Paramagnetic19F Relaxation Enhancement in Nickel(II) Complexes ofN-Trifluoroethyl Cyclam Derivatives and Cell Labeling for19F 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 19 F MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by X-ray diffraction analysis. The average Ni···F distances were determined to be about 5.2 Å. 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 ≈ 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 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.