Towards extracellular Ca2+ sensing by MRI: synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexes

Abstract : Two new bismacrocyclic Gd3+ chelates containing a specific Ca2+ binding site were synthesized as potential MRI contrast agents for the detection of Ca2+ concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca2+-sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L1) or by a propylene (L2) unit [H4BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; H3DO3A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd3+ complexes towards Ca2+ and Mg2+ was studied by 1H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca2+ binding to Gd2L1 and Gd2L2, respectively, with a distinct selectivity of Gd2L1 towards Ca2+ compared with Mg2+. For Ca2+ binding, association constants of log K = 1.9 (Gd2L1) and log K = 2.7 (Gd2L2) were determined by relaxometry. Luminescence lifetime m easureme nts and UV–vis spectrop hotometry on the corresponding Eu3+ analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca2+ binding in the central part of the ligand induces the formation of the monohydrated state. The increasing hydration number accounts for the relaxivity increase observed on Ca2+ addition. A 1H nuclear magnetic relaxation dispersion and 17O NMR study on Gd2L1 in the absence and in the presence of Ca2+ was performed to assess the microscopic parameters influencing relaxivity. On Ca2+ binding, the water exchange is slightly accelerated, which is likely related to the increased steric demand of the central part leading to a destabilization of the Ln–water binding interaction. Electronic supplementary material The online version of this article (doi:10.1007/s00775-007-0296-9) contains supplementary material, which is available to authorized users.
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Submitted on : Thursday, May 29, 2008 - 3:16:54 PM
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Kirti Dhingra, Petra Fousková, Goran Angelovski, Martin E. Maier, Nikos K. Logothetis, et al.. Towards extracellular Ca2+ sensing by MRI: synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexes. Journal of Biological Inorganic Chemistry, Springer Verlag, 2008, 13 (1), pp.35-46. ⟨10.1007/s00775-007-0296-9⟩. ⟨hal-00283262⟩

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