Facile synthesis and relaxation properties of novel bispolyazamacrocyclic Gd3+ complexes: An attempt towards calcium-sensitive MRI contrast agents

Three novel GdDO3A-type bismacrocyclic complexes, conjugated to Ca2+ chelating moieties like ethylenediamine-tetraacetic acid and diethylenetriamine pentaacetic acid bisamides, were synthesized as potential "smart" magnetic resonance imaging contrast agents. Their sensitivity toward 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 (L-1 = 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; L-2 = N,N-bis[1-({[((cx-[1,4,7-tris(carboxymethyl)-1,4,7,10tetraazacyclododecane-l0-yl]-p-tolylamino}carbonyl)methyl]-(carboxymethyl)]amino)eth-2-yl]aminoacetic acid; L-3 = 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 log K-A = 3.6 +/- 10.1 for Gd2L1 and log K-A = 3.4 +/- 0.1 for Gd2L3. For the interaction between Mg2+ and Gd2L1, log K-A = 2.7 +/- 0.1 has been determined, 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 nuclear magnetic relaxation dispersion (NMRD) and O-17 NMR study. Water exchange is relatively slow on Gd2L1 and Gd2L2 (k(ex)(298) = 0.5 and 0.8 x 10(6) s(-1)), while it is faster on Gd2L3 (k(ex)(298) = 80 x 10(6) s(-1)); in any case, it is not sensitive to the presence of Ca2+. The rotational correlation time, tau(298)(R), 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 (r(1) = 10.2 mM(-1)s(-1) at 60 MHz, 298 K). On the basis of all available experimental data from luminescence, O-17 NMR, and NMRD studies on the Eu3+ and Gd3+ complexes of L-1 and L-3 in the absence and in the 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.