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

1,8-Bis(2,2,2-trifluoroethyl)cyclam (te2f) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (Hte2f2a), methylenephosphonic acid (Hte2f2p), (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 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 ≈ Hte2f2p ≪ Hte2f2a. The [Ni(te2f2a)] complex is the most kinetically inert Ni(II) complex reported so far. Paramagnetic divalent nickel caused a shortening of F NMR relaxation time down to the millisecond range. Solubility, stability, and cell toxicity were only satisfactory for the [Ni(te2f2p)] complex. This complex was visualized by 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).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 F MRI achieved by utilization of the paramagnetic (transition) metal complex as F MR tracers coupled with the optimal fast imaging protocol.