Eight-Coordinate, Stable Fe(II) Complex as a Dual ¹⁹F and CEST Contrast Agent for Ratiometric pH Imaging

Abstract

Accurate mapping of small changes in pH is essential to the diagnosis of diseases such as cancer. The difficulty in mapping pH accurately in vivo resides in the need for the probe to have a ratiometric response so as to be able to independently determine the concentration of the probe in the body independently from its response to pH. The complex Fe-DOTAm-F12 behaves as an MRI contrast agent with dual F and CEST modality. The magnitude of its CEST response is dependent both on the concentration of the complex and on the pH, with a significant increase in saturation transfer between pH 6.9 and 7.4, a pH range that is relevant to cancer diagnosis. The signal-to-noise ratio of theF signal of the probe, on the other hand, depends only on the concentration of the contrast agent and is independent of pH. As a result, the complex can ratiometrically map pH and accurately distinguish between pH 6.9 and 7.4. Moreover, the iron(II) complex is stable in air at room temperature and adopts a rare 8-coordinate geometry.

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

“… 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 ). …”

“…A single isomer for a tetra-substituted DOTA complex which exploits the symmetry of the ligand in order to maximize the number of equivalent fluorines can nonetheless be obtained. Examples include M-DOTAm-F12 (2,2′,2″,2 ‴ -(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(N-(2,2,2-trifluoroethyl)acetamide)) (12, Figure 1 ; Srivastava et al, 2017a , b ) and more recently the redox-responsive Eu-complex 39 (Figure 9 ) (Basal et al, 2017 ). Both of these complexes contain 12 19 F nuclei linked to the macrocycle via four amide arms.…”

Non‐Macrocyclic Schiff Base Complexes of Iron(II) as ParaCEST Agents for MRI

“…Many paraCEST agents use electronically anisotropic lanthanide ions installed into macrocyclic ligands appended with exchangeable OH, NH, or C(O)NH 2 functionalities . The smaller number of transition metal paraCEST agents employ similar appended macrocycles; exceptions include a few Fe II compounds,, a Co II complex, a Ni II complex, and a ferromagnetically coupled bimetallic Cu II dimer . Transition metal paraCEST agents are primarily sought to eliminate the use of Ln III based contrast agents.…”

CEST‐MRI for glioma pH quantification in mouse model: Validation by immunohistochemistry

“…The MRI contrast of these probes can be analyzed by using a ratiometric approach, thanks to which pHe can be assessed independently of knowing the actual probe concentration . Both diamagnetic and paramagnetic CEST molecules have been reported for such applications …”

“…29 Both diamagnetic and paramagnetic CEST molecules have been reported for such applications. [30][31][32][33][34][35][36] Recently, YbHPDO3A (ytterbium 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane) has been investigated for this purpose. 37 This chemical compound is analogous to a clinically approved molecule (GdHPDO3A, gadolinium 1,4,7-triscarboxymethyl-1,4,7,10tetraazacyclododecane, ProHance from Bracco Imaging) in which gadolinium (Gd) is replaced by ytterbium (Yb).…”