Evaluation of Eu^II‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

Abstract

EuII-based contrast agents offer physiologically relevant, metal-based redox sensing that is unachievable with GdIII-based contrast agents. To evaluate the in vivo contrast enhancement of EuII as a function of injection type, we performed intravenous, intraperitoneal, and subcutaneous injections in mice. Our data reveal a correlation between reported oxygen content and expected rates of diffusion with the persistence of EuII-based contrast enhancement. Biodistribution studies revealed europium clearance through the liver and kidneys for intravenous and intraperitoneal injections, but no contrast enhancement was observed in organs associated with clearance. These data represent a step toward understanding the behavior of EuII-based complexes in vivo.

Spectroscopic Characterization of the 3+ and 2+ Oxidation States of Europium in a Macrocyclic Tetraglycinate Complex

“…20 We hypothesized that upon reduction of Eu III -DOTA-4AmC to Eu II -DOTA-4AmC, the Eu II ion would relax the nuclear dipole moments of nearby protons resulting in the complete quenching of saturation transfer effects. Instead of CEST contrast, we expected Eu II -DOTA-4AmC to enhance contrast in T 1 -weighted MRI in accordance with previously reported Eu II -based complexes: 8–10,15–17 Eu II -DOTA-4AmC would provide positive contrast enhancement until it was oxidized to Eu III -DOTA-4AmC, at which point it would display CEST contrast (Figure 2). Here, we present luminescence, electron paramagnetic resonance (EPR), NMR, and UV–visible spectroscopic data characterizing the conversion from the +3 to +2 and +2 to +3 oxidation states of Eu III/II -DOTA-4AmC.…”

“…We are interested in studying aqueous Eu II -containing complexes because they are redox-active complexes relevant to responsive magnetic resonance imaging (MRI). 8–10 …”

“…The Eu II ion can undergo a one-electron oxidation to the +3 oxidation state that does not noticeably influence positive contrast enhancement, 8,9 and we recently reported the first use of Eu II -containing complexes as redox-active contrast agents in vivo. 9,10 …”

The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

“…[5,6] Additionally, 1 -Eu II , EuCl 2 (aq), and 2 -Eu II encompass a relatively wide range in reduction potentials (Table 1) with 1 -Eu II being 374 mV more negative than EuCl 2 (aq) [7] and 2 -Eu II being 547 mV more positive than EuCl 2 (aq). [17] Although we have observed rapid oxidation of Eu II by gaseous diatomic molecules, such as O 2 and NO, we elected to study reaction kinetics with non-gaseous oxidants for the ease of quantifying and handling in an inert atmosphere.…”

“…Before performing kinetic measurements, we studied a fundamental reaction between EuCl 2 and O 2 to determine if an oxygen-containing product could be identified. Given the in vivo correlation between tissue p O 2 and the persistence of Eu II -based positive contrast enhancement, [5,6] these studies are important for rationalizing Eu II oxidation-responses.…”