Next-Generation Magnetic Resonance Imaging Contrast Agents

Jun 5, 2017 - Department of Chemistry, University at Buffalo, The State University of New York, Amherst, New York 14260, United States. Éva Tóth (Gu...
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Editorial pubs.acs.org/IC

Next-Generation Magnetic Resonance Imaging Contrast Agents

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also be observed in response to changes in the pH or redox state of the metal-ion complex. Such PARASHIFT and PARACEST agents are featured in addition to the more traditional T1 agents. Nanoparticulate probes that produce MRI contrast through T2 (transverse) relaxation mechanisms are not covered in this virtual issue. Water Exchange, Rotation, and MRI Efficiency. The relaxation efficiency is inherently linked to the microscopic properties of the paramagnetic complex in question. A better understanding of the relationship between the structure of the lanthanide chelate, the rotational dynamics, and the exchange rate of coordinated water is important for the design of more efficient agents and has been the focus of several reports. Woods and co-workers showed that the regiochemistry of bifunctional macrocyclic chelates significantly alters their selfassembly, tumbling, and relaxation effectiveness.8 Water exchange has also been investigated for bishydrated chelates. For complexes of the 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid (AAZTA) ligand, Helm and co-workers demonstrated a changeover in the water-exchange mechanism and also in the hydration state along the lanthanide series.9 In this study, it was also shown that 1H NMR represents a valuable and reliable tool to assess water exchange when 17O NMR is not applicable because of low chelate concentration. Caravan and co-workers reported an unusual trinuclear gadolinium(III) thiacalix[4]arene sandwich cluster.10 This complex has surprisingly high kinetic inertness with respect to acid-catalyzed dissociation, which is a major requirement to ensure nontoxicity. Although the exceedingly slow water exchange of the complex [the second slowest reported so far for a Gd(III) chelate] prevents its application as a relaxation agent, it may be interesting to generate a PARACEST effect for lanthanide analogues other than Gd(III). Manganese and Iron Complexes as T1 Agents. Mn(II) has five unpaired d electrons, a long electronic relaxation time, and labile water exchange, qualities that make it an attractive alternative to Gd(III) in the design of MRI contrast agents. In order to ensure in vivo safety and good contrast agent efficiency, the Mn(II) ion must be chelated by a ligand that affords high thermodynamic stability and kinetic inertness to the complex and must have at least one free coordination site for a water molecule. A series of mono-, bi-, and trinuclear Mn(II) complexes of pentadentate dipicolinic acid derivative ligands were reported by Platas-Iglesias and co-workers,11 and these ligands provide pentagonal-bipyramidal coordination of the Mn(II) ion. While improvement in the stability of the complexes is required, their relaxivities were found to be remarkably high (11.4 mM−1 s−1 at 298 K and 20 MHz for the trinuclear complex) because of bishydration and a relatively slow rotational motion. These relaxivities were further improved upon interaction with human serum albumin. Gale and co-workers exploited the Mn(II)/Mn(III) couple and a biochemically mediated change in the paramagnetism of

he development of magnetic resonance imaging (MRI) contrast agents is an active area of research, and the contrast agents covered in this virtual issue reach new levels of sophistication, featured in 31 papers from Inorganic Chemistry, Journal of the American Chemical Society, ACS Nano, Bioconjugate Chemistry, ACS Macroletters, Biomacromolecules, and Journal of Medicinal Chemistry. The materials studied range from responsive agents for indication of the pH, enzymatic activities, or redox status to probes that are targeted toward tumor microenvironment. There are examples of theranostic agents that function through the delivery of drugs or absorbance of light and agents that contain multiple modalities for carrying out more than one imaging method. Finally, there are improved Gd(III) complexes for contrast or new transitionmetal-ion contrast agents. The basis for this active interest in contrast agents is, of course, the evolution and expansion of MRI as a high-resolution and noninvasive clinically important imaging modality.1 The first contrast agents developed in the late 1970s and 1980s included Gd(III), Mn(II), and Fe(III) complexes.2 These complexes produce contrast by increasing the water proton longitudinal relaxation rate and are known as T1 MRI contrast agents. Because of its seven unpaired f electrons, Gd(III) exhibits a large magnetic susceptibility, long electronic relaxation times, and a relatively rapid water exchange rate, all of which are qualities favorable for T1 contrast agents. Given these properties, Gd(III) complexes presently dominate the contrast agents used in the clinic.3 However, the investigation of transition-metal ions in this area has recently experienced a renaissance because of interest in producing alternatives for Gd(III) as well as for developing new types of responsive agents. Transition-metal-complex contrast agents based on manganese, iron, cobalt, and copper are highlighted in this virtual issue. Agents that produce MRI contrast through different mechanisms have also attracted recent interest. For example, chemical exchange saturation transfer (CEST) or paramagnetic CEST (PARACEST) agents4 have protons on −OH or −NH groups that readily exchange with the protons of water: these exchange rate constants are sufficiently slow that the exchangeable proton resonance is distinct from that of bulk water. The incorporation of a presaturation radio-frequency pulse at the frequency of the exchangeable proton produces negative contrast, which is turned “on” or “off” by the presaturation pulse. The paramagnetic metal ion may be a lanthanide [e.g., Eu(III), Tm(III), and Yb(III)] or a transitionmetal ion [Fe(II) and Co(II)] with a short electronic relaxation time.5 These metal ions produce highly paramagnetically shifted proton resonances that are far from the magnetization transfer effect observed in tissue. This new type of contrast agent is especially useful for responsive contrast agent development. Related metal-ion complexes that function as paramagnetic shift agents can be used for magnetic resonance spectroscopy (MRS) to produce changes in 1H, 19F, or 31P nuclei.6,7 A change in the chemical shift of the resonance may © 2017 American Chemical Society

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their complexes to create redox sensors.12 They designed a Janus chelator, which can interconvert between Mn(III)- and Mn(II)-selective ligands and which is therefore capable of stabilizing both redox states of the metal ion in the physiological milieu. Upon oxidation or reduction, the manganese was bound by the most adapted Janus face of the ligand. This chelator enabled rapid and reversible biochemically induced interconversion between the low-relaxivity Mn(III) and high-relaxivity Mn(II) states, which corresponded to an 8.5-fold increase in the proton relaxivity, unprecedented for an activatable MRI agent. High-spin Mn(III) (S = 2) can also be an efficient relaxation agent. Jasanoff and co-workers investigated a new class of planar tetradentate Mn(III) chelates, assembled from a 1,2phenyldiamido (PDA) backbone, that display relaxivities comparable to those of Gd(III)-based contrast agents.13 Most importantly, the balanced combination of a lipophilic aryl backbone and the hydrophilic metal-binding site of the ligand conferred high membrane permeability to these complexes, which were found to spontaneously localize in the cytosol. Further attachment of intracellular enzyme-cleavable groups to the PDA backbone allowed preferential accumulation of the probe in cells expressing a substrate-selective esterase. A T1 MRI contrast agent based on Fe(III) is presented in work by Gianneschi and co-workers.14 Iron-loaded synthetic melanin nanoparticles, prepared by the polymerization of dopamine under alkaline conditions, were characterized by electron paramagnetic resonance (EPR) spectroscopy, nuclear magnetic resonance dispersion (NMRD), and magnetometry studies. The catechol functionality of the nanoparticle chelates the Fe(III) centers, while improved iron loading is obtained with Fe(III) incorporated in a prepolymerization doping process. A curious property of these agents is that T1 relaxivity decreases with increased Fe(III) loading. NMRD profiles were complicated, suggesting multiple contributions to relaxivity that vary with the field strength, while EPR spectra supported the presence of high-spin Fe(III) in a low-symmetry site (g = 4.3). Studies on the temperature dependence of the magnetic susceptibility were consistent with two general types of Fe(III) centers: one magnetically isolated and one magnetically coupled. Antiferromagnetic coupling of the Fe(III) centers at high iron loading was proposed as a rationale for the unexpected decrease in the T1 relaxivity at high iron loading. PARACEST Agents. Research on PARACEST agents has produced improved lanthanide-based agents that show better CEST efficiency and/or decreased toxicity in animal studies. A recent contribution from Sherry and co-workers showed that Eu(III) complexes of tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tetramide macrocycles with glutamyl phosphonate monoester or diester groups exhibit the slowest waterexchange rate reported to date for this class of compounds.15 The bound water lifetime for one of these complexes is 735 μs. This long-lived bound water is an optimal match for production of the CEST signal at the low radio-frequency power levels that are used for in vivo animal studies. The authors showed that this complex can be observed in the kidneys of live mice after injection of a 0.4 mmol/kg dose. A second study on Ln(III) PARACEST agents by Hudson and co-workers reported on related Tm(III) complexes of DOTA tetramide complexes.16 These complexes display amide proton-based CEST and, in certain cases, feature dipeptide-functionalized pendent groups. The study from Hudson and his team targeted further functionalization of the amide pendent groups with peripheral

carboxylate or aspartic acid groups to decrease the overall positive charge of the complexes and increase their biocompatibility. While the aspartic acid derivatives were shown to be well-tolerated by mice, CEST imaging was hampered by low accumulation of the agent or by T2 darkening effects. The development of new multinuclear transition-metal-ion PARACEST agents is of interest, as shown in a new report by Du and Harris.17 In this study, magnetic exchange coupling between two Cu(II) centers produced a S = 1 ground state with a correspondingly short electronic relaxation time appropriate for a PARACEST agent. A bridging pyrophosphate ligand along with a phenoxo-centered tetraamide chelate was used to bind the two Cu(II) ions, and the CEST peak is produced upon irradiation of the amide protons of the dinuclear complex. While the CEST peak shift was modest, this study is a proof-ofprinciple that transition-metal-ion magnetism can be modulated for the development of new PARACEST agents. PARASHIFT Probes. Certain Ln(III) ions and transitionmetal ions produce large paramagnetic shifts in nuclei such as 1 H and 19F, and paramagnetically shifted 1H resonances can be monitored by MRS. A recent study by Parker and co-workers reported a detailed analysis of pseudocontact shifts in Yb(III) complexes that feature tert-butyl groups as substituents on pyridine pendents.18 This group has pioneered studies of Ln(III) PARASHIFT probes that may be administered in doses similar to that of Gd(III) agents for in vivo imaging. The most recent study combined structural analysis, theoretical calculations, and solution NMR studies to show that unexpectedly large shifts for one high-performing complex are due to a change in the orientation of the pseudocontact shift field. Paramagnetic Probes for 19F MRI. A study that compares the effect of different paramagnetic metal ions for improvement of the 19F MRI sensitivity was reported by Pierre and coworkers.19 In this study, derivatives of DOTA tetramide macrocycles with fluorine substituents were prepared and complexed to a series of Ln(III) and Fe(II) ions. The overall goal of the work was to increase the sensitivity of the NMR/ MRI signal by promoting a decrease in the T1 value of the 19F nuclei through interaction with the paramagnetic center. MRI phantoms showed that the Fe(II) complex exhibits the largest signal in blood and is thus the most promising for the development of in vivo probes. Responsive/Activatable Agents. Given the inherent capability of paramagnetic complexes to change their relaxation efficiency or PARACEST behavior as a function of a biomarker, they offer unique opportunities to create responsive MRI probes. Such agents provide an MRI signal that selectively depends on the presence or concentration of a specific biomarker or on the value of a given physiological parameter (such as the pH or temperature). The design of responsive probes has been a particularly active area of research and very often utilizes coordination chemistry principles to modulate, via interaction with the biomarker, the environment of the metal ion, which, in turn, influences the relaxation or CEST properties. Morrow and co-workers exploited the strongly pH-dependent frequency shift of −NH protons in the high-spin Fe(II) and Co(II) complexes of a 2-amino-6-picolyl-appended cyclen ligand to create pH-responsive PARACEST agents.20 The shift in the CEST peak was shown to correlate with protonation of the unbound 2-amino-6-picolyl pending groups. This system is the first transition-metal complex that produces a pH6030

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this yields an increase of the hydration number and relaxivity (from 5.46 to 7.17 mM−1 s−1). Allen and co-workers investigated europium complexes of the macrocyclic tetraglycinate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamidoacetate) ligand,27 and for both Eu(II) and Eu(III) oxidation states, the metal ion remains chelated. The redoxresponsive behavior of this system could potentially be monitored through chemical exchange saturation transfer, displayed by Eu(III), or proton relaxation, displayed by Eu(II). Que and co-workers reported a pair of fluorinated, redox-active copper complexes as 19F MRI contrast agent candidates for the detection of cellular hypoxia.28 The 19F NMR signal of the probe is quenched by the proximity of the paramagnetic Cu(II). When the trifluorinated CuATSM-F3 derivative selectively accumulates in hypoxic cells, Cu(II) is reduced to Cu(I) and the complex undergoes dissociation, leading to the appearance of the 19F NMR signal. This turn-on response could be recorded in cells grown under hypoxic conditions. In a fundamentally different approach, GdDOTP [H8DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)], a vascular oxygenation responsive probe, was loaded into red blood cells by the group of Aime.29 The pO2-responsive properties of GdDOTP are retained when it is entrapped in red blood cells, and maps of the actual deoxyhemoglobin/oxyhemoglobin ratio could be obtained in vivo. The information obtained by MRI on the vascular oxygenation level could be validated by photoacoustic imaging as well. This method has great potential to refine tumor staging in preclinical MRI. Multimodal Agents. Coordination complexes that produce MRI contrast in addition to serving as probes for other modalities are an active area of research. Such multimodal agents may feature complexes with several different metal ions with useful imaging properties. Two studies that combine T1 MRI contrast agents and luminescence probes for optical imaging have been reported. Picard and co-workers reported a metallostar complex with dual optical imaging and MRI contrast properties.30 This complex has a central ruthenium(II) tris(bipyridine) type complex, with each of the bipyridine ligands functionalized to bind a Ln(III) ion. With Gd(III), an effective T1 MRI contrast agent is produced with a relaxivity of 51 and 36 mM−1 s−1 at 20 and 300 MHz, respectively. The Ru(II) complex emits at 660 nm upon excitation at 472 nm. Photophysical studies on the RuL3Nd3 or RuL3Yb3 derivatives showed sensitized luminescence of these near-IR (NIR)emitting lanthanide ions. In a second study of multimodal agents, Durand and co-workers reported the first example of an activatable Ln(III) complex that can be used as a T1 MRI contrast agent for the Gd(III) derivative, as a PARACEST agent for the Tb(III) or Yb(III) derivatives, or as a NIR luminescent probe for the Yb(III) derivative.31 This ligand features a benzyl carbamate-protected aminopyridine pendent. Cleavage of the benzyl carbamate affords an aminopyridine pendent with an −NH group that produces CEST. This transformation was also detectable in luminescence studies because the excitation wavelength is shifted upon cleavage. The r1 values of the Gd(III) complex are also modulated by cleavage. The development of a more biologically relevant enzyme-based reaction is necessary for further applications of this agent. A third study on multimodal agents reported by Sun and coworkers features a versatile dendritic platform for dual MRI and positron emission tomography (PET) imaging.32 These

responsive shift in the CEST frequency, which can afford a concentration-independent method to assess the pH. Kotek and co-workers proposed to use MRS and a europium(III) aminophosphonate derivative, DO3A (H3do3a = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) chelate, to measure the pH, also in a concentration-independent manner.21 Protonation of this complex is associated with an unusually slow time scale, which originates from an important geometric change from a twisted-square-antiprismatic to a squareantiprismatic arrangement. These distinct conformers are characterized by very different 31P chemical shifts (+70 and −118 ppm, respectively), which can be employed to measure the pH, as was demonstrated by 31P MRS experiments. A thermosensitive microgel based on a manganese porphyrin core incorporated in a cross-linked poly(N-isopropylacrylamide) material was investigated for the monitoring of subtle temperature changes by Zhong and co-workers.22 Such microgels are known to show distinctly rapid swelling and shrinking behavior at a lower critical solution temperature. When paramagnetic complexes were embedded, the temperature-sensitive microgel volume changes were translated into a variation in the rotational motion of the metal chelates, resulting in a considerable increase in relaxivity (up to 67%) within a few degrees of temperature variation. MRI detection of endogenous metal ions has long been another research focus. Now, important steps have been made toward monitoring the Ca(II) concentration by achieving unprecedented signal variation and using cell-permeable probes. Angelovski and co-workers incorporated an amphiphilic ligand [with specific Ca(II) and Gd(III) binding sites] into liposomes23 and labeled only the outer sites of the liposome bilayer with Gd(III). Upon Ca(II) binding, a remarkable 400% increase in the relaxivity was observed. This increase was shown to correlate with an increase in the hydration number and to a restriction in the motion of the chelate when Ca(II) is coordinated to the EGTA-derived recognition motif. Meade and co-workers conjugated the ethyl ester derivative of the Ca(II)-responsive 1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′tetraacetic acid unit to two Gd(III) complexes to increase their cell permeability and prevent extracellular Ca(II) binding.24 Once inside the cell, this molecule is activated by intracellular esterases and becomes available for Ca(II) binding. This probe design allows for discrimination between extra- and intracellular Ca(II) by MRI. The detection of Zn(II) is of interest in various pathologies, including diabetes or prostate cancer. The sensitivity of the previously reported Zn(II)-responsive 1,4,7,10-tetraazacyclododecane-1,4 -bis[N,N-bis(2pyridylmethyl)aminoethyleneacetamide]-7,10-acetic acid was amplified by Sherry and co-workers via alteration of the water-exchange rates.25 The new sensors exhibit fine-tuned water-exchange rates and significantly enhanced proton relaxivity changes upon interaction with Zn(II) and human serum albumin. The complexes could also be successfully used to monitor Zn(II) release in a mouse pancreas upon stimulated insulin secretion. Redox-responsive agents and the detection of abnormal redox states have been the subject of several studies exploiting very different chemistries. Goldsmith and co-workers tackled the problem of monitoring oxidative stress and the accumulation of reactive oxygen species.26 They reported a Mn(II) complex formed with a redox-active diquinol derivative ethylenediamine ligand. When the complex reacts with H2O2, the quinol moieties of the ligand are oxidized to p-quinone, and 6031

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glycol)−polyaspartic acid block copolymers.37 Thermal neutron irradiation in cell culture studies showed a decreased cell survival rate, and the toxicity of the complexes was attributed to γ-ray production upon absorption of the neutrons by the Gd(III)-containing nanoparticles. The nanoparticle formulation was also advantageous from the standpoint that the delivery of Gd(III) to tumors was increased, as shown by MRI on a T1 scanner. These nanoparticles may facilitate MRI-imagingguided thermal neutron irradiation for cancer therapy. Finally, a report from Sessler and co-workers featured a theranostic agent for targeting metastatic liver cancer.38 This agent has a gadolinium(III) texaphyrin core attached to doxorubicin through a disulfide linkage. An increase in doxorubicin fluorescence was observed upon cleavage of the disulfide bond. Upregulation of GSH in cancer cells was anticipated to facilitate release of the doxorubicin anticancer drug as an inhibitor of topoisomerase II. To enhance tumor delivery, the conjugated texaphyrin was loaded into folatereceptor-targeted liposomes. In vitro studies showed an improved uptake and anticancer efficacy of cell lines that expressed folate receptors. This multimodal optical and MRI agent demonstrates T1 imaging in vivo to follow the progression of metastatic cancer, in concert with fluorescence images to track drug release. The therapeutic efficacy was evidenced by reduced tumor burden in subcutaneous and metastatic liver cancer mouse models. The articles collected for this virtual issue demonstrate some of the exciting new developments in the field of MRI contrast agents, where a renewed emphasis on transition-metal ions has driven the development of new coordination chemistry. Agents that combine multiple types of metal ions, especially toward theranostic applications or for multimodality agents, are a second area of emphasis. It will be interesting to see what these agents might teach us about solution chemistry, disease diagnosis, and biology. We look forward to seeing future excellent and ground-breaking research on MRI contrast agents in Inorganic Chemistry and other ACS journals.

dendritic structures contain both a triazamacrocycle for binding to 68Ga(III) as a PET probe and a tetraazamacrocycle for binding Gd(III) as an MRI contrast agent. Further, a targeting moiety may be attached to the molecular probe, and in this study, an integrin targeting peptide was used. Dual MRI/PET in vivo imaging of a tumor model was also demonstrated. Sancey and co-workers reported a study of the in vivo clearance of a multimodal agent that has been developed for dual MRI and radiosensitization of X-ray-mediated cancer treatment. These agents contain Gd(III) macrocyclic complexes linked to a polysiloxane matrix to produce ultrasmall nanoparticles of 3 nm diameter. Analytical and spectroscopic studies showed that these nanoparticles rapidly accumulate in the kidneys but are eliminated through a two-step process, involving rapid elimination of smaller biodegraded particles and slower elimination of larger particles.33 Theranostics and Targeted Agents. A long-term goal of researchers is to prepare contrast agents that are targeted to a particular type of tumor in order to better categorize the cancer status and assess the risk. Targeted contrast agents have added value in comparison to the more traditional agents that are used to indicate the size of the tumor. A new report from Lu’s group showed that a peptide-conjugated Gd(III) MRI contrast agent has potential for the detection of aggressive prostate cancer.34 This agent has a pentapeptide (CREKA) that is specific to an oncoprotein, extradomain B fibronectin (EDB-FN), found in the tumor microenvironment. Levels of EDB-FN were shown to be 3 times higher in metastatic PC3 cancer cells than in nonmetastatic LNCaP cells. Uptake of the targeted Gd(III) agent into PC3 tumor xenografts produced 2-fold higher T1weighted contrast than did the LNCaP tumor xenografts. This agent may be useful for the parsing of prostate cancers into different risk groups and for image-guided therapy applications. The combination of diagnostic imaging and a therapeutic agent produces a theranostic agent. Several new reports of theranostic agents containing MRI contrast agents have been reported. The first of these featured a bifunctional agent with a photosensitizing mesotetraphenylporphyrin core for photodynamic therapy (PDT) linked to four Gd(III) ions chelated by diethylenetriamine-N,N,N″,N″-tetraacetate, as reported by Ventura and co-workers.35 This complex has a very high relaxivity of 44 mmol−1 s−1 per Gd(III) center at 20 MHz, which is attributed to the high rigidity of the complex. Upon irradiation with light, the complex produces singlet oxygen with high yield. The complex is taken up by HeLa cells and demonstrates phototoxicity in cell culture. Ultrasound sensitizers for therapeutic applications are attractive, given the good penetration of ultrasound waves, in contrast to PDT, which suffers from low depth penetration of light in tissue. Shi and co-workers reported on manganese-ionbased protoporphyrin complexes that are anchored and encapsulated in mesoporous silica.36 The biodegradability of the particles is incorporated by disulfide linkages, which degrade in the presence of glutathione (GSH). The paramagnetic manganese complexes produce T1 MRI contrast and, upon irradiation with ultrasound frequencies, singlet oxygen. Sonotoxicity of the particles was also demonstrated in cell culture and in vivo. These complexes are proposed for applications of MRI-guided tumor growth reduction. A third type of therapeutic sensitizer is activated by neutron capture. Kataoka and co-workers presented 100 nm nanoparticles consisting of Gd(DTPA) complexes trapped in micelles formed by Ca(II), phosphate, and poly(ethylene

Janet R. Morrow,* Associate Editor

Department of Chemistry, University at Buffalo, The State University of New York, Amherst, New York 14260, United States

Éva Tóth, Guest Editor, Editorial Advisory Board Member

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Centre de Biophysique Moléculaire, CNRS UPR 4301, Université d’Orléans, Rue Charles Sadron, 45071 Orléans 2, France

AUTHOR INFORMATION

Corresponding Author

*E-mail: jmorrow@buffalo.edu. ORCID

Janet R. Morrow: 0000-0003-4160-7688 Notes

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

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REFERENCES

(1) Boros, E.; Gale, E. M.; Caravan, P. MR imaging probes: design and applications. Dalton Trans 2015, 44, 4804−4818. (2) Lauffer, R. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem. Rev. 1987, 87, 901−927.

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(3) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem. Rev. 1999, 99, 2293−352. (4) Viswanathan, S.; Kovacs, Z.; Green, K. N.; Ratnakar, S. J.; Sherry, A. D. Alternatives to gadolinium-based metal chelates for magnetic resonance imaging. Chem. Rev. 2010, 110, 2960−3018. (5) Dorazio, S. J.; Olatunde, A. O.; Tsitovich, P. B.; Morrow, J. R. Comparison of divalent transition metal ion paraCEST MRI contrast agents. J. Biol. Inorg. Chem. 2014, 19, 191−205. (6) Coman, D.; Trubel, H. K.; Rycyna, R. E.; Hyder, F. Brain temperature and pH measured by 1H chemical shift imaging of a thulium agent. NMR Biomed. 2009, 22, 229. (7) Harvey, P.; Kuprov, I.; Parker, D. Lanthanide complexes as paramagnetic probes for 19F magnetic resonance. Eur. J. Inorg. Chem. 2012, 2012, 2015−2022. (8) Webber, B. C.; Cassino, C.; Botta, M.; Woods, M. Aggregation in amphiphilic macrocycle-substituted Gd3+ DOTA-type chelates is affected by the regiochemistry of substitution. Inorg. Chem. 2015, 54, 2085−7. (9) Karimi, S.; Tei, L.; Botta, M.; Helm, L. Evaluation of Water Exchange Kinetics on [Ln(AAZTAPh-NO2)(H2O)q]x Complexes Using Proton Nuclear Magnetic Resonance. Inorg. Chem. 2016, 55, 6300−7. (10) Iki, N.; Boros, E.; Nakamura, M.; Baba, R.; Caravan, P. Gd3CAS2: An Aquated Gd3+-Thiacalix[4]arene Sandwich Cluster with Extremely Slow Ligand Substitution Kinetics. Inorg. Chem. 2016, 55, 4000. (11) Forgacs, A.; Regueiro-Figueroa, M.; Barriada, J. L.; EstebanGomez, D.; de Blas, A.; Rodriguez-Blas, T.; Botta, M.; Platas-Iglesias, C. Mono-, bi-, and trinuclear bis-hydrated Mn2+ complexes as potential MRI contrast agents. Inorg. Chem. 2015, 54, 9576−87. (12) Gale, E. M.; Jones, C. M.; Ramsay, I.; Farrar, C. T.; Caravan, P. A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range. J. Am. Chem. Soc. 2016, 138, 15861−15864. (13) Barandov, A.; Bartelle, B. B.; Gonzalez, B. A.; White, W. L.; Lippard, S. J.; Jasanoff, A. Membrane-Permeable Mn(III) Complexes for Molecular Magnetic Resonance Imaging of Intracellular Targets. J. Am. Chem. Soc. 2016, 138, 5483−6. (14) Li, Y.; Xie, Y.; Wang, Z.; Zang, N.; Carniato, F.; Huang, Y.; Andolina, C. M.; Parent, L. R.; Ditri, T. B.; Walter, E. D.; Botta, M.; Rinehart, J. D.; Gianneschi, N. C. Structure and function of ironloaded synthetic melanin. ACS Nano 2016, 10, 10186−10194. (15) Fernando, W. S.; Martins, A. F.; Zhao, P.; Wu, Y.; Kiefer, G. E.; Platas-Iglesias, C.; Sherry, A. D. Breaking the Barrier to Slow Water Exchange Rates for Optimal Magnetic Resonance Detection of paraCEST Agents. Inorg. Chem. 2016, 55, 3007−14. (16) Suchy, M.; Milne, M.; Elmehriki, A. A.; McVicar, N.; Li, A. X.; Bartha, R.; Hudson, R. H. Introduction of Peripheral Carboxylates to Decrease the Charge on Tm3+ DOTAM-Alkyl Complexes: Implications for Detection Sensitivity and in Vivo Toxicity of PARACEST MRI Contrast Agents. J. Med. Chem. 2015, 58, 6516−32. (17) Du, K.; Harris, T. D. A Cu(II)2 Paramagnetic Chemical Exchange Saturation Transfer Contrast Agent Enabled by Magnetic Exchange Coupling. J. Am. Chem. Soc. 2016, 138, 7804−7. (18) Mason, K.; Rogers, N. J.; Suturina, E. A.; Kuprov, I.; Aguilar, J. A.; Batsanov, A. S.; Yufit, D. S.; Parker, D. PARASHIFT Probes: Solution NMR and X-ray Structural Studies of Macrocyclic Ytterbium and Yttrium Complexes. Inorg. Chem. 2017, 56, 4028−4038. (19) Srivastava, K.; Weitz, E. A.; Peterson, K. L.; Marjanska, M.; Pierre, V. C. Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood. Inorg. Chem. 2017, 56, 1546−1557. (20) Tsitovich, P. B.; Cox, J. M.; Spernyak, J. A.; Morrow, J. R. Gear Up for a pH Shift: A Responsive Iron(II) 2-Amino-6-picolylAppended Macrocyclic paraCEST Agent That Protonates at a Pendent Group. Inorg. Chem. 2016, 55, 12001−12010. (21) Krchova, T.; Herynek, V.; Galisova, A.; Blahut, J.; Hermann, P.; Kotek, J. Eu(III) Complex with DO3A-amino-phosphonate Ligand as

a Concentration-Independent pH-Responsive Contrast Agent for Magnetic Resonance Spectroscopy (MRS). Inorg. Chem. 2017, 56, 2078−2091. (22) Zheng, X.; Qian, J.; Tang, F.; Wang, Z.; Cao, C.; Zhong, K. Microgel-based thermosensitive MRI contrast agents. ACS Macro Lett. 2015, 4, 431−435. (23) Garello, F.; Vibhute, S.; Gunduz, S.; Logothetis, N. K.; Terreno, E.; Angelovski, G. Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity. Biomacromolecules 2016, 17, 1303−11. (24) MacRenaris, K. W.; Ma, Z.; Krueger, R. L.; Carney, C. E.; Meade, T. J. Cell-permeable esterase-activate Ca(II) sensitive MRI contrast agent. Bioconjugate Chem. 2016, 27, 465−473. (25) Yu, J.; Martins, A. F.; Preihs, C.; Clavijo Jordan, V.; Chirayil, S.; Zhao, P.; Wu, Y.; Nasr, K.; Kiefer, G. E.; Sherry, A. D. Amplifying the sensitivity of zinc(II) responsive MRI contrast agents by altering water exchange rates. J. Am. Chem. Soc. 2015, 137, 14173−9. (26) Yu, M.; Ward, M. B.; Franke, A.; Ambrose, S. L.; Whaley, Z. L.; Bradford, T. M.; Gorden, J. D.; Beyers, R. J.; Cattley, R. C.; IvanovicBurmazovic, I.; Schwartz, D. D.; Goldsmith, C. R. Adding a Second Quinol to a Redox-Responsive MRI Contrast Agent Improves Its Relaxivity Response to H2O2. Inorg. Chem. 2017, 56, 2812−2826. (27) Ekanger, L. A.; Mills, D. R.; Ali, M. M.; Polin, L. A.; Shen, Y.; Haacke, E. M.; Allen, M. J. Spectroscopic Characterization of the 3+ and 2+ Oxidation States of Europium in a Macrocyclic Tetraglycinate Complex. Inorg. Chem. 2016, 55, 9981−9988. (28) Xie, D.; King, T. L.; Banerjee, A.; Kohli, V.; Que, E. L. Exploiting Copper Redox for 19F Magnetic Resonance-Based Detection of Cellular Hypoxia. J. Am. Chem. Soc. 2016, 138, 2937−40. (29) Di Gregorio, E.; Ferrauto, G.; Gianolio, E.; Lanzardo, S.; Carrera, C.; Fedeli, F.; Aime, S. An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2-Responsive GdAgent. ACS Nano 2015, 9, 8239−48. (30) Boulay, A.; Deraeve, C.; Vander Elst, L.; Leygue, N.; Maury, O.; Laurent, S.; Muller, R. N.; Mestre-Voegtle, B.; Picard, C. Terpyridinebased heteroditopic ligand for RuIILn3III metallostar architectures (Ln = Gd, Eu, Nd, Yb) with MRI/optical or dual-optical responses. Inorg. Chem. 2015, 54, 1414−25. (31) He, J.; Bonnet, C. S.; Eliseeva, S. V.; Lacerda, S.; Chauvin, T.; Retailleau, P.; Szeremeta, F.; Badet, B.; Petoud, S.; Toth, E.; Durand, P. Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities: Visible/NearInfrared Luminescence, PARACEST-, and T1-MRI. J. Am. Chem. Soc. 2016, 138, 2913−6. (32) Kumar, A.; Zhang, S.; Hao, G.; Hassan, G.; Ramezani, S.; Sagiyama, K.; Lo, S. T.; Takahashi, M.; Sherry, A. D.; Oz, O. K.; Kovacs, Z.; Sun, X. Molecular platform for design and synthesis of targeted dual-modality imaging probes. Bioconjugate Chem. 2015, 26, 549−58. (33) Sancey, L.; Kotb, S.; Truillet, C.; Appaix, F.; Marais, A.; Thomas, E.; van der Sanden, B.; Klein, J.-P.; Laurent, B.; Cottier, M.; Antoine, R.; Dugourd, P.; Panczer, G.; Lux, F.; Perriat, P.; Motto-Ros, V.; Tillement, O. Long-Term in Vivo Clearance of Gadolinium-Based AGuIX Nanoparticles and Their Biocompatibility after Systemic Injection. ACS Nano 2015, 9, 2477−2488. (34) Han, Z.; Li, Y.; Roelle, S.; Zhou, Z.; Liu, Y.; Sabatelle, R.; DeSanto, A.; Yu, X.; Zhu, H.; Magi-Galluzzi, C.; Lu, Z. R. Targeted Contrast Agent Specific to an Oncoprotein in Tumor Microenvironment with the Potential for Detection and Risk Stratification of Prostate Cancer with MRI. Bioconjugate Chem. 2017, 28, 1031−1040. (35) Sour, A.; Jenni, S.; Orti-Suarez, A.; Schmitt, J.; Heitz, V.; Bolze, F.; Loureiro de Sousa, P.; Po, C.; Bonnet, C. S.; Pallier, A.; Toth, E.; Ventura, B. Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer. Inorg. Chem. 2016, 55, 4545−4554. (36) Huang, P.; Qian, X.; Chen, Y.; Yu, L.; Lin, H.; Wang, L.; Zhu, Y.; Shi, J. Metalloporphyrin-Encapsulated Biodegradable Nanosystems 6033

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for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy. J. Am. Chem. Soc. 2017, 139, 1275−1284. (37) Mi, P.; Dewi, N.; Yanagie, H.; Kokuryo, D.; Suzuki, M.; Sakurai, Y.; Li, Y.; Aoki, I.; Ono, K.; Takahashi, H.; Cabral, H.; Nishiyama, N.; Kataoka, K. Hybrid Calcium Phosphate-Polymeric Micelles Incorporating Gadolinium Chelates for Imaging-Guided Gadolinium Neutron Capture Tumor Therapy. ACS Nano 2015, 9, 5913−5921. (38) Lee, M. H.; Kim, E. J.; Lee, H.; Kim, H. M.; Chang, M. J.; Park, S. Y.; Hong, K. S.; Kim, J. S.; Sessler, J. L. Liposomal Texaphyrin Theranostics for Metastatic Liver Cancer. J. Am. Chem. Soc. 2016, 138, 16380−16387.

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DOI: 10.1021/acs.inorgchem.7b01277 Inorg. Chem. 2017, 56, 6029−6034