Paramagnetic 19F Relaxation Enhancement in Nickel(II) Complexes of N-Trifluoroethyl Cyclam Derivatives and Cell Labeling for 19F MRI

1,8-Bis(2,2,2-trifluoroethyl)cyclam (te2f) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (H(2)te2f2a), methylenephosphonic acid (H(4)te2f2p), (2-pyridyl)methyl (te2f2py), and 2-aminoethyl arms (te2f2ae) in 4,11-positions were prepared, and their nickel(II) complexes were investigated as possible F-19 MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by Xray diffraction analysis. The average Ni center dot center dot center dot 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 approximate to H(4)te2f2p << H(2)te2f2a. The [Ni(te2f2a)] complex is the most kinetically inert Ni(II) complex reported so far. Paramagnetic divalent nickel caused a shortening of F-19 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 F-19 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). F-19 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 F-19 MRI achieved by utilization of the paramagnetic (transition) metal complex as F-19 MR tracers coupled with the optimal fast imaging protocol.