A Eu^II‐Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

Abstract

EuII rivals GdIII in its ability to enhance contrast in magnetic resonance imaging; however, all reported EuII-based complexes have been studied in vitro largely because the tendency of EuII to oxidize to EuIII has been viewed as a major obstacle to in vivo imaging. Here, we present solid- and solution-phase characterization of a EuII-containing cryptate and first in vivo use of EuII to provide contrast enhancement. The results are indicative of a water-coordination number between one and two upon dissolution and are a demonstration of the ability to observe EuII-based contrast enhancement for hours in a mouse.

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

“…9 The oxygen-sensitive nature of the complex is expected to permit the differentiation of necrotic tissue while oxidizing elsewhere. Additionally, we recently demonstrated the transitory behavior of Eu II in vivo in a report evaluating Eu II after intravenous, intraperitoneal, and subcutaneous injections.…”

“…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 …”

“…9 The persistence of Eu II within the necrotic tissue allowed the visualization of necrotic tissue using positive contrast enhancement. To highlight the positive contrast enhancement provided by Eu II in vivo, we have assembled previously unpublished data from these studies to create web-enhanced objects for this forum article (Figure 1).…”

Evaluation of EuII‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

“…The Gd III ion has dominated the clinical landscape and preclinical research in MRI because it provides excellent T 1 ‐shortening (positive) contrast enhancement , but Gd III is restricted to the +3 oxidation state under physiological conditions preventing metal‐based redox responses . The Eu II ion is isoelectronic with Gd III (4f 7 ), and both ions provide positive contrast enhancement in MRI . Additionally, Eu II can be oxidized by one electron to produce the Eu III ion that does not enhance positive contrast .…”

Oxidative Conversion of a Europium(II)‐Based T1 Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

“…They generate image contrast by shortening the longitudinal (T 1 )relaxation time of bulk water protons.T he efficiencyo faT 1 agent is defined by r 1 relaxivity,w hich is dependent on several parameters,i ncluding the metal bound water exchange rate, rotational correlation time of the complex, and the electronic relaxation time of the metal ion. [4,5] Eu 2+ complexes have been proposed as redox sensitive T 1 agents, [3,5,6] because oxidation of Eu 2+ leads to the formation of weakly paramagnetic Eu 3+ ,w hich has little impact on water proton T 1 .T he Eu 3+ ion however generates am oderately strong magnetic dipolar field that produces large hyperfine shifts of NMR signals of nearby ligand protons.W hile Eu 3+ complexes are very poor T 1shortening agents,E u 3+ DOTAt etra(amides) (Figure 1) belong to ac onceptually different class of MRI contrast agents,k nown as paraCEST agents that alter image contrast by transferring selectively saturated spins from ah ighly shifted small pool of proton spins (metal-bound water) to the bulk water pool. [2] Both ions have a4f 7 electron configuration and asymmetric 8 S 7/2 ground state but Eu 2+ complexes in general display much faster water exchange rates and faster electronic relaxation times.…”