A. Sigel, E. Freisinger and R. K. O. Sigel (Editors and Series Editors): Metal Ions in Bio-Imaging Techniques: Volume 22 of the series Metal Ions in Life Sciences

The use of exogenous metal ions as a diagnostic tool dates back to the early 20th century, when orally administered insoluble barium salts were employed as contrast media in X-ray examinations. Since that time, new techniques of bio-imaging using insoluble and soluble metal salts have been developed and research was driven by the remarkable success with these new tools. The new techniques include magnetic resonance imaging (MRI), positron emission tomography (PET), X-ray computed tomography (CT), single photoemission computed tomography (SPECT), and luminescent imaging. For all these methodologies suitable carriers for the metal ions had to be designed and probed in preclinical and clinical studies, where finally the combination of imaging with therapy is also a prime target (“thera(g)nostics”). In multimodal imaging, these techniques may also be combined to produce a consistent time-resolved picture of the tissues or organs under examination. The thickness of the present volume (500 pages for 17 chapters!) reflects the enormous current expansion of research in bio-imaging based on the physical performance of molecular metal ion complexes and their assembly in nanoparticles and support systems.

The series editors provide a brief introduction pointing out that bio-imaging with metals is now an interdisciplinary field ranging from chemistry, physics and biology to engineering and computer science. To cover the broad range of topics, more than 15 international teams of authors based in research institutions in Europe, the United States and Asia have been recruited to present all pertinent aspects.

Chapter 1 (by S. Shuvaev and P. Caravan of the Harvard Medical School) extends this introduction under the general title: Metal ions in Bio-Imaging Techniques: A Short Overview. As the currently most prominent MRI technique, the use of gadolinium-based contrast agents (GBCAs) is presented which are by far the most widely applied metal-based drugs, the number of administrations being estimated at multimillions per year. These contrast agents are not detected directly by NMR, but by the effect they have on the relaxation times of the protons of their aqueous environment. Gd(III) cations have the highest possible number of unpaired electrons of a lanthanide element (f⁷ configuration) and are thus strongly paramagnetic leading to a pronounced relaxation effect of its complexes with a flexible coordination sphere on the neighboring aqueous media. The same applies to europium(II) which can be used as an alternative. In the manganese-based complexes, the Mn(II) cations feature five unpaired electrons, the maximum that can be arrived at for a transition metal (d⁵ configuration). Unfortunately, these simple facts are first mentioned as late as p. 72. There are currently debates about the safety of Gd-complexes because it was found that the metal may affect kidneys, bones and tissues causing unacceptable side-effects, which call for more efficient demetallation. The complex anion [Gd(DOTA)H₂O]⁻ is the preferred form owing to its kinetic inertness and thermodynamic stability (DOTA = 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid). Nanoparticle-based contrasting agents with Gd, Eu, Dy, and Mn oxides have also been probed. Chapter 1 further introduces the Chemical Exchange Saturation Transfer (CREST)-based probes using europium and dysprosium complexes. This is followed by the principles of PET, SPECT and CT imaging methods and their contrast agents. Examples of multimodal imaging, such as PET/MRI with a dual ⁶⁸Ga/^natGd imaging probe with the gallium isotope as the radiation source (the “radiometal”) are also mentioned.

Chapter 2 (by G. Tircsó, E. Molnár, T. Csupász, Z. Garda, R. Botár, F. K. Kálmán, Z. Kovács, E. Brücher, and I. Tóth of the Universities of Debrecen and Texas (at Dallas)), with the title Gadolinium(III)-Based Contrast Agents for MRI. A Re-Appraisal gives a short (one page) account of the physical principles which is followed by a review of commercial Gd complexes with macrocyclic and “open-chain” ligands that regulate the kinetics of decomplexation under physiological conditions (pH 7.4). New pathways for improving the effect of existing agents are outlined which aim at enhanced inertness and higher relaxivity or pH sensitivity.

Chapter 3 (by S. Lacerda, D. Ndiaye and E. Tóth of the Université d’Orléans) has the title Manganese Complexes as Contrast Agents for MRI and describes the progress in research of manganese-based alternatives for GBCAs. The major classes of hitherto probed Mn(II) complexes, their relaxation properties, thermodynamic stabilities and kinetic inertness are presented. The majority are “linear ligands” with a fexible or partly rigidified polyfunctional (multi-donor) chain that can be wrapped around the Mn(II) center leaving limited access for a water molecule. Nine- and 12-membered macrocyclic ligands are equally common. Owing to their redox capacity, Mn(III)/Mn(II), these complexes can also be used as “responsive probes” (redox sensing). It is important to note that Mn-complexes were the first contrast-enhancing substances, only later replaced by GBCAs with their superior performance, but also associated with toxicity concerns.

Chapter 4 (by A. Rodríguez-Rodríeguz, M. Zaiss, D. Esteban-Gómez, G. Angelovski, and C. Platas-Iglesias of the Universities of La Coruña and of Erlangen-Nürnberg, and the Max Planck Institute of Biological Cybernetics, Tübingen) has the title Metal Ion Complexes in Paramagnetic Chemical Exchange Saturation Transfer (ParaCEST).This technique is applied in MIR to provide improved contrast. CEST agents are compounds that contain a pool of exchangeable protons with regard to the water molecules in surrounding tissues. Upon excitation, saturation is transferred to bulk water attenuating the intensity of the water signal. Mainly paramagnetic probes with lanthanide and transition metals are used. The ligand design follows the concepts already common for other MRI methods, but is extended to include responsive side groups. Critical issues are the proton exchange optimization and the response to different biomarkers. ParaCEST agents have also been integrated into nanometric structures such as dendrimers.

Chapter 5 (by T. J. Sørensen and S. Faulkner of the Universities of Copenhagen and Oxford) introduces Lanthanide Complexes Used for Optical Imaging. Lanthanide complexes have recently also been used for optical imaging because it has been recognized that their large pseudo Stokes shift and their long luminescence lifetimes facilitate the elimination of background signals, while the nature of the energy transfer pathways involved in sensitizing lanthanide emission makes them amenable to perturbation by the surroundings. The excitation process involves an antenna fixed to the lanthanide-centered complex for energy transfer. Europium is generally the element of choice, as in Eurotracker^® dyes. There are still problems with the sensitivity and specificity of the response.

Chapter 6 (by S. H. Ahn, A. G. Cosby, A. J. Koller, K. E. Martin, A. Pandey, B. A. Vaughn, and E. Boros of Stony Brook University) with the title Radiometals for Positron Emission Tomography (PET) Imaging “provides the reader with a timely review on recent developments in radiometal isotope synthesis, ideal separation and subsequent chelation strategies followed by illustrative examples of applications for preclinical and clinical imaging” (Abstract). Table 1 shows the list of currently available positron sources and their radiation characteristics which have allowed the widespread availability of stand-alone PET or PET/CT clinical scanners. Among the transition metals, ⁶⁸Ga has a prominent position in this series, followed by ⁶⁴Cu, ⁵¹Mn, and ⁵⁵Co, while for the (pseudo)lanthanides the isotopes of ⁴⁴Sc, ⁸⁶Y, ¹³²La, and ¹⁵²Tb are most common. Other elements have followed and are considered in current studies. For the ⁶⁸Ga DOTATATE complex (DOTA-tyrosine³-octreotate) there is FDA-approval for both imaging and therapy.

Chapter 7 (by R. Alberto and Q. Nadeem of the University of Zürich) addresses the topic of ^99mTechnetium-Based Imaging Agents and Developments in⁹⁹Tc Chemistry. Technetium is one of the most important radionuclides for routine applications in radiopharmacy and molecular imaging. Hundreds of thousands of ⁹⁹Mo/^99mTc generators are produced for the imaging of millions of patients per year. ^99mTc is a long-lived emissive excited nuclear state, comparable to a phosphorescent electronic state. The pertechnetate (Tc^VIIO₄⁻) produced in the generator is converted into chelate complexes of lower-valent Tc, in part with Tc^V=O or Tc^V≡N core units, but also with carbonyl and isocyanide ligands. Corresponding rhenium complexes have also long been explored. Both elements are the functional centers in “theranostics” following new concepts. With fewer nuclear reactors functioning, there may soon be a shortage of ⁹⁹Mo sources for the generators to produce ^99mTc, and unfortunately, the situation is similar for ¹¹⁸W which is needed for the ¹⁸⁶Re and ¹⁸⁸Re isotopes.

Chapter 8 (by P. Hermann, J. Blahut, J. Kotek, and V. Herynek of the Charles University Prague) is dedicated to Paramagnetic Metal Ion Probes for¹⁹F Magnetic Resonance Imaging. This method is similar to standard MRI, where the resonances of water protons are followed, but it addresses the nuclear spin of the ¹⁹F nuclei which have similar nuclear magnetic properties (s = ½, comparable gyromagnetic ratio, 100% abundance). Owing to the very low abundance of fluorine in a healthy body (except for teeths), the element has to be provided exogenously for imaging. Fluorine-substituted ligands are therefore applied for metal complexation of lanthanide or transition elements. The complexes show pH-, redox- or temperature-response. Combinations of ¹H and ¹⁹F MRI are promising as an optimum approach for clinical practice.

Chapter 9 (by C. F. G. C. Geraldes and M. H. Delville of the Universities of Coimbra and Bordeaux) describes the use of Iron Oxide Nanoparticles for Bio-Imaging. These strongly paramagnetic nanoparticles (IONPs) are used to exert MIR contrast enhancement effects in what is addressed as magnetic particle imaging (MPI) and its multimodality applications. The authors report the design, synthesis and characterization of IONPs including the in vivo distribution, toxicity and degradation. This is followed by a discussion of the mechanism of the contrast enhancement. The various forms of administration of superparamagnetic iron oxide (SPIO, mainly Fe₃O₄) in preclinical studies are presented.

Chapter 10 (by J. Teh and L. M. Kauwe of the Cedars-Sinai Medical Center, Los Angeles) with the title Magnetic Resonance Contrast Enhancement and Therapeutic Properties of Corrole Nanoparticles summarizes work on tumor-targeted biological particles delivering sulfonated metallated corroles for theranostics. The sulfonation of corrols makes the units amphiphilic and the metal atoms are not readily released from the complexes owing to the efficient chelation. Proteins are used as carriers for the corrole cargo to be delivered to tumor cells. The tissue- or cell-triggered contrast enhancement allows for specific MRI diagnostics. Bis-sulfonated manganese(III) corrole (S2Mn) is most widely used.

Chapter 11 (by S. Pandey, G. B. Giovenzana, D. Szikra, and Z. Baranyai of the Bracco Research Center, Colleretto Giacosa, and the Universities of Novara and Debrecen, respectively): Positron Emission Tomography (PET) Driven Theranostics. The authors summarize thermodynamics, formation and dissociation kinetics of metal ion-based radiopharmaceuticals used for “personalized medicine”, where the therapy is tailored to the needs of a given patient through a specific diagnosis, thereby monitoring the therapy. There is only a small selection of approved radiopharmaceuticals with non-metal isotopes, mainly based on ¹⁸F-substituted molecules or compounds with iodine isotopes. All others use metal isotopes for diagnosis and therapy. As mentioned in previous chapters, these include several lanthanide, transition and main group metals, of which ⁴⁴Sc, ⁶⁸Ga, ⁶⁴Cu, ⁸⁹Zr serve for diagnosis and ⁴⁷Sc, ⁶⁷Cu, ⁹⁰Y, ¹⁷⁷Lu and others for therapy. There are thus cases where the same element can be used for both purposes with the same ligand system leading to the same biodistribution.

Chapter 12 (by S. M. McLeod and T. J. Meade of Northwestern University): Magnetic Resonance Theranostics: An Overview of Gadolinium(III)-Based Strategies and Magnetic Particle Imaging. The review focuses on MRI with Gd-based contrast agents providing biomarker and tumor metabolism information over the course of a treatment. Both small molecule conjugates and nanomaterial agents are considered. The former include i. a. those with platinum anticancer drugs, while the latter are based on gadolinium oxide or superparamagnetic iron oxide nanoparticles that may also be loaded onto carbon or carbon oxide nanomaterials.

Chapter 13 (by J. H. S. K. Monteiro, J. A. Sobrinho and A. de Bettencourt-Dias of Humboldt State University, Arcata, California and the University of Nevada, Reno): Luminescence Imaging of Cancer Cells. The authors “highlight recent advancements in the development and use of metal-containing systems, molecular, polymeric and nanostructures, for bio-imaging of cancer cells and tumors in animals” (Abstract). The review starts with gold-based nanoparticles and -clusters which show an optimum in biocompatibility and an outstanding two-photon absorption allowing easy-tunable surface plasmon resonance. This is followed by transition metal based nanoparticles (NPs) featuring cadmium, zinc, lead, and silver sulfide or selenide quantum dots. Lanthanides are also used in cellular luminescence both in NP and in molecular imaging.

Chapter 14 (by C.-P. Tan, J. Wang, L.-N. Ji, Z.-W. Mao of Sun Yat-sen University, Guangzhou): Iridium(III) Complexes in Bio-Imaging Including Mitochondria. Cyclometallated iridium(III) complexes have many advantages as bio-probes and as mitochondrial imaging agents owing to their high emission quantum yields, long phosphorescence lifetimes, large Stokes shifts, and high photostability. These characteristics endows them with the ability to activate molecular oxygen making them also candidates for photodynamic therapy. A rich variety of ligands have been probed to optimize the affinity for bio-substrates.

Chapter 15 (by C. J. Adams and T. J. Meade of Northwestern University): Imaging Bacteria with Contrast-Enhanced Magnetic Resonance. The field of bacteria-targeted magnetic resonance imaging contrast agents is not yet well developed. Both molecular and nanomaterial agents have been probed based on discrete functional Gd(III) complexes or on copolymers loaded with these complexes. Magnetosomes and magnetotactic bacteria containing magnetite Fe₃O₄ in subcellular compartments can also be applied as contrasting agents for tumor cells.

Chapter 16 (H. Y. Au-Yeung and K. Y. Tong of the University of Hong Kong): Transition Metals and Imaging Probes in Neurobiology and Neurodegenerative Diseases. Selected examples of fluorescent probes for imaging endogenous iron, copper and zinc ions, and small molecule neurotransmitters are discussed to highlight their diverse roles and applications in neurobiology. The choice of these probes for Cu and Fe sensing is determined by the oxidation states of the metal cations. Neurotransmitter molecules like amino acids and catecholamines can be traced by metal ions like exogenous Cu(II) or as iminium salts.

Chapter 17 (by Y. C. Dong and D. P. Cormode of the University of Pennsylvania): Heavy Elements for X-Ray Contrast. This last chapter brings the reader back to the Introduction, where he was remembered that barium sulfate was the first contrasting agent for X-ray screening. Known alternatives are iodinated CAs, but recently also gold and silver metallic clusters and tantalum and bismuth oxide nanoparticles have been probed. Gadolinium and ytterbium complexes show comparable X-ray attenuation, and there are also first moves into theranomics with these compounds.

Each of the chapters has its list of references, and there is a Subject Index of 19 pages. Lists of abbreviations are also provided for the articles, and these are really necessary since the text often is overloaded with acronyms that make “reading” a puzzling task. The chapters are not ordered following an obvious concept, as different imaging techniques appear and reappear in a random sequence, which leads to redundancies and does not invite to a browsing of the articles. The reader will instead better consult the Table of Contents, and he will then be happy to find step by step a wealth of new information on the specific subject he is interested in. While all authors clearly are excellent scientists at the frontiers of research, they are not necessarily great communicators.

The book is produced in highest quality regarding the paper, the binding, the layout for text and artwork, and the language. It will be a most valuable source of information on an inter- und multidisciplinary field which is of enormous importance to modern medicine.