Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain. Upon interaction with Ca2+, they exhibit high and reversible relaxivity changes in buffered solution or in a model of the brain extracellular medium. These efficient Ca2+ magnetic resonance imaging sensors might open new perspectives in functional molecular imaging

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 0 ,N 0 -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.

The replacement of an acetate function of the macrocyclic DOTA4-(DO3A-Nprop4-) or the acyclic DTPA5- in terminal position (DTTA-Nprop5-) has been recently shown to result in a significant increase of the water exchange rate on the Gd3+ complexes, which makes these chelates potential contrast agents for MRI applications. Here, two novel and straightforward synthetic routes to H4DO3A-Nprop are described. Protonation constants of DO3A-Nprop4- and stability constants with several alkaline earth and transition metal ions have been determined by potentiometry. For each metal, the thermodynamic stability constant is decreased in comparison to the DOTA chelates. The formation reaction of LnDO3A-Nprop- complexes (Ln=Ce, Gd and Yb) proceeds via the rapid formation of a diprotonated intermediate and its subsequent deprotonation and rearrangement in a slow, OH- catalyzed process. The stability of the LnH2DO3A-Nprop* intermediates is similar to those reported for the corresponding DOTA analogues. The rate constants of the OH- catalyzed deprotonation step increase with decreasing lanthanide ion size, and are slightly higher than for DOTA complexes. The kinetic inertness of GdDTTA-Nprop2- was characterized by the rates of its exchange reactions with Zn2+ and Eu3+. The rate of the reaction between GdDTTA-Nprop2- and Zn2+ increases with Zn2+ concentration, while it is independent of pH, implying that the exchange takes place predominantly via direct attack of the metal ion on the complex. In the Eu3+ exchange, the rate decreases with increasing concentration of the exchanging ion which is accounted for by the transitional formation of a dinuclear GdDTTA-NpropEu+ species. The kinetic inertness of the monopropionate GdDTTA-Nprop2- is decreased in comparison to GdDTPA2-: all rate constants, characterizing the dissociation reaction via either proton- or metal-catalyzed pathways being higher by 1-2 orders of magnitude. Similarly, a study of the acid-catalyzed dissociation of the macrocyclic CeDO3A-Nprop- showed a partial loss of the kinetic inertness with regard to the tetraacetate derivative CeDOTA-.