Dissociation kinetics of Mn2+ complexes of NOTA and DOTA

The kinetics of transmetallation of [Mn(nota)](-) and [Mn(dota)](2-) was investigated in the presence of Zn2+ (5-50-fold excess) at variable pH (3.5-5.6) by H-1 relaxometry. The dissociation is much faster for [Mn(nota)](-) than for [Mn(dota)](2-) under both experimental and physiologically relevant conditions (t(1/2) = 74 h and 1037 h for [Mn(nota)](-) and [Mn(dota)](2-), respectively, at pH 7.4, c(Zn2+) = 10(-5) M, 25 degrees C). The dissociation of the complexes proceeds mainly via spontaneous ([Mn(nota)](-) k(0) = (2.6 +/- 0.5) x 10 (6) s (1); [Mn(dota)](2) k(0) = (1.8 +/- 0.6) x 10 (7) s (1)) and proton-assisted pathways ([Mn(nota)] k(1) = (7.8 +/- 0.1) x 10(-1) M-1 s(-1); [Mn(dota)](2-) k(1) = (4.0 +/- 0.6) 10(-2) M-1 s(-1), k(2) = (1.6 +/- 0.1) 10(3) M-2 s(-1)). The observed suppression of the reaction rates with increasing Zn2+ concentration is explained by the formation of a dinuclear Mn2+-L-Zn2+ complex which is about 20-times more stable for [Mn(dota)](2-) than for [Mn(nota)](-) (K-MnLZn = 68 and 3.6, respectively), and which dissociates very slowly (k(3) similar to 10(-5) M-1 s(-1)). These data provide the first experimental proof that not all Mn2+ complexes are kinetically labile. The absence of coordinated water makes both [Mn(nota)](-) and [Mn(dota)](2-) complexes inefficient for MRI applications. Nevertheless, the higher kinetic inertness of [Mn(dota)](2-) indicates a promising direction in designing ligands for Mn2+ complexation.