Complexation properties of N,N ',N '',N '''-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayltetrakis(1-oxoethane-2,1-diyl)]tetrakis[glycine] (H(4)dotagl). Equilibrium, kinetic, and relaxation behavior of the lanthanide(III) complexes

Eu3+,Dy3+, and Yb3+ complexes of the dota-derived tetramide N,N ',N '',N '''-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayltetrakis(1-oxoethane-2,1-diyl)]tetrakis[glycine] (H(4)dotagl) are potential CEST contrast agents in MRI. In the [Ln(dotagl)] complexes, the Ln(3+) ion is in the cage formed by the four ring N-atoms and the amide O-atom donor atoms, and a H2O molecule occupies the ninth coordination site. The stability constants of the [Ln(dotagl)] complexes are ca. 10 orders of magnitude lower than those of the [Ln(dota)] analogues (H(4)dota = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The free carboxylate groups in [Ln(dotagl)] are protonated in the pH range 1-5, resulting in mono-, di-, tri-, and tetraprotonated species. Complexes with divalent metals (Mg2+, Ca2+, and Cu2+) are also of relatively low stability. At pH > 8, Cu2+ forms a hydroxo complex; however, the amide H-atom(s) does not dissociate due to the absence of anchor N-atom(s), which is the result of the rigid structure of the ring. The relaxivities of [Gd(dotagl)] decrease from 10 to 25 degrees, then increase between 30-50 degrees. This unusual trend is interpreted with the low H2O-exchange rate. The [Ln(dotagl)] complexes form slowly, via the equilibrium formation of a monoprotonated intermediate, which deprotonates and rearranges to the product in a slow, OH--catalyzed reaction. The formation rates are lower than those for the corresponding Ln(dota) complexes. The dissociation rate of [Eu(dotagl)] is directly proportional to [H+] (0.1 - 1.0m HClO4); the proton-assisted dissociation rate is lower for [Eu(H(4)dotagl)] (k(1) = 8.1 (.) 10(-6) m(-1) s(-1)) than for [Eu(dota)] (k(1) = 1.4 (.) 10(-5) m(-1) s(-1)).