Abstract

As calcium plays an important role in regulating a great variety of neuronal processes, there is a strong interest to generate gadolinium complexes which can act as calcium-sensors in magnetic resonance imaging (MRI). Here we report a new series of potential CAs based on DO3A, having alkylaminobis(methylenephosphonate) side chains (propyl L1, butyl L2, pentyl L3 or hexyl L4). The high complexation efficiency towards the biologically important metal ions of the aminopolyphosphonic acids could be used for the sensing of the extracellular calcium in the brain. On the other hand the introduction of negatively charged phosphonate groups into common Gd3+-based CAs increases their r1 which is important to improve the MR signal especially in high field magnets. The paramagnetic response of the complexes GdL1-GdL4 to Ca2+ was studied by means of relaxometric titrations. The initial relaxivities of the complexes found to be higher than usually reported for the DO3A type ligands at high field magnets (9.4T). r1 values of 6.92, 7.43, 6.70 and 5.76 mM-1s-1 were determined for GdL1, GdL2, GdL3, and GdL4 respectively. Interestingly complexes exhibit unusual properties in the presence of Ca2+. In contrast to previously reported probes the longitudinal relaxivities decrease upon addition of Ca2+. This is favourable for novel fMRI techniques as it could allow transforming the real in vivo decrease in Ca2+ concentration into a positive contrast during physiological processes. The sensitivity of the complexes towards Ca2+ increases with the extension of the aliphatic side chain. No changes in r1 of GdL1 were found over the whole span of Ca2+ concentration. In the case of GdL2, a moderate decrease of r1 was observed on addition of Ca2+, whereas the r1 of the GdL3 and GdL4 solutions showed a strong dependency on the calcium concentration resulting in the decrease to 66% and 61% of the initial r1 values, respectively.