Responsive lanthanide complexes for metal ion sensing

Abstract

The speciation and distribution of zinc (II) within cells is not well established and the range of zinc (II) probes available are of limited use. The quest was to develop responsive lanthanide complexes to bind selectively and respond (by change in hydration state) to biologically relevant concentrations of zinc at physiological pH for possible application in MRI and luminescence. A pyridyl sulfonamide ligand with an a-CH(_2)NHSO(_2)CF(_3) substituent was found to have the desired properties for strong zinc (II) coordination. The presence of a methyl group at 6', inhibited the formation of related square planar copper (II) complexes. Pyridyl amide appended europium and gadolinium (III) complexes, based on cyclen were developed with C(_2) and (C_3) spacers separating the macrocyclic ring and the amide. The mono-aqua C(_2) complex exhibited fast water exchange, due to the steric hindrance of the seven-membered chelate between the amide carbonyl and the lanthanide centre. The increase in steric hindrance caused by the eight-ring chelate in the C(_3) analogue rendered it q = 0. A trifluoromethanesulfonamide moiety at the 6' position of the pyridine group resulted in a mono-aqua complex for the C(_2) and C(_3) appended systems. This system showed no change in hydration state on addition of Zn(^2+). The addition of a-N- carboxyalkyl groups to give a GdaD03A system resulted in the formation of q = 2 complexes which showed no zinc (II) responsive properties. However, the C(_2)- linked species exhibited a high binding affinity to HSA which resulted m a dramatic increase in the relaxivity. Eu and Gd complexes of an octadentate N(_5)O(_3) pyridyl sulfonamide containing ligand were developed as pH and pZn responsive probes. The pyridyl nitrogen bound irreversibly to the lanthanide centre, resisting protonation even in the presence of zinc and copper ions, for which the pyridyl sulfonamide group has an establiblished high affinity.