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An international journal of inorganic chemistry www.rsc.org/dalton Number 23 | 21 June 2008 | Pages 3017–3124 ISSN 1477-9226 COMMUNICATION COVER ARTICLE Wang et al. Lukes et al. A new heart-like Co-containing Gadolinium(III) complexes as MRI polyoxoanion based on the contrast agents lacunary Preyssler anion 1477-9226(2008)23;1-4 PERSPECTIVE www.rsc.org/dalton | Dalton Transactions Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes Petr Hermann, Jan Kotek, Vojtechˇ Kub´ıcekˇ and Ivan Lukes*ˇ Received 21st December 2007, Accepted 11th February 2008 First published as an Advance Article on the web 27th March 2008 DOI: 10.1039/b719704g Magnetic resonance imaging is a commonly used diagnostic method in medicinal practice as well as in biological and preclinical research. Contrast agents (CAs), which are often applied are mostly based on Gd(III) complexes. In this paper, the ligand types and structures of their complexes on one side and a set of the physico-chemical parameters governing properties of the CAs on the other side are discussed. The solid-state structures of lanthanide(III) complexes of open-chain and macrocyclic ligands and their structural features are compared. Examples of tuning of ligand structures to alter the relaxometric properties of gadolinium(III) complexes as a number of coordinated water molecules, their residence time (exchange rate) or reorientation time of the complexes are given. Influence of the structural changes of the ligands on thermodynamic stability and kinetic inertness/lability of their lanthanide(III) complexes is discussed. Introduction In the course of time, it was found that in some examinations of, e.g. the gastrointestinal tract (GIT) or cerebral area, the Tomography of magnetic resonance (Magnetic Resonance Imag- information obtained from a simple MRI image might not be ing, MRI) has gained great importance in the last three decades sufficient. In these cases, the administration of a suitable contrast- in medicinal diagnostics as an imaging technique with a superior enhancing agent (CA) proved to be extremely useful. Quite soon, 1 spatial resolution and contrast. The most important advantage of it was demonstrated that the most promising class of CAs could MRI over the competing radio-diagnostic methods such as X-Ray be compounds comprising paramagnetic metal ions. The first Computer Tomography (CT), Single-Photon Emission Computed CA tested in vivo was the Cr(III) complex of EDTA (EDTA = Tomography (SPECT) or Positron Emission Tomography (PET) ethylenediaminetetraacetic acid).3 Unfortunately, this candidate is definitely no use of harmful high-energy radiation. Moreover, suffered from a lack of long-term stability and has never been MRI often represents the only reliable diagnostic method for, e.g. used clinically. The first example of a modern MRI CA is cranial abnormalities or multiple sclerosis. The resolution reached considered to be the gadolinium(III) complex of DTPA (DTPA = 3 is close to 1 mm with contemporary MRI clinical scanners, diethylenetriaminepentaacetic acid) approved for clinical usage in and the resolution on the cellular level was demonstrated in 1988.4 a laboratory experimental setup. Consequently, the diagnostic From the physical point of view, there are two major fami- potential of MRI seems to be still enormous. In addition to lies of CAs classified according to the relaxation process they the assessment of anatomical changes, MRI can be utilized for predominantly accelerate, i.e. T 1-CAs (paramagnetic) and T 2- monitoring of organ functions. For instance, MRI has been used 1 CAs (superparamagnetic). Whereas T 1-CAs induce a positive to follow functions of the human brain on a real time-scale by a contrast, i.e. a 1H NMR signal of the affected tissue increases, method called functional-MRI or fMRI.2 compounds affecting the T 2 relaxation cause lowering of a local Physical principles of MRI rely on the monitoring of the dif- proton signal and, thus, they show a “negative enhancement” ferent distribution and properties of water in the examined tissue pattern.5 and also on a spatial variation of its proton longitudinal (T 1)and Besides this classification, all CAs can be divided (according to 1 transversal (T 2) magnetic relaxation times. Thus, an MRI scanner the site of action) into extracellular, organ-specific and blood pool is able to generate several types of images. A significant benefit of agents. Historically, the chemistry of the T 1-CAs has been explored MRI to medicinal diagnostics arises from a contrast produced by more extensively as the T 1 relaxation time of diamagnetic water local differences in healthy and pathologically changed parts of solutions is typically five-times longer than T 2 and, consequently the same tissue. In particular, T 1 and T 2 were proved to be rather 1 easier to shorten. From the chemical point of view, T 1-CAs are sensitive to biochemical conditions (such as water concentration, complexes of paramagnetic metal ions, such as Fe(III), Mn(II)or temperature, pH, salt or fat concentration etc.) of the tissue under Gd(III), with suitable organic ligands. study. On the other hand, T 2-CAs, developed slightly later, are conceptually microcrystalline iron oxide nanoparticles (MION), called also small superparamagnetic iron oxides (SPIO) or Department of Inorganic Chemistry, Faculty of Science, Universita Karlova 1,6 (Charles University), Hlavova 2030, 128 40, Prague 2, Czech Republic. ultrasmall superparamagnetic iron oxides (USPIO). In addition E-mail: [email protected]; Fax: +420-221951253; Tel: +420-221951259 to their effect on T 2, these agents also induce faster T 1-relaxation; This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 3027–3047 | 3027 Petr Hermann started graduate Jan Kotek is a former student studies with Prof. Lukesˇ in 1988 Prof. I. Lukesˇ and Dr. P. Her- and graduated in 1993. He was a mann. He received his PhD de- postdoctoral fellow at University gree in 2004. He was then a post- of Massachusetts (Amherst) doctoral fellow in Leuven (Bel- with Prof. L. D. Quin (1993– gium) under the supervision of 1995). At his alma mater,he Prof. K. Binnemans. He has been became a lecturer (1993) and a lecturer in the department since docent (2004). His current re- 2000 and is a member of Prof. search is focused on synthesis Lukes’ˇ team involved mostly in and investigations of complex- the synthesis, potentiometry and ing ability of polyazamacrocy- X-ray studies of macrocyclic lig- cles with phosphorous acid pen- ands and their complexes. Petr Hermann Jan Kotek dant arms. Vojtechˇ Kub´ıcekˇ was born in Ivan Lukes’ˇ studies (PhD 1976) 1978. He obtained his PhD de- as well as his career are con- gree in inorganic chemistry in nected with Universita Karlova 2007. Now, he works in the group except stays in Orsted Insti- of Coordination and Bioinor- tute in Copenhagen (1984) and ganic Chemistry at Charles Uni- University of Massachusetts at versity in Prague. His scientific Amherst (1991–92). Through interest is focused on the synthe- the years his research inter- sis and coordination chemistry est has focused on coordination of organophosphorus compounds chemistry and also on phospho- and on the design of macrocyclic rus chemistry. At present, he is chelators for molecular imaging. concerned with lanthanide com- plexes and their biomedical ap- Vojtechˇ Kub´ıcekˇ Ivan Lukesˇ plication. nevertheless, they are mostly used as negative CAs. Basically, they complexes are written, according to the IUPAC nomenclature, in consist of nonstoichiometric Fe3O4/Fe2O3 cores of various sizes small letters. (from several nanometers to several tens of nanometers) covered by e.g. dextrans or polysiloxanes; hence, their final size reaches Structures of gadolinium(III)-based contrast agents several hundred nanometers. In practice, they are used as blood- pool and more recently as organ-specific CAs. As highlighted above, the T 1-CAs are mostly based on coordina- In clinical practice, more than 35% of MRI examinations tion compounds where the paramagnetic metal ion is wrapped in are performed with the use of CAs. The T 1-CAs based on a multidentate organic ligand. At present, the most widespread gadolinium(III) complexes are mostly applied; thus, in this paper, family of the T 1-CAs consists of complexes with the Gd(III) ion. we focus on them and, especially, on the coordination chemistry Although there are other candidates in the lanthanide series that that controls the properties of such CAs. Utilization of the iron have a high magnetic moment, the intrinsic relaxation time of oxide nanoparticles is rather limited, an estimated proportion is the electron-spin state of the cation has to be long enough for less than 10% of all CA administrations. efficient transfer of magnetic information to the bulk water. Thus, In this rapidly developing field, a number of reviews on different the prominent position of the Gd(III) ion relies not only in a high aspects of the chemistry of complexes associated with CAs magnetic moment (7.9 BM) given by seven unpaired f -electrons, 1,7,8 8 developments and usages have been published: monographs, but also in a totally symmetric electronic state ( S7/2 ground state), reviews of general interest,9–18 reviews on physical aspects,19 solid- which makes the electronic relaxation time much longer than for − − state structures,20,21 thermodynamic/kinetic stability,20–24 pro- other Ln(III) ions, 10 8–10 9 s.5 However, the main problem of totropic exchange,25 second-sphere effects,26 quantum chemi- the medical utilizations of heavy metal ions like the Gd(III)ion cal calculations,27 targeted/responsive CAs,28–31 macromolecular is a significant toxicity of their “free” (aqua-ion) form. Thus, for CAs32,33 or multimodal CAs.34 clinical use of gadolinium(III), it must be bound in a complex of To avoid any ambiguity, fully protonated free ligands (e.g.

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