM^-1 s^-1 for the MnEDTA-like chelates and 27-30 mM^-1 s^-1 for the 1,4-DO2A-like systems (at 298 K and 20 MHz), thanks to their fast water exchange rate.