The chemistry of the less familiar elements is a fascinating topic especially for the inorganic minded. The lanthanides, or rare earths, comprise the 5d block of the periodic table and represent a huge array of applications from catalysis to lasers, and of course, imaging agents.1

Recent advances in luminescence and magnetic resonance microscopy have, in part, been stimulated by extraordinary success in the development of new lanthanide probes. The unique properties of the lanthanides provide for a deep tool chest for the chemist, biologist and the imaging scientist to exploit, and that exploitation is in full swing.

In this review we focus on two classes of lanthanide probes that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides. In Section 2 we discuss the general design and photophysical properties of lanthanides and how these parameters are tuned to develop bioresponsive probes for optical imaging. In Section 3 we provide a brief description of how MR images are acquired and the how MRI contrast agents are engineered to respond to biological events of interest. These guiding principles have driven research that has produced a truly diverse number of new agents that are target specific and bioresponsive (or bioactivatable). While other imaging modalities utilize lanthanide-based probes, these topics are beyond the scope of this review. We direct the reader to explore some excellent reviews in the important areas of radiometals and multimodal imaging.2–5

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Lanthanide probes for bioresponsive imaging.

Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

Chemical exchange saturation transfer (CEST) has emerged as a novel MRI contrast mechanism that is well suited for molecular imaging studies This new mechanism can be used to detect small amounts of contrast agent through the saturation of rapidly exchanging protons on these agents, allowing a wide range of applications CEST technology has a number of indispensable features, such as the possibility of simultaneous detection of multiple 'colors' of agents and of changes in their environment (eg pH, metabolites, etc) through MR contrast Currently, a large number of new imaging schemes and techniques are being developed to improve the temporal resolution and specificity and to correct for the influence of B0 and B1 inhomogeneities In this review, the techniques developed over the last decade are summarized with the different imaging strategies and post-processing methods discussed from a practical point of view, including the description of their relative merits for the detection of CEST agents The goal of the present work is to provide the reader with a fundamental understanding of the techniques developed, and to provide guidance to help refine future applications of this technology This review is organized into three main sections ('Basics of CEST contrast', 'Implementation' and 'Post-processing'), and also includes a brief Introduction and Summary The 'Basics of CEST contrast' section contains a description of the relevant background theory for saturation transfer and frequency-labeled transfer, and a brief discussion of methods to determine exchange rates The 'Implementation' section contains a description of the practical considerations in conducting CEST MRI studies, including the choice of magnetic field, pulse sequence, saturation pulse, imaging scheme, and strategies to separate magnetization transfer and CEST The 'Post-processing' section contains a description of the typical image processing employed for B0 /B1 correction, Z-spectral interpolation, frequency-selective detection and improvement of CEST contrast maps

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Nuts and bolts of chemical exchange saturation transfer MRI

This tutorial review highlights progress in the development of responsive magnetic resonance imaging (MRI) contrast agents for detecting and sensing biologically relevant metal ions. Molecular imaging with bioactivatable MRI indicators offers a potentially powerful methodology for studying the physiology and pathology of metals by capturing dynamic three-dimensional images of living systems for research and clinical applications. This emerging area at the interface of inorganic chemistry and the life sciences offers a broad palette of opportunities for researchers with interests ranging from coordination chemistry and spectroscopy to supramolecular chemistry and molecular recognition to metals in biology and medicine.

https://faculty.missouri.edu/~glaserr/3700s11/Ind-Comp_2010_Que.pdf

Responsive magnetic resonance imaging contrast agents as chemical sensors for metals in biology and medicine

The synthesis of a novel Tb(III) luminescent probe for the detection of thiols is presented. The probe 1.Tb, possessing a maleimide moiety, as its sulfhydryl acceptor, was poorly emitting in aqueous pH 7 solution in the absence of a thiol. However, upon addition of thiols such as glutathione (GSH), large enhancements were observed, particularly within the physiological pH range. In contrast no enhancements were observed in the presence of the oxidized form of glutathione (GSSG), except in the presence of the enzyme glutathione reductase and NADPH which enabled 1.Tb to be used to observe the enzymatic reduction of GSSG to GSH in real time.

Selective detection of the reduced form of glutathione (GSH) over the oxidized (GSSG) form using a combination of glutathione reductase and a Tb(III)-cyclen maleimide based lanthanide luminescent 'switch on' assay.

The properties of a novel Gd3+-based MRI zinc sensor are reported. Unlike previously reported Gd3+-based MRI contrast agents, this agent (GdL) differs in that the agent alone binds only weakly with human serum albumin (HSA), while the 1:2 GdL:Zn2+ ternary complex binds strongly to HSA resulting in a substantial, 3-fold increase in water proton relaxivity. The GdL complex is shown to have a relatively strong binding affinity for Zn2+ (KD = 33.6 nM), similar to the affinity of the Zn2+ ion with HSA alone. The agent detects as little as 30 μM Zn2+ in the presence of HSA by MRI in vitro, a value slightly more than the total Zn2+ concentration in blood (∼20 μM). This combination of binding affinity constants and the high relaxivity of the agent when bound to HSA suggests that this new agent may be useful for detection of free Zn2+ ions in vivo without disrupting other important biological processes involving Zn2+.

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A new gadolinium-based MRI zinc sensor.

A Zn2+ specific GdDOTA derivative containing two bis-(3-pyrazolyl) units was prepared and characterized. Unlike a previously reported Zn2+ binding agent, the new agent binds to human albumin both in the presence and absence of Zn2+.

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A second generation MRI contrast agent for imaging zinc ions in vivo

C–Br bond activation followed by a C–C coupling reaction of the 2-bromo-pyridyl unit of [1-phenyl-2-(6-bromopyridin-2-yl)-benzoimidazole] was performed by Pd(CH2CMe2-o-C6H4)(η4-COD). Two new seven membered palladacycles were obtained. A combined experimental and theoretical DFT study elucidates the mechanism for this reaction.

Gabriel Andreu-de-Riquer

Papers

A new gadolinium-based MRI zinc sensor.

A second generation MRI contrast agent for imaging zinc ions in vivo

New seven membered palladacycles: C–Br bond activation of 2-bromo-pyridine derivative by Pd(II)

Ni(II) and Pd(II) organometallic and coordination complexes with a new tridentate N,N,O-donor ligand