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

Three novel GdD03A-type bismacrocyclic complexes, conjugated to Ca 2+ 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 Gd 2L3, 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-({[({α-[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 log KA = 3.6 ± 0.1 for Gd2L 1 and log KA = 3.4 ± 0.1 for Gd2L 3. For the interaction between Mg2+ and Gd 2L1, log KA = 2.7 ± 0.1 has been determined, while no relaxivity change was detected with Gd2L 3. 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 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 (k ex298 = 80 × 106 s-1); in any case, it is not sensitive to the presence of Ca2+. The rotational correlation time, τR298, differs for the three complexes and reflects their rigidity. Due to the benzene linker, the Gd 2L2 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). On the basis of all available experimental data from luminescence, 17O NMR, and NMRD studies on the Eu3+ and Gd3+ complexes of L1 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. © 2008 American Chemical Society.