Complexation Properties of N,N′,N″,N′′′‐[1,4,7,10‐Tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(1‐oxoethane‐2,1‐diyl)]tetrakis[glycine] (H4dotagl). Equilibrium, Kinetic, and Relaxation Behavior of the Lanthanide(III) Complexes

Abstract

AbstractEu3+, 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] (H4dotagl) are potential CEST contrast agents in MRI. In the [Ln(dotagl)] complexes, the Ln3+ 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 (H4dota=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°, then increase between 30–50°. 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(H4dotagl)] (k1=8.1⋅10−6 M−1 s−1) than for [Eu(dota)] (k1=1.4⋅10−5 M−1 s−1).