Facile Synthesis and Relaxation Properties of Novel Bis-polyazamacrocyclic Gd3+ Complexes: an Attempt towards Calcium Sensitive MRI Contrast Agents
Résumé
Three novel GdDO3A-type bismacrocyclic complexes, conjugated to Ca2+ chelating moieties like EDTA- and DTPA-bisamides, were synthesized as potential ‘smart' MRI contrast agents. Their sensitivity towards Ca2+ was studied by relaxometric titrations. A maximum relaxivity increase of 15, 6 and 32 % was observed upon Ca2+ binding for Gd2L1, Gd2L2 and Gd2L3, respectively (L1 = N,N-bis{1-[{[({1-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]eth-2-yl}amino)carbonyl]methyl}-(carboxymethyl)amino]eth-2-yl}aminoacetic acid; L2 = N,N-bis[1-({[({alpha-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]-p-tolylamino}carbonyl)methyl]-(carboxymethyl)}amino)eth-2-yl]aminoacetic acid; L3 = 1,2-bis[{[({1-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]eth-2-yl}amino)carbonyl]methyl}-(carboxymethyl)amino]ethane). The apparent association constants are logKA = 3.6±0.1 for Gd2L1 and logKA = 3.4±0.1 for Gd2L3. For the interaction between Mg2+ and Gd2L1, logKA = 2.7±0.1 has been det ermined, while no relaxivity change was detected with Gd2L3. Luminescence lifetime measurements on the Eu3+ complexes in the absence of Ca2+ gave hydration numbers of q = 0.9 (Eu2L1), 0.7 (Eu2L2) and 1.3 (Eu2L3). The parameters influencing proton relaxivity of the Gd3+ complexes were assessed by a combined NMRD and 17O NMR study. Water exchange is relatively slow on Gd2L1 and Gd2L2 (kex298 = 0.5 and 0.8106 s-1), while it is faster on Gd2L3 (kex298 = 80106 s-1); in any case, it is not sensitive to the presence of Ca2+. The rotational correlation time, R298, differs for the three complexes and reflects their rigidity. Due to the benzene linker, the Gd2L2 complex is remarkably rigid, with a correspondingly high relaxivity despite the low hydration number (r1 = 10.2 mM-1s-1 at 60 MHz, 298 K). Based on all available experimental data from luminescence, 17O NMR and NMRD studie s on the Eu3 + and Gd3+ c omplexes of L1 and L3 in the absence and presence of Ca2+, we conclude that the relaxivity increase observed upon Ca2+ addition can be mainly ascribed to the increase in the hydration number, and, to a smaller extent, to the Ca2+ induced rigidification of the complex.