Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood

Abstract

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is La, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Fe, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T) of the fluorine nuclei. The shorter T allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T/T ratio. In water, the optimal metal complexes for imaging applications are those containing Ho and Fe, and to a lesser extent Tm and Yb. Whereas T of the lanthanide complexes are little affected by blood, the T are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, Ho-DOTAm-F12, could not be detected in blood. Tm yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of Fe-DOTAm-F12 are similar in water and in blood. That complex has the highest T/T ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T/T of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

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.…”

“…Recently, our lab reported the relaxation properties of the Fe II and Ln III complexes of another macrocyclic ligand, DOTAm-F12 ( 12 ) (Srivastava et al, 2017a , b ). Complexes of this series, including the Fe II complex, have a number of advantageous properties for 19 F imaging.…”

Fluorinated EuII-based multimodal contrast agent for temperature- and redox-responsive magnetic resonance imaging

“… 16 , 17 , 19 Eu II is isoelectronic with Gd III , which is commonly used in contrast agents for MRI. Fluorinated Gd III -containing complexes influence the signal of 19 F in a distance-dependent manner; 22 – 28 consequently, we hypothesized that introducing 19 F nuclei near Eu II would cause severe line-broadening ( via shortening of the transverse relaxation time of 19 F) to the point of no observable signal. However, unlike Gd III that is not redox-active in vivo , oxidation of Eu II to Eu III would be expected to remove quenching of 19 F signal.…”

Cyclotriphosphazene, a scaffold for 19 F MRI contrast agents

“…It is noteworthy that the T 2 /T 1 ratio is above 0.9 for compound 1 at all testing conditions, highlighting the good 19 F MR imaging sensitivity. 12 The 19 F T 1 of 1 is significantly shorter than the majority of fluorinated small compounds, such as trifluoroethanol (TFE), under same conditions (~1500 vs. ~2400 ms). 13 From a sensitivity point of view, a shorter T 1 allows for a greater number of scans to be obtained in an equivalent time frame and thus better sensitivity.…”