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Abstract

Calcium plays an important role in regulating a great variety of neuronal processes. A strong interest exists to generate gadolinium complexes which can act as calcium-sensors, in particular for magnetic resonance imaging (MRI). Here we report a new series of potential contrast agents based on DO3A, having an alkylaminobis(methylenephosphonate) side chain (propyl L1, butyl L2, pentyl L3 or hexyl L4). The complexation efficiency of the aminopolyphosphonic acid towards Ca2+, along with the ability to increase the presence of water in the secondary sphere and thus the longitudinal relaxivities (r1) of Gd3+-based CAs, was combined for potential use in sensing the extracellular calcium in the brain, especially at high field magnets. The paramagnetic response of the complexes GdL1-GdL4 was studied by means of relaxometric titrations at different Ca2+ concentrations. The initial relaxivities of the complexes were found to be higher than usually reported for the DO3A type ligands at high field magnets (9.4T). The 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 the complexes exhibit unusual properties in the presence of Ca2+. The sensitivity of the complexes towards Ca2+ increases with the extension of the aliphatic side chain. In contrast to previously reported probes r1 decreases upon addition of Ca2+. 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 upon addition of Ca2+, whereas 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. This is favorable for novel fMRI techniques as it could allow transforming the decrease in extracellular Ca2+ concentration into a positive MR contrast during the neuronal activity. Financial support of the Max-Planck Society, the Hertie Foundation, the Louis-Jeantet Foundation and the Centre National de la Recherche Scientifique (CNRS, France) is gratefully acknowledged. J.H. thanks the Fonds der Chemischen Industrie for a PhD scholarship. This work has been performed within the frame of the European COST Action D38 “Metal-Based Systems for Molecular Imaging Applications”.