Paramagnetic 19F Relaxation Enhancement in Nickel(II) Complexes of N-Trifluoroethyl Cyclam Derivatives and Cell Labeling for 19F MRI
Abstract
1,8-Bis(2,2,2-trifluoroethyl)cyclam (te2f) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (H2te2f2a), methylenephosphonic acid (H4te2f2p), (2-pyridyl)methyl (te2f2py), and 2-aminoethyl arms (te2f2ae) in 4,11-positions were prepared, and their nickel(II) complexes were investigated as possible (19)F MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by Xray diffraction analysis.
The average Ni...F distances were determined to be about 5.2 angstrom. All complexes exhibit a trans-III cyclam conformation with pendant arms bound in the apical positions.
Kinetic inertness of the complexes is increased in the ligand order te2f2ae << te2f < te2f2py ~ H4te2f2p << H2te2f2a. The [Ni(te2f2a)] complex is the most kinetically inert Ni(II) complex reported so far.
Paramagnetic divalent nickel caused a shortening of (19)F NMR relaxation time down to the millisecond range. Solubility, stability, and cell toxicity were only satisfactory for the [Ni(te2f2p)](2-) complex This complex was visualized by (19)F MRI utilizing an ultrashort echo time (UTE) imaging pulse sequence, which led to an increase in sensitivity gain.
Mesenchymal stem cells were successfully loaded with the complex (up to 0.925/5.55 pg Ni/F per cell). (19)F MRI using a UTE pulse sequence provided images with a good signal-to-noise ratio within the measurement time, as short as tens of minutes. The data thus proved a major sensitivity gain in (19)F MRI achieved by utilization of the paramagnetic (transition) metal complex as (19)F MR tracers coupled with the optimal fast imaging protocol.