Towards extracellular Ca(2+) sensing by MRI: synthesis and calcium-dependent (1)H and (17)O relaxation studies of two novel bismacrocyclic Gd(3+) complexes

Two new bismacrocyclic Gd(3+) chelates containing a specific Ca(2+) binding site were synthesized as potential MRI contrast agents for the detection of Ca(2+) concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca(2+)-sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L(1)) or by a propylene (L(2)) unit [H(4)BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; H(3)DO(3)A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd(3+) complexes towards Ca(2+) and Mg(2+) was studied by (1)H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca(2+) binding to Gd(2)L(1) and Gd(2)L(2), respectively, with a distinct selectivity of Gd(2)L(1) towards Ca(2+) compared with Mg(2+). For Ca(2+) binding, association constants of log K = 1.9 (Gd(2)L(1)) and log K = 2.7 (Gd(2)L(2)) were determined by relaxometry. Luminescence lifetime measurements and UV–vis spectrophotometry on the corresponding Eu(3+) analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca(2+) 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 Ca(2+) addition. A (1)H nuclear magnetic relaxation dispersion and (17)O NMR study on Gd(2)L(1) in the absence and in the presence of Ca(2+) was performed to assess the microscopic parameters influencing relaxivity. On Ca(2+) 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.