Amphiphilic EuDOTA-tetraamide complexes form micelles with enhanced CEST sensitivity

The synthesis and characterization of four new DOTA-tetraamide ligands having variable alkyl chain lengths (C₁, C₁₂, C ₁₄, and C₁₆) and their respective europium(III) complexes are reported. The three EuL complexes having long alkyl chains spontaneously form micelles of variable size. The critical micelle concentration differed for each complex (lower for the C₁₆ complex than the C₁₂ complex) while micelle size increased with increasing alkyl chain length. Chemical exchange saturation transfer (CEST) experiments showed that all four Eu^III complexes displayed slow-to-intermediate water exchange kinetics. As expected, the CEST signals in these complexes decreased with increasing temperatures due to faster water exchange but, interestingly, the CEST signals for the C₁₄ and C₁₆ complexes approached a maximum near 25 °C consistent with exchange limited CEST at or near room temperature. The water residence lifetimes obtained by fitting the CEST spectra to the Bloch equations increased in parallel with an increase in alkyl carbon chain-length. By comparisons with the monomethylamide complex, which served as control, the data illustrate that micelle formation serves to slow the rate of water exchange in these systems. The complex having the largest CEST effect per unit Eu^III concentration (the C₁₆ analog) had a detection limit of 5.3 μM. This represents an approximate 250-fold increase in sensitivity relative to the monomethylamide control (detection limit â 1.3 mM). These features highlight the potential of using micelle-based systems such as these as paramagnetic chemical exchange saturation transfer (PARACEST) agents for molecular imaging by MRI. Four new EuDOTA-tetraamides with variable alkyl chains lengths were synthesized and their CEST properties were extensively studied. Three of these complexes werefound to spontaneously form micelles due to their long alkyl chains which resulted in a dramatic increase in their CEST sensitivities.