Paramagnetic¹⁹F Relaxation Enhancement in Nickel(II) Complexes ofN-Trifluoroethyl Cyclam Derivatives and Cell Labeling for¹⁹F MRI

Abstract

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 asF MR tracers coupled with the optimal fast imaging protocol.

Fluorinated Paramagnetic Complexes: Sensitive and Responsive Probes for Magnetic Resonance Spectroscopy and Imaging

“…As in Parker's study, the paramagnetic metal ions decrease the T 1 of the 19 F nuclei by up to two orders of magnitude with the greatest decrease observed with those metal ions having the highest μ eff , namely Tb III , Dy III , Ho III , and Fe II . Paramagnetic Ni II cyclam complexes featuring trans -trifluoroethyl groups were also recently reported by Blahut et al ( 2016 , 2017 ). The trans- [Ni(te2f2p)] 2− ( 13 , Figure 1 ) with phosphate ligands has a 19 F–Ni distance of ~ 5 Å which facilitates a nearly 180-fold reduction in T 1 vs. the free ligand (Table 2 ).…”

“… Chemical structures of non-responsive paramagnetic 19 F probes ( 1 , Kim et al, 1997 ; 2 , Cakic et al, 2016 ; 3 , Placidi et al, 2013 ; 4 , Chalmers et al, 2010 ; 5–6 , Chalmers et al, 2011a ; 7 , Chalmers et al, 2011a , b ; 8–9 , Davies et al, 2015 ; 10 , Jiang et al, 2011 ; 11 , Chalmers et al, 2010 ; 12 , Srivastava et al, 2017a , b ; 13 , Blahut et al, 2016 , 2017 ). …”

Fluorine polymer probes for magnetic resonance imaging: quo vadis?

“…Various types of fluorinated agents are available in the form of fluorinated perfluorocarbon (PFC) nanoemulsions [37], fluorinated lanthanide chelates [2, 6], fluorinated nucleotides [32], fluoride-based nanocrystals [38], multicompartment amphiphilic polymers [19, 39–41], etc. A brief overview of fluorine-containing probes, including their systematic names, abbreviations, chemical structures, molecular weights and fluorine content, can be found in Table 1.…”

A Trimodal Imaging Platform for Tracking Viable Transplanted Pancreatic Islets In Vivo: F-19 MR, Fluorescence, and Bioluminescence Imaging

“…Other errors in quantification of the F-19 MRI signal may arise from filtering during post-processing, low measurement matrices, and Fourier transform, potentially resulting in partial signal dispersion within the whole measurement matrix [ 29 , 41 ]. To overcome these sensitivity problems and to improve F-19 SNR, various data acquisition methods, such as compressed sensing [ 39 ] and ultrashort echo sequences [ 42 ], have been proposed, which could reduce imaging time while maintaining or even improving the SNR. These advanced methods were not available for our imaging system.…”