Towards extracellular Ca sensing by MRI: Synthesis and calcium-dependent H and O relaxation studies of two novel bismacrocyclic Gd complexes

Two new bismacrocyclic Gd chelates containing a specific Ca binding site were synthesized as potential MRI contrast agents for the detection of Ca concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca-sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L) or by a propylene (L) unit [H BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′- tetraacetic acid; HDOA is 1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd complexes towards Ca and Mg was studied by H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca binding to GdL and GdL, respectively, with a distinct selectivity of GdL towards Ca compared with Mg . For Ca binding, association constants of log K = 1.9 (GdL) and log K = 2.7 (GdL) were determined by relaxometry. Luminescence lifetime measurements and UV-vis spectrophotometry on the corresponding Eu analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca 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 addition. A H nuclear magnetic relaxation dispersion and O NMR study on Gd L in the absence and in the presence of Ca was performed to assess the microscopic parameters influencing relaxivity. On Ca 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. © 2007 SBIC.