Hypoxia-Responsive ¹⁹F MRI Probes with Improved Redox Properties and Biocompatibility

Abstract

F magnetic resonance imaging (MRI), an emerging modality in biomedical imaging, has shown promise for in vitro and in vivo preclinical studies. Here we present a series of fluorinated Cu(II)ATSM derivatives for potential use as F magnetic resonance agents for sensing cellular hypoxia. The synthesized complexes feature a hypoxia-targeting Cu coordination core, nine equivalent fluorine atoms connected via a variable-length poly(ethylene glycol) linker. Introduction of the fluorine moiety maintains the planar coordination geometry of the Cu center, while the linker length modulates the Cu reduction potential, F NMR relaxation properties, and lipophilicity. In particular, theF NMR relaxation properties were quantitatively evaluated by the Solomon-Bloembergen model, revealing a regular pattern of relaxation enhancement tuned by the distance between Cu and F atoms. Finally, the potential utility of these complexes for sensing reductive environments was demonstrated using both F MR phantom imaging andF NMR, including experiments in intact live cells.

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

“…Reduction of CuATSM-F 3 ( 37 , Figure 9A ) from Cu II (d 9 , paramagnetic) to Cu I (d 10 , diamagnetic) and subsequent ligand dissociation increases T 2 of the 19 F and restores their signal intensity. A second generation version of this probe ( 38 ) was designed to be more sensitive (Xie et al, 2017 ). It includes a higher density of 19 F nuclei, a polyethylene glycol linker that increases the hydrophilicity of the probe and positions the 19 F nuclei at an optimal distance from the copper ion.…”

“…With a 19 F–Cu distance of ~ 18 Å, the 19 F signal is attenuated but remains visible by NMR when the probe is in the Cu II state. Reduction to Cu I generates a sharp signal which is 6-fold more intense, leading to a 4.5-fold increase in SNR in the 19 F MRI images obtained at 7 T. The large differences in relaxation times between the two species allow them to be independently imaged using short (TE = 10 ms for Cu II ) or long (TE = 100 ms for Cu I ) echo pulse sequences (Xie et al, 2017 ).…”

“… Responsive fluorine probes which function by altering either (A) the oxidation state of a redox active metal ( 35 , Tanaka et al, 2009 ; 36 , Kitamura et al, 2012 ; 37 , Xie et al, 2016 ; 38 , Xie et al, 2017 ; 39 , Basal et al, 2017 ; 40 , Yu et al, 2016 ) or (B) the spin state of Fe II ( 41–42 , Thorarinsdottir et al, 2017 ). …”

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

“…[14][15][16][17][18][19][20] Due to the instability of PFCe mulsions, [21,22] encapsulating PFCs into alginatec apsuleso rs ilica nanoparticles has recently been pursued. [23][24][25][26][27] Lastly,h ypoxia-responsive 19 F probesu tilizing paramagnetic relaxation enhancement (PRE) have been shown to accumulate selectively in hypoxic cells, [28][29][30][31] but the low loading of 19 Fn uclei limits their sensitivity.…”

Towards an MMP-2-activated molecular agent for cancer imaging

“…12 Several responsive MRI agents based on different NMR nuclei have been previously reported. [13][14][15] In particular, 19 F MRI probes have been used for sensing cellular hypoxia, 16 detection of protein-protein interactions 17 as well as MMP-2 activity. 18 Scheme 1 -Proposed mode of action of MMP-2 probe with either 68 Ga or Gd…”