Molecular Sensors for NMR-Based Detection - Chemical Reviews

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Molecular Sensors for NMR-Based Detection Zhenchuang Xu, Chao Liu, Shujuan Zhao, Si Chen, and Yanchuan Zhao*

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Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China ABSTRACT: Reliable and precise methods capable of unambiguously identifying target analytes in real-world samples are indispensable in various fields, ranging from biological studies and diagnosis to quality control. Among various analytic techniques, nuclear magnetic resonance (NMR) is uniquely powerful as it provides multidimensional data useful for structural analysis at the atomic level. The rich information obtained from various NMR experiments allows one to access not only molecular structures and interactions but also the dynamics and diffusional properties. However, the interpretation of NMR data in the analysis of real-world mixtures can be challenging and is often complicated by the overlap of the NMR resonances of each component. Moreover, the inherently low sensitivity of the NMR technique hampers its implementation in many detections, where the analytes of interest are present at low concentrations. By a combination of heteronuclear NMR, dedicatedly designed sensors, ingenious transduction mechanisms, and powerful NMR pulse sequences, significant advancements were made to conquer these limitations. The present review summarizes the sensing systems that effectively facilitate NMR-based detection with an emphasis on the chemical perspective of sensor design and transduction mechanism. Advances in hyperpolarized sensors to boost the sensitivity of detection will also be included where appropriate.

CONTENTS 1. Introduction 1.1. Scope of the Review 2. Sensors Relying on the Perturbation of NMR Chemical Shifts 2.1. Background 2.2. Detection of Enzyme and Enzymatic Activity 2.3. Detection of Reactive Oxygen Species (ROS) and Reductive Environments 2.4. Reaction-Based Functional Group Identification and Quantification 2.5. Detection of Ions and Neutral Organic Analytes 3. Sensors Relying on the Modulation of Relaxation and Chemical Exchange Properties 3.1. Background 3.2. Detection of Enzyme and Enzymatic Activity 3.2.1. Modulation of the Relaxation Properties Based on PRE Effect 3.2.2. Modulation of the Relaxation Properties Based on Restriction of Molecular Motions 3.3. Detection of Reactive Oxygen Species (ROS) and Reductive Environment 3.4. Detection of Ions and Neutral Organic Analytes 4. Sensors Based on the Miscellaneous NMR Techniques 4.1. Triple Resonance NMR Analysis

© XXXX American Chemical Society

4.2. Nanoparticle-Assisted Affinity NMR Spectroscopy 5. Concluding Remarks and Future Directions Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION

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1.1. Scope of the Review

Novel sensing methods to detect analytes of biological, medicinal, and environmental importance have attracted increasing research interest over the last two decades.1−13 The capability to precisely determine the composition of a target system and to monitor its variation/evolution over time is highly desirable in various fields, including biological studies, diagnosis, and quality control because any decision-making process has to rely on an in-depth and comprehensive understanding of the system under investigation. Among

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Received: March 29, 2018

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DOI: 10.1021/acs.chemrev.8b00202 Chem. Rev. XXXX, XXX, XXX−XXX

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This review is written from the perspective of an organic chemist with an emphasis on the strategy and mechanism of NMR sensing responses. Some biological applications that are less geared toward detection, such as the investigation of conformational changes and binding properties of proteins,44−52 peptides,53−57 DNAs,58−60 RNAs,61−68 and nucleotides69−72 will not be included in this review. The MR imaging techniques that rely on the manipulation of relaxation properties of 1H with contrast agents have already been reviewed and will not be discussed in detail.73−77 NMR-based sensors to detect pH and oxygen usually rely on dynamic and relatively nonspecific interactions, and thus they are outside the scope of this review.78−83 We will begin with some fundamental aspects of NMR spectroscopy and provide a brief discussion on its limitations and potential solutions. The subsequent sections contain the detailed discussion of dedicatedly designed NMR-based sensors.

various analytic techniques, nuclear magnetic resonance (NMR) is uniquely powerful because it provides structural information at the atomic level in a multidimensional manner.14,15 The chemical shifts, signal intensities, as well as relaxation and chemical exchange properties are crucial for structural elucidation and the investigation of various molecular interactions and dynamic processes. These distinguished capabilities make NMR an indispensable tool for various demanding characterizations. The high permeability of radio frequency radiation through deep tissues makes magnetic resonance (MR) imaging an ideal technique for the in vivo study of large and opaque organs noninvasively, which is usually difficult to achieve with optical-based methods.16−19 Despite its robustness, the NMR technique has its own limitations. The characteristic NMR signals and the corresponding spectroscopic changes upon reaction/binding are not often easily discernible in the analysis of complex mixtures, which is further complicated by the presence of interference. Furthermore, the sensitivity of NMR spectroscopy is inherently low because the signal intensity depends on the population difference between spin states. This population difference is extremely low even under an ultrastrong magnetic field (ca. 1/ 32 000 for 1H at 9.4 T).20 In fact, only a few NMR-active nuclei with sufficient natural abundance and high gyromagnetic ratio are suitable for detection purposes with routinely equipped NMR spectrometers. Chemosensing methods that transduce physical, chemical, and biological events into measurable NMR responses are employed to widen the scope of the NMR technique for analytic purposes. These systems utilizing designed molecular and nanosized sensors offer a number of benefits and are well suited to address the above-mentioned limitations encountered in conventional NMR analysis. For instance, 19F-containing substrates are often used for enzymatic assays to simplify the interpretation of the NMR spectrum.21−29 The binding-induced shifts of the NMR resonances of 19F-labeled chelators were exploited to detect various metal ions.26,27 Exquisitely designed hyperpolarized sensing systems were developed to boost the sensitivity of NMR-based detection, which allows the realtime detection of analytes at biologically relevant concentrations.30 Compared to fluorescence and luminescence-based sensing schemes,31−43 NMR spectroscopy is usually sufficiently informative by itself such that it is more frequently used to validate the sensing results obtained from other approaches. Furthermore, modern synthetic chemistry has provided scientists with robust toolboxes to tailor the properties of NMR-based sensors for detection under various circumstances. In this review, we focus on molecular and nanosized sensors that facilitate NMR-based detection in a number of ways, including (1) simplifying the NMR spectrum and facilitating data interpretation; (2) visualizing analytes that are NMRinactive or of low NMR sensitivity; and (3) boosting detection sensitivity and selectivity. We limit the scope of this review to heteronuclear-containing sensors with highly specified reactivity or recognition properties. The sensing responses are reflected by the change of NMR properties of an isotopelabeled or nonbiological nucleus in mainly two ways: (1) to change the chemical shifts and (2) to shorten or lengthen the relaxation time. Sensing systems devoid of these properties but which facilitate detection through miscellaneous NMR techniques will be discussed in a subsequent section. Detection relying on conventional 1H NMR analysis will be discussed briefly where appropriate.

2. SENSORS RELYING ON THE PERTURBATION OF NMR CHEMICAL SHIFTS 2.1. Background

NMR chemical shifts and splitting patterns provide rich information for the characterization of organic molecules. Under a strong magnetic field, the resonances of NMR-active nuclei are well resolved as separated peaks, which reflect the subtle differences in the chemical environment surrounding the nuclei. It is usually possible to identify chemical transformations and recognition events by monitoring the characteristic NMR signals of the reactant/product or the interacting partners. For systems involving organic molecules, this can be easily performed by using either conventional 1H or 13 C NMR. NMR has been routinely used under a variety of circumstances, ranging from process monitoring and structural determination to mechanistic studies. 19F, 31P, and 129Xe are the most frequently used nuclei for the design of sensing systems based on the perturbation of NMR chemical shifts. The large chemical shift dispersion of these nuclei enables the facile visualization of subtle changes in the local environment surrounding these heteronuclear labels via distinctive NMR signals. The lack of endogenous xenon and organofluorine compounds in the body eliminates background signals and simplifies data interpretation. Notably, a chemical shift difference of 0.03 ppm is usually sufficient to achieve baseline separation of two singlet 19F resonances by using a 400 MHz NMR spectrometer. Chemical shift perturbations as small as 0.01 ppm can be still useful for the purpose of qualitative analysis. These advantages allow the simultaneous identification of multiple labeled-species in complex mixtures. When the nuclei under detection are of low natural abundance (e.g., 13C and 15N), isotope-labeling is an effective way to enhance NMR sensitivity. For nuclei with 100% natural abundance, such as 19 F, multiple magnetically equivalent 19F atoms are usually incorporated into the sensor to intensify the NMR detection signals. More significant signal enhancement is usually achieved through various hyperpolarization techniques,84−92 which generate more pronounced population differences between spin states. Implementation of these sensitivity enhancement strategies in sensing systems effectively widens the scope of NMR-based detection. In this section, we will focus on sensors based on perturbation of chemical shifts. The application of these sensors includes (1) detection of enzyme and enzymatic activity; (2) detection of reactive oxygen species B

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hydrolysis of 19F-labeled glucuronide prodrug (Figure 1, 4,5) revealed the kinetics of the release of antitumor nitrogen mustard.99 Gene therapy has great potential for the treatment of various diseases; however, its implementation is hampered by the lack of precise methods to verify the success of transfection. Phosphocreatine (Figure 1, 7), the metabolic product of the creatine kinase reaction, is often used as an indicator to check the effectiveness of gene transfection. A variety of metabolic products can be detected based on their correlated 31P NMR resonances, which provides a noninvasive approach for monitoring gene expression.100 Despite the convenience of this label-free approach, its wide application is hampered by the low sensitivity of 31P NMR (about 6.5% relative to that of 1 H) and the presence of other endogenous 31P-containing molecules. In addition to the above-mentioned drugs/prodrugs and endogenous biological molecules, substrates with strategically positioned fluorine probes are designed to detect the presence of enzymes and to quantify their activities. β-Galactosidase (βgal) produced by the lacZ gene is another useful indicator to verify the success of gene transfection. Mason and co-workers disclosed that 4-fluoro-2-nitrophenyl-β-D-galactopyranoside (PFONPG, 8) could be used as a sensor for the detection of β-gal (Figure 2). Upon enzymatic reactions, 4-fluoro-2-

and reductive environments; (3) functional group identification and quantification; and (4) detection of ions and neutral organic analytes. 2.2. Detection of Enzyme and Enzymatic Activity

The detection of enzymatic activity is of major interest to biological investigation and diagnosis. An abnormal level of enzyme activity is often associated with underlying ailments and has many biological and pathological implications. Enzymatic activity can usually be determined by monitoring an enzymatic transformation, where the rate of consumption of the substrate and the generation of the enzymatic product can be used to derive the activity of a specific enzyme. Although optical-based sensing strategies to detect enzyme activity are well documented, these approaches often suffer from potential modes of interference present in biological samples. Imaging of large opaque organs is also difficult to achieve with opticalbased sensors due to the limited depth of light penetration. NMR-based detection methods using strategically designed sensors offer alternative solutions to deal with these challenges by providing precise and unambiguous sensing results. 19Fcontaining substrates have been extensively used to aid the monitoring of enzymatic reactions owing to the high sensitivity and low background signals of 19F NMR spectroscopy.22,23 Well-established synthetic methods allow selective incorporation of fluorine atoms and fluorinated moieties into various target substrates, thereby making the desired fluorinated substrates readily accessible. Owing to the unique electronic properties of fluorine, fluorinated molecules often display superior biological and pharmaceutical properties compared to their nonfluorinated counterparts.93−95 It is therefore not surprising that many drug molecules contain one or multiple fluorine atoms. As fluorine is isosteric to the hydrogen, the fluorinated analogs of biomolecules are excellent candidates to investigate the metabolism of bioactive molecules. When metabolism is specifically promoted or catalyzed by an enzyme, the monitoring of newly formed 19F-containing products allows for evaluation of enzymatic activities. For instance, the imaging of the metabolic products of 3-fluoro-3-deoxy-Dglucose (Figure 1, 1) allows the mapping of the spatial distribution of aldose reductase activities.96 The transgene expression of cytosine deaminase was evaluated based on the rate of the conversion of 5-fluorocytosine (Figure 1, 2) to 5fluorouracil (Figure 1, 3).97,98 The monitoring of the

Figure 2. Detection of β-gal with PFONPG (8).

nitrophenol (9) is rapidly released, whose 19F NMR resonance is 5−10 ppm shifted compared to that of 8. As the amplitude of chemical-shift change depends on the ionic state of the phenol 9, the enzyme activity and the pH value of the sample can be simultaneously determined.101,102 The cytotoxicity of the sensor and its substrate efficacy toward β-gal were tuned by multiple strategies, including variation of the substituents on the phenyl group (Figure 3,

Figure 3. Structurally modified sensors for detection of β-gal.

10),103 conjugation with heterocyclic moieties, 104 and incorporation of multiple glycosyl groups (Figure 3, 11,12).105,106 The use of CF3-containing sensors was attempted to increase the sensitivity of this approach; however, the induced 19F NMR chemical-shift changes upon enzymatic reaction is minimal.107 In vivo studies through MR imaging with this sensing system are feasible, which was demonstrated by the detection of β-gal in living Escherichia coli.108,109 Iron is often accumulated in cancer cells due to accelerated metabolism and rapid replication. Its paramagnetic relaxation property has been utilized to design 1H MR imaging contrast agents. As the paramagnetic relaxation enhancement (PRE)

Figure 1. Molecules to evaluate enzyme activities through monitoring the metabolism. C

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effect of Fe3+ is spatially anisotropic, the fluorine atoms in proximity to Fe3+ can sometimes remain NMR-visible, while their chemical shifts become more sensitive to the change in surrounding environment. These properties were utilized by Yu and co-workers for the construction of a 19F MRS/1H MRI probe for the detection of β-gal. The key to the success of this sensing system is to use a fluorinated iron chelator as the aglycon to produce an iron complex (15) after the action of βgal (Figure 4). The newly formed iron complex could serve as a 1H NMR contrast agent to visualize the spatial distribution of β-gal.110

Figure 4. 19F MRS/1H MRI dual functional sensor to detect β-gal. Figure 6. (A and B) Evaluation of enzymatic activity using fluorophosphate nucleotide analogues. (C) The time course of cleavage of 2 mM cPAPPF (22) by Ribonuclease T2, determined by 19 F NMR. S stands for 22, P stands for 23. Panel C reproduced with permission from ref 113. Copyright 2015 American Chemical Society.

As many enzymes are capable of promoting the hydrolysis of adenosine triphosphate (ATP), a fluorine-labeled ATP is therefore a general probe to examine the activity of various enzymes. Among various ATP analogs, 2-fluoro-ATP (Figure 5, 16) is found to be a versatile substrate for diverse enzymes,

As fluorine is sterically similar to hydrogen, the binding property of the monofluorinated analogue is often similar to the corresponding parent molecule.114 In this context, a CH2Fcontaining γ-butyrobetaine derivative (GBBNF, 24) was synthesized by the Schofield group for the evaluation of the enzymatic activities for carnitine biosynthesis. The oxidation of GBBNF through the introduction of a β-hydroxyl group induces an upfield shift of >1.0 ppm in 19F NMR, which is sufficient for the real time monitoring of the activity of the γbutyrobetaine hydroxylase (BBOX; Figure 7). The hydroxylation of fluorinated trimethyllysine was monitored with a similar strategy; however, the 19F NMR signals of the trimethyllysine analog and the corresponding hydroxylated product are hardly distinguishable. As the quaternary

Figure 5. 19F-labeled ATP analogue used for detection of the activity of diverse enzymes.

including adenylate kinase, hexokinase, pyruvate kinase, and the myosin ATPase. The 19F NMR signal of the produced 2fluoro-AMP (17) is easily resolved from that of 2-fluoro-ATP, which allows its use as a broadly applicable sensors for the activity assay of diverse enzymes.111 Although the monitoring of the transformation from ATP to ADP is feasible with 1H NMR by observing purine H8 protons in ATP (18) and ADP (19), the chemical-shift difference induced by the reaction is merely 0.01 ppm, which precludes precise quantitative studies.112 Alternatively to the introduction of 19F-labels on the nucleobase moiety, fluorophosphates nucleotide analogs produced through the replacement of the terminal hydroxyl group by a fluorine atom were found to be viable substrates for various enzymatic reactions. The hydrolysis of adenosine 5′-(3fluorotriphosphate) (ATPF, 20) in the presence of snake venom phosphodiesterase (SVPDE) can be easily followed with 19F NMR spectroscopy (Figure 6A). The structural alternation distant to the fluorophosphates moiety produces discernible changes in 19F NMR signals. Based on this property, the cleavage of the 2′-phosphoester bond by ribonuclease T2 was successfully visualized (Figure 6B,C).113

Figure 7. (A) Fluoromethylated γ-butyrobetaine analog for the detection of BBOX. (B) Quantification of BBOX activity in cell lysates by 19F NMR. Panel B reproduced with permission from ref 115. Copyright 2014 Royal Society of Chemistry (https:// creativecommons.org/licenses/by/3.0/). D

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ammonium derivatives are extensively used in pharmaceutical industry, their monofluorinated analogues are expected to find wide applications in biological research.115,116 Closely related enzymes are often difficult to differentiate by conventional sensing modalities. Monoamine oxidase (MAO) is known to catalyze the oxidation of amines and to promote their conversion to aldehydes through the formation of hydrolyzable iminium intermediates (Figure 8).117 hMAO-A

Figure 9. Evaluation of ChT-L activity of proteasome using a labeled sensor.

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Figure 10. Evaluation of the GST activity using a 9F-labeled sensor.

The sesquiterpene lactones are potential mechanism-based inhibitors because they react with sulfhydryl groups, resulting in the covalent modification of enzymes. Due to its low solubility, its amino-derivatives are often used as prodrugs. The Colby group found that one of the CF3-labeled prodrug analogs has reactivity similar to the parent molecule. The release of the 19F-labeled amine can be easily monitored by 19F NMR under deuterium-free conditions. The elimination was found to proceed faster in the presence of GSH, which competes with the amine for nucleophilic addition to the sesquiterpene lactone (Figure 11).124 This observation

Figure 8. (A) 19F-labeled sensor to selectively detect hMAO-A. (B) 1 H and 19F chemical shift-selective imaging of probe 26 and product 27 in HEPES buffer. Panel B reproduced with permission from ref 120. Copyright 2011 American Chemical Society.

and hMAO-B are two isoforms of MAO found in humans, which have distinct physiological functions. Although fluorinated serotonin118 and dopamine119 were attempted as the sensors for 19F NMR-based MAO assay, no selectivity for MAO-A/B was observed. Sando and co-workers found the ortho/para-substituted phenol moiety is the key scaffold to achieve hMAO-A specific binding. As the enzymatic product (28) exists in the phenolate form under physiological conditions, a pronounced shift (4.2 ppm) of the 19F NMR signal was induced (Figure 8). The specificity toward hMAO-A along with the sufficiently large change in 19F chemical shifts enable the selective visualization of hMAO-A activity through 19 F MR imaging.120 Based on the strategy of monitoring the distinct NMR signals of the labeled substrate and its enzymatic product, NMR-based sensors targeting diverse enzymes are created. The proteasome possesses three distinct proteolytic active sites.121 It was suggested that the presence of a substrate in one active site activates or inhibits the activity of other sites. In order to obtain more insights into this catalytic behavior, a 19F-labeled substrate 29 for the ChT-L (chymotrypsin-like) site was developed by the Ongeri group for the monitoring of the ChTL activity in the presence of trypsin-like (T-L) and postacid (PA) substrate (Figure 9). The allosteric regulation of the ChT-L activity is proposed based on enzyme activities determined by 19F NMR.122 Glutathione (GSH) transferases (GSTs) are overexpressed in certain tumors and are valuable indicators for diagnosis. A 19 F NMR-based sensor for the direct targeting of the GST activity in living cells was achieved based on the nucleophilic aromatic substitution of a fluorine-containing moiety through a Meisenheimer intermediate (Figure 10). The released molecule (32) possesses a 19F NMR signal distinct from the probe (31), thereby allowing the detection of GST activity in the cell.123

Figure 11. 19F-labeled prodrug for the monitoring of the release of the sesquiterpene lactone.

indicates that the release of the antitumor agents may be more rapid in GSH-rich cancer cells. The GSH-triggered cleavage of the disulfide bond is an effective strategy for the design of tumor-targeting prodrugs. By using fluorine-labeled toxoids as the probe, Ojima and co-workers successfully evaluated the metabolic stability of some drug delivery systems.125−128 Compared to fluorescence and luminescence-based methods, the sensitivity of NMR spectroscopy is much lower because it utilizes radiation of very low energy. In order to increase the sensitivity of NMR-based detection, sensors with multiple magnetically equivalent fluorine labels are often employed. In particular, the strategy utilizing CF3-labeled substrates was termed 3-FABS (three fluorine atoms for biochemical screening) by Dalvit and co-workers. In their study, enzymatic reactions are monitored by the detection of CF3-labeled substrates and their enzymatic products, which allows the screening of inhibitors for the Ser/Thr kinase, AKT1, and the protease trypsin.129,130 The sensitivity of the 19 F NMR-based enzymatic assay can be further increased by the incorporation of two or even four magnetically equivalent CF3 moieties onto the substrates (Figure 12, 39 and 40). The significantly enhanced sensitivity decreases the concentration required for detection, making the NMR-based screening E

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Figure 12. CF3-containing amino acids used for syntheses of substrates for 3-FABS.

Figure 14. 19F-labeled sensor with enhanced relaxation property.

methods suitable for pharmaceutical applications.131−134 Notably, 0.235 μg of enzyme is sufficient for the screening of 100 000 compounds.132 The perfluoro-tert-butyl group is often utilized for highly sensitive NMR-based detection owing to its nine magnetically equivalent fluorine atoms. In one of the applications utilizing the perfluoro-tert-butyl group as the 19F probe, the oneelectron reduction by reductase was studied by the Nishimoto group using an indolequinone derivative. Upon the activation of 41 by NADPH:cytochrome P450 reductase under hypoxia conditions, the nonafluoro-tert-alcohol (42) was released, accompanied by the appearance of a new 19F NMR signal at −73.6 ppm (Figure 13). The monitoring of the biotransformation of 41 by means of chemical-shift selective MR imaging allows the visualization of the occurrence of reductase and its activity.135

Figure 15. (A) 13C spectrum of urea (natural abundance 13C) hyperpolarized by the DNP-NMR method. The concentration of urea was 59.6 mM, and the polarization was 20%. (B) Thermal equilibrium spectrum of the same sample at 9.4 T and room temperature. The signal is averaged during 65 h (232 128 transients). Reprinted with permission from ref 137. Copyright (2003) National Academy of Sciences, U.S.A.

microwave irradiation is needed to promote this process, which is achieved with high-power gyrotron microwave sources. Unpaired electrons are ideal source of polarization because their high gyromagnetic ratio allows near-unity polarization to be attained at low temperature. Liquid samples amenable for the in vitro and in vivo applications are obtained by a dissolution process, during which the nuclear polarization are preserved.86−88 With the increased sensitivity, the MR imaging of hyperpolarized endogenous substances with relatively long lifetime becomes possible and is not interfered with the presence of substances in thermal equilibrium. As the lifetime of hyperpolarization of 13C is significantly shortened by the presence of attached 1H, the carbonyl carbon is usually employed as the probe for the investigation of distribution and metabolism of the target molecule. With this approach, the metabolic imaging with hyperpolarized [13C]urea and [1-13C]pyruvate has been demonstrated.138−144 Based on the chemical-shift change of the hyperpolarized 13C, various enzymes can be detected and imaged by strategically designed sensors. For instance, the activity of aminoacylase-1 is measured based on the conversion of hyperpolarized [1-13C]N-acetyl-L-methionine (Figure 16A).145 A pyruvic acid derivative was developed by Sando and co-workers to selectively target mouse lactate dehydrogenase X (mLDH-X). The specificity was achieved by the incorporation of an isopropyl group on the pyruvic acid, which restricts its access to enzymes with more sterically demanding binding pockets (Figure 16B).146 In a similar way, the activities of aminopeptidase N147 and γ-glutamyl transpeptidase148 were successfully evaluated.

Figure 13. (A) One-electron reduction of the 19 F-labeled indolequinone derivative under hypoxic conditions. (B) 19F NMR spectra and MR images of 41 incubated with cell lysate of A549 for 0 (I), 6 (II and V), 12 (III and VI), and 24 h (IV and VII) under aerobic (II, III, and IV) or hypoxic (V, VI, and VII) conditions: (middle) 41 signal selected image and (right) 42 signal selected image. Panel B reproduced with permission from ref 135. Copyright 2009 American Chemical Society.

Unlike the Gd3+ ion, whose magnetic susceptibility tensor is almost isotropic due to the absence of orbital degeneracy, paramagnetic lanthanide complexes could induce pseudocontact shifts and amplify chemical-shift differences between probe species. This effect was exploited by Parker and coworkers to devise 19F-labeled probe for the detection of metal ions, citrate levels, and ester hydrolysis (Figure 14). The accompanied enhanced rate of longitudinal relaxation allows for faster data acquisition, thereby leading to signals of higher signal-to-noise ratios.136 In contrast to the moderate increase in sensitivity achieved through 3-FABS, hyperpolarization techniques such as dynamic nuclear polarization (DNP) can increase the signalto-noise ratio by >10 000 times in liquid-state NMR (Figure 15).137 This technique relies on the transfer of high electron spin polarization to the nuclear spins. High-frequency F

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signals. The use of 19F chemical-shift-selective imaging allows the visualization of enzymatic production of H2O2.118 The hypochlorite ion (−OCl) is another important ROS found in living organisms. A high level of hypochlorite is believed to be associated with a series of diseases.152,153 Based on its oxidative reactivity, Sando and co-workers designed a fluorine-labeled p-aminophenyl alkyl ether as the NMR sensor for the detection of hypochlorite ion. The oxidation of the substrates induces an ipso-substitution of the fluorinecontaining alkoxyl moiety to produce a trifluoroethanol (Figure 19). Sensor 53 shows a high specificity for −OCl, as no trifluoroethanol was observed when mixing it with other biologically relevant ROS, such as H2O2, ROO•, O2•−, and •OH.154

Figure 16. Hyperpolarized 13C-labeled sensors for the monitoring of enzymatic activities.

Although hyperpolarizable nuclei are not restricted to 13C, sensors utilizing other nuclei have received very limited attention. As nitrogen is extensively found in naturally occurring substances, the 15N-based probes have great potentials for the investigation of various biological processes. Through the perdeuteration of a 15N-containing sensor, a remarkably long 15N spin−lattice relaxation time was achieved, which allowed for the highly sensitive detection of esterase activity (Figure 17).149,150

Figure 19. 19F-labeled sensor for the detection hypochlorite ion.

The transient and highly reactive nature of some ROS poses significant challenges to their detection. Peroxynitrite (ONOO−) generated from the combination of superoxide anion (O2•−) and NO• is a highly oxidative species, the formation of which could induce deleterious consequences.155−157 In order to alleviate the problems of low selectivity and slow reaction kinetics, fluorinated isatins (56) were designed and utilized for selective detection of ONOO− in live cells. New 19F NMR signals corresponding to the fluorinated anthranilic acids (57) were observed in the presence of ONOO−. These isatin-based sensors show a high resistance to peroxide and display negligible reactivity toward other oxidants (Figure 20). The noninvasive detection of ONOO− in living lung epithelial cells was demonstrated with this method.158

Figure 17. (A) Hyperpolarized 15N-labeled sensor for the monitoring of esterase activity. (B) Stacked single-scan 15N NMR spectra of hyperpolarized probe 49 (every 90 s) after mixing (left) with or (right) without esterase in phosphate-buffered saline. Reproduced with permission from ref 150. Copyright 2017 Nature Publishing Group (https://creativecommons.org/licenses/by/4.0/).

Figure 20. 19F-labeled sensor for the detection of peroxynitrite.

2.3. Detection of Reactive Oxygen Species (ROS) and Reductive Environments

Hyperpolarization techniques have been implemented in NMR-based sensing schemes to achieve ultrasensitive detection of ROS. Based on the selective reaction between H2O2 and α-ketoacids to produce carboxylic acids, Chang and co-workers developed a hyperpolarized 13C-based H2O2responsive sensor (58). This sensor proved to be very selective since only minimal amounts of decarboxylative product were observed in the presence of other biologically relevant ROS, such as O2−, tBuOOH, NO, OCl−, and ONOO−. The hyperpolarization of the 13C-nucleus in benzoic acid has a long lifetime and is retained after the H2O2-mediated transformation, thereby providing a viable way for the in vivo detection of H2O2 at concentrations as low as 10 μM (Figure 21).159 Other reaction-based sensors, such as hyperpolarized 13C-thiourea, were also utilized for the in vivo detection of H2O2.160 Carbonyl carbons are most commonly utilized to create hyperpolarized sensors with sufficiently long lifetime.86 Such a

Reactive oxygen species (ROS) have a close relationship with a variety of ailments. Hydrogen peroxide (H2O2) is one of the most important ROS that has been used as a diagnostic marker as a result of its stability and diffusivity. The oxidation of aryl boronic acids by H2O2 was widely utilized to design H2O2repsonsive sensors.151 Sando and co-workers found that 19Flabeled boronic acids react rapidly with H2O2 to produce the corresponding phenols (Figure 18). The structural change significantly alters the electron density on the 19F nucleus, which is easily discernible by the appearance of new 19F NMR

Figure 18. 19F-labeled phenyl boronic acid for the detection of H2O2. G

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Figure 23. Hyperpolarized H2O2.

Xe-based sensor for the detection of

cage induces an analyte-dependent chemical-shift change of the encapsulated xenon, which allows the discrimination of cysteine from homocysteine and glutathione.164 Limit of detection of 10 μM can usually be achieved with hyperpolarized 129Xe sensors using a single scan.162

Figure 21. (A) Hyperpolarized 13C-labeled sensor for the detection of H2O2. (B) Phantom images of 5 M thermally polarized 13C-BFA 58 in H2O, 5 M thermally polarized 13C-BA 59 in DMA, and 20 mM hyperpolarized 13C-BFA in 100 mM phosphate, 0.3 mM EDTA buffered at pH 7.8 with 0, 25, 50, 100, and 200 mM H2O2. 1H spin echo image (left) and Frequency-specific images (right). Panel B reproduced with permission from ref 159. Copyright 2011 American Chemical Society.

2.4. Reaction-Based Functional Group Identification and Quantification

Being one of the most informative characterization techniques, NMR is usually capable of identifying and quantifying the organic molecules in their pure state. However, the direct analysis of complex mixtures is challenging due to the severe background interferences and the presence of a series of closely related analytes. Various reaction-based sensors have been developed to address this limitation. The binding between hydroxyl-containing analytes and synthetic receptors is often weak in solution, which results in a rapid exchange between species in equilibrium. Under this circumstance, the observed NMR signal only reflects the population average of chemical shifts of the bound and free receptors and cannot be used to precisely identify the analyte. As a consequence, covalent derivitization is often required to simultaneously sense multiple hydroxyl-containing analytes. The 31P NMR analysis of the phosphite esters produced by the reaction with 2-chloro-4,4,5,5-tetramethyl-1,3,2-diazaphospholane (TMDP) provides a viable way for the detection of analytes bearing hydroxyl groups (Figure 24). The determi-

structural constraint limits the diversity of hyperpolarized 13Clabeled sensors. A HOCl-responsive sensor, [13C, D3]panisidine (60) bearing a perdeuterated methoxyl group (O13CD3) was developed by Sando and co-workers to extend the lifetime of hyperpolarization. By the replacement of C−H bond with C−D bond, quick dissipation of hyperpolarization is prevented. This probe reacts with HOCl selectively to produce hyperpolarized 13CD3OH. A signal enhancement of 6100-fold was achieved through this approach (Figure 22). As the structural constraint to use the carbonyl carbon as the hyperpolarized probe is addressed, this strategy significantly increases the diversity of hyperpolarized sensors.161

Figure 22. Hyperpolarized HOCl.

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C-based sensor for the detection of

Figure 24. 31P NMR-based sensor for the identification and quantification of analytes bearing hydroxyl groups.

The transformation of arylboronic acid groups appended on the periphery of cryptophane-111 into phenol groups by H2O2 can be sensed by the encapsulated xenon due to the extreme sensitivity of 129Xe chemical shifts to the change in its surrounding environment. The progress of the oxidative hydrolysis of the arylboronic acid groups are easily monitored and characterized with the newly formed 129Xe NMR signals, which correlate to xenon encapsulated in cryptophanes with different numbers of boronate and phenol groups (Figure 23). The simulation of the chemical shifts of the encapsulated xenon via DFT calculations provides valuable insights toward understanding the progression of the transformation.162 In a similar way, the use of an azide-modified cryptophane cage allows the detection of H2S. A downfield shift of 1.1 ppm of the 129Xe NMR signal was observed upon the addition of HS−, which was attributed to the HS−-mediated reduction of azide.163 Thiol-addition reaction has been utilized to create 129 Xe-based biosensors selective for biothiols. The addition of biothiols to the acrylate group appended on the cryptophane

nation of the identity of the analyte is often feasible with this approach as the phosphite esters derived from diverse alcohols and carboxylic acids possess distinct and differentiable 31P NMR signals.165 This method is particularly useful for the analysis of biodiesel samples, in which the glycerol and fatty acids may be present as containment due to the incomplete reaction. The 31P NMR analysis allows for the rapid detection of alcohols and fatty acids content and the determination of substitution pattern on partially esterified glycerols, which is valuable for process control in the biodiesel industry.166 The application of the 31P NMR-based probe has been extended to the analysis of coal pyrolysis condensates,165 phenolic moieties in lignins,167−170 vegetable oils,171 cellulose esters,172 and others.173 The reviews focusing on the usage of TMDP and related 31P-based reagent are available, and we would like to refer the interested readers to the relevant literature.172,174,175 H

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problems.180−182 As separation is not needed for the direct analysis by 19F NMR spectroscopy, sensitive and reactive substances can be precisely quantified in solution. A 19F-labeled reaction-based sensor targeting biothiols was developed by Zhou and co-workers. The acrylate moiety is used as the reaction site to achieve specificity for thiolcontaining analytes. Various thiols can be easily detected by observing the distinct 19F NMR signals upon the Michael addition. Interestingly, an intramolecular cyclization only occurs in the experiment with cysteine (Cys). This process is accompanied by a much more pronounced change in the 19F chemical shift, which allows facile discrimination of Cys from homocysteine (Hcy) and GSH (Figure 27).183

One of the limitations of using 31P NMR for analytic applications is its low sensitivity. As a result of the long relaxation time of the 31P nucleus, a prolonged acquisition is usually required to produce a spectrum with sufficient signalto-noise ratio. In contrast, the 19F-labeled sensor is capable of providing much higher sensitivity. Drouza and co-workers demonstrated that the analysis of hydroxyl-containing analytes can be easily performed through an esterification with trifluoroacetic anhydride (Figure 25). Similar to 31P NMR,

Figure 25. Trifluoroacetic anhydride used for the identification and quantification of alcohols and phenols.

the wide chemical shift dispersion of 19F NMR allows the identification of primary, secondary, and cyclic aliphatic alcohols and phenols.176 The analysis of edible oils with this method affords 19F NMR fingerprints useful for the differentiation between virgin olive oil and sunflower oil. The quantification of total hydroxyl groups in a mixture is feasible based on the integration of the corresponding 19F NMR signals. The evaluation of the activity of various phenols under oxidative conditions was achieved using this strategy.177 The condensation between hydrazine and carbonyl compounds is rapid and highly selective. The 19F-labeled hydrazine (71) can therefore be used as a probe for carbonyl compounds (Figure 26). Based on the characteristic 19F NMR signals of the condensed products, the carbonyl groups in industrial humins and lignins can be readily quantified.178,179 This strategy has also been used by Ragauskas and co-workers for quantification of aldehydes and ketones in pyrolysis oils, the presence of which is responsible for corrosion and aging

Figure 27. 19F-labeled sensor to simultaneously differentiate Cys, Hcy, and GSH.

The nonstabilized diazoalkanes are versatile synthetic intermediates, which are involved in a number of highly useful transition-metal catalyzed reactions. As a result of their limited stability, calibration is often needed before each usage. A 19Flabeled aryl carboxylic acid (77) was utilized to quantify the nonstabilized diazoalkanes (78) in solution based on the 19F NMR signal of the ester products (Figure 28). As only a minute amount of diazoalkane is needed, this safer procedure is expected to facilitate the routine use of these versatile synthetic intermediates.184

Figure 28. 19F-labeled aryl carboxylic acid used for the quantification of nonstabilized diazoalkanes.

The application of 19F-labeled sensors for the functional group quantification is not limited to small molecules. Hoye and co-workers developed a convenient and precise method for the determination of the NH2 content of various polymers. In this method, the NH2-functionalities react rapidly and cleanly with 3,5-bis(trifluoromethyl)benzaldehyde (81) to produce the corresponding imines. The newly formed 19F NMR signals are easily discernible and are used for the determination of the NH2 content of polymers with diverse molecular weight distributions (Figure 29).185

Figure 26. (A) 19F-labeled hydrazine used for the identification and quantification of carbonyl compounds. (B) Partial 1H NMR spectra of 5-methylfuran-2-carbaldehyde, partial 1H and 19F NMR spectra of the reaction mixture of 5-methylfuran-2-carbaldehyde and 4(trifluoromethyl)phenylhydrazine. Panel B reproduced with permission from ref 179. Copyright 2017 American Chemical Society.

2.5. Detection of Ions and Neutral Organic Analytes

Metal ions play vital physiological roles in biological systems.186,187 The real-time tracking and detection of metal I

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an optical indicator for intracellular free Ca2+.196 The binding strength of 19F-labeled BAPTA toward various ions and the dynamics of the BAPTA-metal association are influenced by the position of the fluorine substituents. The complexation of Ca2+ with BAPTA bearing fluorine labels at 4,4′ (4F-BAPTA) and 5,5′(5F-BAPTA) positions display fast and slow exchange behaviors on the NMR time scale, respectively, when a 188 MHz NMR spectrometer is used. The measurement of free Ca2+ concentration with 5F-BAPTA/4F-BAPTA is unaffected by Mg2+ at low concentrations or the presence of other divalent metal ions, such as Zn2+, Fe2+, and Mn2+ (Figure 31).

Figure 29. 19F-labeled aldehyde used for the quantification of NH2 group in polymers.

ions under cellular environment are of great interest.188−190 As most of the metal ions are NMR inactive or have very low sensitivity, direct analysis of metal ions by NMR is challenging. Heteroatom-labeled chelators are thus designed to enable the detection of metal ions noninvasively. The exchange rate between the free and bound chelators has a significant impact on how the detection and quantification are performed. Typically, distinct NMR signals correlated to the bound and free chelators are observed if the association is slow on the NMR time scale. The concentration of the target ion is often calculated based on the ratio between the bound and free chelators if the association constant is known. When the association is sufficiently strong, the signal intensity of the bound chelator can be used to quantify the metal ions directly. In contrast, when the association is fast on the NMR time scale, a single NMR signal is observed, which reflects the population average of NMR shifts from the bound and free chelators. The observed NMR signal will be influenced by the concentration of the target ion, which hampers the precise identification of metal ions in complex mixtures. As the measurement of chemical shifts is more precise than the measurement of areas of NMR signals, fast-exchange metal ion sensors are usually capable of detecting ions at a wider range of concentrations. It is noteworthy that the NMR time scale discussed here depends on the chemical-shift difference between interconverting species in hertz, which is influenced by the strength of magnetic field and the type of nucleus under investigation.191 Ethylenediaminetetraacetic acid (EDTA) is well-known for its capability to bind various metal cations and to form stable complexes in aqueous solution. This property makes the EDTA an ideal scaffold to create NMR-based sensors for the detection of metal ions. The chelating of EDTA to calcium and magnesium ions is found to result in complexes with characteristic 1H NMR signals (2.70 ppm for Mg2+ and 2.56 ppm for Ca2+), which allows the detection of metal ion at very low concentrations (Figure 30). Limits of detection for Mg2+ and Ca2+ were determined to be 0.27 mg/L and 0.42 mg/L, respectively.192−194 The 19F-labeled chelator was first used by Smith et al. for the detection of various metal ions in cellular environment.195 This probe is created by the incorporation of fluorine labels onto 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), which was developed by Tsien and co-workers as

Figure 31. 19F-labeled BAPTA for the detection of various metal ions.

In addition, the binding strength, cellular toxicity, and permeability of the ion sensors can be finely tuned through varying the substituents on the phenyl group.197,198 These favorable sensing properties promised the wide application of BAPTA-based ion sensors in the investigation of various Ca2+related biological processes.199−214 Zn2+ ion also binds strongly to tetraacetate acid−based ligand. Its presence often hampers the precise quantification of cellular calcium with optical-based sensors due to the undesired fluorescence quenching. In contrast, the slowexchange 19F NMR-based sensors produce distinct NMR signals for Ca2+ and Zn2+, which provides unambiguous results by mitigating the interference from similar ions. The simultaneous visualization of both metal ions in complex systems can be achieved.215 In addition to various divalent metal ions, 19F-labeled sensors for Na+ has also been created. 15-crown-5 or cryptand were typically used as the basic recognizing scaffold, which was modified with 19F-labels and additional chelating groups to enhance the binding with Na+. In order to achieve the quantification of intracellular Na+, the water solubility, pKa as well as the association constant with Na+ have to be finely tuned. The chelator 87 was identified as the structurally simplest chelator useful for detection of Na+ with a moderate Na+/K+ selectivity.216 In order to increase Na+/K+ selectivity, an additional chelating arm was attached to the chelator with the hope to restrict the access of K+ through creation of a more confined binding pocket. Consistent with this design, sensor 88 displays a very high Na+/K+ selectivity, whereas its association with Na+ is too strong to be applied to the quantification of intracellular Na+. This problem was addressed by the replacement of the oxygen bridge with a −NR− linkage, which reduces chelator’s affinity to Na+ but does not deteriorate the Na+/K+ selectivity (Figure 32). Membrane permeability is usually a prerequisite for a sensor to be adapted for the analysis of the intracellular environment. This property is usually rendered through esterification of the metal ion chelator. The modified chelator with an appropriate lipophilicity then undergoes a hydrolysis within the cell to release the real metal ion probe. To ensure the retention in the cytosol, both free and bound chelators have to be charged during the detection. This is usually achieved by introducing

Figure 30. 1H NMR analysis of chelation of Mg2+ and Ca2+ with EDTA. J

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Figure 32. 19F-labeled sensors for the detection of Na+.

Figure 34. 19F-labeled sensor for the detection of metal ions with fluorine−metal interactions.

multiple carboxylate acid groups onto the chelator, which exist in the ionic form at normal intracellular pH. In order to meet these criteria, structurally optimized 19F NMR-based sensors for Na+ continues to be developed.217,218 In addition to the alternation of the electronic properties of the ligand with metal ion complexation, fluorine−metal interactions were also exploited to design 19F NMR-based sensors with the aim to achieve more pronounced chemicalshift change. Fluorinated crown ethers are great candidates for probing the metal−fluorine interaction, whereas these molecules cannot readily form stable complexes with metal ions due to the strong electron-withdrawing ability of fluorine (Figure 33).219−223 The complexation of group I metal ions

with the slow chemical exchange behavior allows the simultaneous detection of as many as 7 cations in solution, including H+, K+, Ba2+, Sr2+, Na+, Ca2+, and Li+ (Figure 35).227−230

Figure 35. 19F-labeled cryptand for the detection of various metal ions based on metal−fluorine interactions.

The metal-ion induced conformational change of biomolecules has also been exploited for the design of NMR-based ion sensors. The thrombin aptamer is known to undergo an intramolecular conformational change to promote the Gquadruplex formation in the presence of K+. Based on this K+dependent rearrangement, Fujimoto and co-workers created a K+ sensor (Figure 36, 97) by introducing a 3,5-bis-

Figure 33. Fluorinated macrocyclic receptors.

with partially fluorinated cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives (91) is also weak because nitrogen donors are now well suited for hard metal ions.224 The Plenio group found that the tetrafluoro analog of the [2S, 2O, 2O]-cryptand displays good binding capabilities toward various metal ions. A similar change in 19F chemical shifts of the chelator was observed for Li+, Na+, K+, Rb+, and Ba2+ upon complexation, which suggested the interaction between the metal ion and fluorine atom may not occur. This observation was attributed to a uniformed conformational change induced by the ion chelation. Consistent with this assumption, the X-ray singlecrystal structure of chelator 92 complexed with Na+ disclosed that the distance between sulfur and Na+ is too far to form a bond.225 1-Fluoro-2,6-bis(methylene-iminodiacetate)benzene (93) was later attempted by Plenio et al. for the investigation of direct metal−fluorine interactions. Upon complexation, the bound metal ion is positioned in proximity to the C−F bond, which promotes the formation of intimate metal−fluorine interactions (Figure 34). Surprisingly, the least electronwithdrawing ion, Ba2+, induced the largest 19F chemical-shift change. This observation was attributed to the favorable σdonor bond of fluorine to Ba2+ as a result of its suitable size. The metal−fluorine interaction was also supported by the fact that the 19F-labeled chelator (93) displayed high affinity to Ba2+ than its nonfluorinated counterpart.226 Such direct metal−fluorine interaction was also observed in a number of partially fluorinated crown ethers and cryptands with complexed metal ions. The pronounced chemical-shift change induced by the metal−fluorine interaction, together

Figure 36. 19F-labeled sensor for the detection of metal ions based on the conformational change of biomolecules.

(trifluoromethyl)benzene moiety at the 5′ terminal of the aptamer. A new 19F NMR signal was observed upon the addition of KCl, which suggests the complexation of K+ and the accompanied conformational change (Figure 36). This biomolecule-based sensing system displays excellent selectivity since the addition of other metal ions, such as Li+, Na+, Mg2+, and Ca2+, neither produces new NMR signals nor induces chemical-shift change of the 19F-labeled aptamer.231 Transition-metals are known to display a variety of catalytic reactivities. Many chemical transformations proceed only in the presence of suitable transition metals. The occurrence of the metals can, therefore, be evaluated with such transformations. 1,4,7,10-Tetraazacyclododecane (cyclen) is a versatile ligand used to form robust Lewis acidic zinc complexes. In aqueous solution, the water molecule bound to zinc is readily deprotonated and acts as a nucleophile. This unique property allows the creation of a reaction-based Zn2+ K

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chemical exchange, an approximately 10 to 1000-fold increase in detection sensitivity relative to the direct magnetic resonance spectroscopy (MRS) analysis can be achieved. Knchel and co-workers demonstrated magnetization transfer between Ca2+ bound and free 5F-BAPTA, which indicates the feasibility to implement CEST in 19F NMR-based ion detection. The exchange kinetic is crucial for the generation of CEST-based MR imaging contrast. In a 19F CEST experiment for the analysis of solutions containing Ca2+ (slow to intermediate exchange), Zn2+ (very slow exchange), and Mg2+ (fast exchange), respectively, with 5F-BAPTA, McMaho and co-workers found that a pronounced saturation transfer contrast was detected only in the Ca2+-containing solution. This observation indicates that the chemical exchange should be relatively slow to allow the generation of resolvable NMR signals for the ion-free and ion-bound chelators, whereas at the same time it should be sufficiently fast to enable the saturation transfer between these two interconverting species during the experiment. Based on the attenuation of the 19F NMR signal of 5F-BAPTA, Ca2+ at a concentration of 500 nM can be detected.236 By switching the ion receptor to TFBAPTA (103), exchange rates for Fe2+ and Zn2+-containing complexes fall into the suitable range for CEST. The simultaneous detection of Zn2+ and Fe2+ in the presence of potential competitive ions was demonstrated (Figure 40).237

sensor, wherein a cyclen ligand bearing an internally tethered aryl boronic acid was used as a probe (Figure 37). The complexation of Zn2+induces a rapid cleavage of the C−B bond to produce B(OH)3, the amount of which can be used to quantify Zn2+ with concentrations as low as 2.5 μM.232

Figure 37. 11B NMR-based sensor for the detection of Zn2+.

Using a similar strategy, Aoki and co-workers modified the nido-o-carborane with a metal chelator to create a hybrid sensor (100) for Cu2+. A catalytic amount of Cu2+ is sufficient for the complete decomposition of the nido-o-carborane to produce 9 equiv of B(OH)3 (Figure 38). This unique mechanism for signal amplification allows the detection of Cu2+ at low mM concentrations.233,234

Figure 38. 11B NMR-based sensor for the detection of Cu2+.

The sensitivity is one of the limitations of NMR-based sensing methods. Extensive data acquisition is often required to detect analytes at low concentrations. One way to increase the sensitivity of the NMR-based detection is to modify the relaxation properties of the sensor because greater accumulation of signals is achieved in a given time period with reduced T1. London and co-workers found that the introduction of a large number of protons spatially close to the fluorine atom is an effective strategy to reduce the T1 of the 19F-labeled Ca2+ sensor 5F-BAPTA (Figure 39). The T1 of the modified sensor

Figure 39. property.

19

F-labeled Ca2+ sensor with optimized relaxation Figure 40. (A) CEST-based 19F-labeled sensors for metal ion imaging. (B) 1H and 19F MR phantom images of different samples. Samples in the phantom containing 10 mM 103 and 200 μM ion. Panel B reproduced with permission from ref 237. Copyright 2015 American Chemical Society (https://pubs.acs.org/doi/10.1021/ ja511313k). Note: further permissions related to the material excepted should be directed to the ACS.

was reduced to 0.40 s, which is much shorter compared to 0.78 s for the most frequently used 5F-BAPTA. Owing to the more favorable relaxation properties, a 1.4 times increase in signal-tonoise ratio was achieved with the same acquisition time.235 The chemical exchange saturation transfer (CEST) technique is another way to enhance the sensitivity of 19F NMR-based ion detection. This technique relies on the rapid chemical exchange between the ion-free and ion-complexed 19 F-labeled ion receptors. The 19F frequency of the ioncomplexed sensor is radiofrequency labeled, resulting in a significant attenuation of the 19F NMR signal of the free sensor through magnetization transfer. As a result of the rapid

The Jiang group also utilized the CEST-based technique for the visualization of various metal ions. New 19F-labeled metal chelator with an internally tethered hexafluoroisopropanol group was created as the ion sensor. The binding of Ca2+, Zn2+, and Mg2+ produced new 19F NMR signals that are 0.2, 0.2, and 0.4 ppm upfield shifted compared to that of ion-free ligand, L

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presence of an excess amount of Ca2+, which hampers its implementation in the analysis of complex mixtures. A structurally optimized sensor utilizing the 15N as the coordinating atom was developed to address this limitation. By design, the coordination of 15N to Ca2+ decreases its conjugation with the phenyl group, which potentially induces a more pronounced electronic perturbation on 15N. Consistent with the design, an upfield shift of 5.0 ppm was observed when 2 equiv of Ca2+ was added to the solution containing sensor 108 (Figure 43). A signal enhancement about 4800 times relative to the signal intensity obtained with thermally equilibrated state NMR was achieved with this approach.239

respectively (Figure 41). Although the hexafluoroisopropanol group is known to bind metal ions effectively, the observed

Figure 43. Hyperpolarized sensor for the detection of Ca2+ with 15N as a coordinating atom.

19

Figure 41. (A) CEST-based F-labeled sensor bearing hexafluoroisopropanol moiety for metal ion imaging. (B) 19F NMR of sensor 105 without and with Mg2+, Ca2+, and Zn2+. Panel B reproduced with permission from ref 238. Copyright 2017 Royal Society of Chemistry.

Hyperpolarized 13C-label EDTA and egtazic acid (EGTA) were utilized by the Westmeyer group to achieve highly sensitive detection of metal ions at biologically relevant concentrations. Unlike the fast chemical exchange observed with hyperpolarized 15N-based sensors reported by the Sando group,239 the complexation between EDTA/EGTA and various metal ions is slow on the NMR time scale. Upon incremental addition of Ca2+ to the solution containing the 13 C-EGTA, the intensity of newly formed 13C NMR signal correlated to the Ca2+-complexed chelator increased accordingly (Figure 44), the chemical shift of which is about 9.9 ppm downfield to that of the ion-free chelator. As the 13C NMR

small chemical-shift change indicates that hexafluoroisopropanol group may not participate in the ion complexation. Owing to the six chemically equivalent fluorine atoms on the ligand, the sensitivity of the method is significantly higher compared to the detection based on 5F-BAPTA. The detection of Mg2+ at 10 μM concentration was achieved by this method using an acquisition time of 6.5 min.238 More significant enhancement of the sensitivity can be achieved through NMR hyperpolarization techniques. A hyperpolarized 15N-labeled Ca2+ sensor with a remarkably long relaxation time was developed by the Sando group. The key to the success of this ion sensor is the use of perdeuterated methyl substitutions on the 15N, which prevents the rapid relaxation caused by the presence of C−H bonds (Figure 42).

Figure 42. Hyperpolarized Ca2+.

15

N-labeled sensor for the detection of

The addition of Ca2+ induced a downfield shift of the 15N NMR signal of the ligands, the magnitude of which is dependent on the concentration of Ca2+. This behavior indicated the binding between the 15N-labeled sensor and Ca2+ is in fast exchange regime. Thanks to the long relaxation time (T1 = 129 s, 14.1 T) and fast kinetics of Ca 2+ complexation, Ca2+ in human blood at a concentration of 8 mM can be detected with only one scan.149 Despite the high sensitivity, the change in 15N chemical shift of the above-mentioned sensor is merely 1.5 ppm in the

Figure 44. (A) Hyperpolarized 13C-labeled sensor for the detection of various ions. (B) Identification of divalent metals by chemical shifts of 13 C-EGTA. Panel B reproduced with permission from ref 240. Copyright 2016 American Chemical Society. M

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signal of the Ca2+-complexed chelator is not shifted by the change of Ca2+ concentration or the presence of other metal ions, the unambiguous detection of Ca2+ can be achieved. The slow complexation/uncomplexation kinetics also allows the simultaneous visualization of multiple metal ions by chemicalshift selective imaging.240 Independently, the Sando group also utilized the hyperpolarized 13C-labeled EDTA for the detection of calcium based on a similar approach.241 In addition to 13C and 15N, the hyperpolarized 129Xe has also been exploited to increase the sensitivity of metal ion detection. The ease to produce hyperpolarized 129Xe through spin exchange optical pumping (SEOP) promotes extensive use of 129Xe-based sensors.242−245 In this approach, the vapor of alkali metal atoms is first irradiated with resonant circularly polarized light in a magnetic field. The generated electronic spin polarization is then transferred to noble gases, such as 3 He, 83Kr, and 129Xe. The relatively low cost, natural abundance, and favorable NMR property (spin 1/2) make the hyperpolarized 129Xe ideal for clinical applications. To achieve target-specific detection, cryptophane-based molecular cages modified with diverse recognizing units are usually used. Due to the spatial separation between the metal chelating groups and xenon by the cryptophane cage, the sense of metal ion is relatively challenging. By tuning the distance between the metal-chelating group and the cryptophane cage, Rousseau and co-workers created a 129Xe NMR-based probe responsive to Zn2+. Although the probe was obtained as a 50:50 diastereoisomeric mixture, only one 129Xe NMR signal was observed before the metal complexation, which indicates the distant chiral center does not have an impact on the chemical shift of the encapsulated xenon. In contrast, the addition of Zn2+ produced two new NMR signals, which correlates to the diastereoisomeric probes with complexed Zn2+. This observation suggests that the flexibility of linker connecting the cage and the chelating group is reduced, which allows the stereochemistry information to be sensed (Figure 45). This assumption is further supported by the fact that the complexation of Zn2+ with probe prepared from the enantiopure cryptophane leads to the appearance of a single new peak. Through the introduction of hyperpolarized xenon to the NMR tube, Zn2+ at a concentration of 100 nM was detected.246

Figure 45. Hyperpolarized Zn2+.

129

Simultaneous detection of multiple metal ions in complex mixtures is also feasible with the 129Xe-based sensors. Based on the characteristic 129Xe NMR signals produced upon metal ion complexation, Pb2+, Zn2+, and Cd2+ were simultaneously identified. The dynamic xenon encapsulation allows the implementation of the CEST technique, wherein the saturation of the NMR signal of xenon encapsulated in a metal ioncomplexed molecular cage leads to the attenuation of bulk 129 Xe signals. The combination of hyperpolarization technique and CEST enables the precise detection of metal ions at nanomolar concentrations (Figure 46).247 Through the

Figure 46. Hyperpolarized 129Xe-labeled sensor for the simultaneous detection of Zn2+, Pb2+, and Cd2+. Reprinted with permission from ref 247. Copyright 2014 American Chemical Society.

optimization of the metal chelator incorporated onto the cryptophane cage, as many as 10 metal ions were detected and differentiated based on the distinct chelation-induced shifts of the 129Xe NMR signals.248 The ion-induced conformational change was exploited by Zhou and co-workers as a novel strategy to produce pronounced shifts of the 129Xe NMR signals. A molecular clamp was constructed based on the dipyrrolquinoxaline (DPQ) scaffold, which carries two cryptophane-A cages for xenon encapsulation. The chelation between Hg2+ and DPQ closed the molecular clamp and induced intimate interactions between two cryptophane-A cages. An abnormal upfield shift of the 129Xe NMR signal was observed, which was attributed to the shielding effect of the two interacting cryptophane-A cages (Figure 47).249 The limit of detection of Hg2+ ion is determined to be 1 μM when hyperpolarized xenon gas is used. NMR-based sensors for anion detection are less explored.250−254 The creation of potent anion receptors is relatively challenging because anions often have high solvation energies and only exist in ionic form within a certain pH

Xe-labeled sensor for the detection of Figure 47. N

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range.33,255−262 Optical-based chemosensors for anions are well developed but often suffer from interference from coexisting anions.250−254 Many anion receptors are created based on hydrogen bonding interactions. Their association with anions are often fast on the NMR time scale due to the dynamic nature of hydrogen bonding. Indolocarbazole-based anion receptors display excellent binding capabilities toward a variety of anions and were used by the Beer group to create optical-based anions sensors.263 However, the implementation of these receptor to NMR-based anion sensors is hampered by the high chemical exchange rate. Similar to the detection of metal cations, slow-exchange ion receptors are needed to produce characteristic NMR signals for precise identification of anions in complex mixtures. Jeong and co-workers found that the macrocyclic indolocarbazole-based receptors (115) displayed unique binding properties toward various anions.264 The anion complexation through multiple intimate hydrogen bindings inside the cavity slows down the chemical exchange rate such that the free and complexed receptors display separated set of 1H NMR signals. The observed distinct 1H NMR signals of the NH are uniquely assignable to the anion sensors complexed with various anions (Figure 48). As many as 10 anions, including F−, AcO−, H2PO4−, Cl−, N3−, HSO4−, NO3−, CN−, Br−, and I3−, can be simultaneous identified.

Figure 49. (A) Bambusuril-based sensor for the detection of various anions. (B) 1H NMR spectra of 117-anion mixtures. Panel B reproduced with permission from ref 265. Copyright 2014 Royal Society of Chemistry (https://creativecommons.org/licenses/by/3.0/ ).

Figure 50. 19F-labeled zinc dipicolylamine complex for the detection of PPi, ATP, ADP, and Pi.

step, this NMR-based method allows the monitoring of sequential transformations in the same assay sample.266 The molecular sensors to detect neutral organic analytes are even less exploited. As most organic molecules can be readily characterized through NMR spectroscopy in a straightforward manner, the need to use molecular sensors for the detection of neutral organic analytes is alleviated. NMR sensors for organic species were created with the aim to simplify the data interpretation and to identify closely related analytes that are not easily distinguishable by conventional NMR techniques. In the absence of electrostatic interactions, the binding strength between the receptors and neutral organic analytes tend to be attenuated. The molecular interactions, such as hydrogen bonding and halogen bonding, are often too dynamic for the design of the NMR-based sensors that display slow chemical exchange behaviors. Therefore, most of the NMR-based sensors for organic analytes rely on the metal−ligand coordination or dynamic covalent bond. The 19F-labeled calix[4]arene tungsten-imido complexes (121) were developed by Swager and co-workers for the detection of neutral organic analytes. The design of the sensor is based on the fact that the binding of a Lewis basic organic analytes increases the electron density on tungsten and thereby changes the chemical shift of the 19F label appended on the imido group (Figure 51). The amplitude of the induced chemical-shift changes were found to be highly dependent on the electron-donating property of the analytes. More pronounced shifts of the 19F NMR signals were observed with analyte bearing electron-donating groups, which allows the differentiation of various neutral organic analytes based on their distinctive electronic property.267

Figure 48. Indole-based macrocyclic sensor for the detection of anions.

The above-mentioned anion detection is usually performed in organic solvents. Anion sensing in pure water is more challenging due to the high sovalting energy of anions with water. Sindelar and co-workers found that the bambusurilbased receptors complexed various anions strongly in aqueous solution, producing distinct 1H NMR signals (Figure 49). This observation indicates the anion association is in the slow exchange regime. As a result of the high sensitivity of 1H NMR, perchlorate (ClO4−) at 0.1 μM can be precisely quantified with this approach by using a 600 MHz NMR spectrometer.265 A 19F-labeled phosphate anion sensor was designed by Smith group for the detection of biologically relevant phosphate anions. The complexation of phosphate anions by the zinc dipicolylamine complex (119) increases the electron-density on the fluorine atom appended on phenol group and induces an upfield shift of the 19F NMR signal. Various phosphate anions are effectively differentiated on the basis of their distinct electronic properties. As such, a more pronounced upfield shift is observed with more electron-rich phosphate anions. The binding-induced chemical-shift change is sufficient for revolving the 19F signals correlated to sensors complexed with ATP (adenosine triphosphate), ADP (adenosine diphosphate), and Pi (phosphate; Figure 50). The hydrolysis of ATP to ADP catalyzed by apyrase can, therefore, be readily monitored with this approach. In contrast to the optical-based methods which are mostly used for reporting a single biological O

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Figure 51. 19F-labeled calixarene tungsten complex for the detection of nitriles and amides.

In order to distinguish the analytes with same or similar electronic properties, the spatial-proximity induced chemicalshift change was exploited by the Swager group to create NMR-based sensors with more robust discriminatory power. In this scheme, pentafluorophenyl moieties were incorporated onto the upper rims of the calix[4]arene tungsten complex with the aim to comprehensively sense the structural information on the target analyte with spatially arranged 19F probes. The imido- and o-, m-, and p-fluorine probes on the pentafluorophenyl group are chemically nonequivalent and possess well-separated 19F NMR signals, which constitute a sensing array (Figure 52). The obtained multidimensional

Figure 53. (A) 19F-labeled pincer complexes for the detection of amines and N-heterocycles. (B) 19F NMR spectrum of a mixture of the complex 125 and 12 different chiral amines. Only benzylic CF3 region was shown. (C) 19F NMR spectrum of a mixture of complex 126 and analytes. Panel B reproduced with permission from ref 270. Copyright 2015 American Chemical Society. Panel C reproduced with permission from ref 269. Copyright 2016 John Wiley and Sons.

analyte are transduced to the nearby appended 19F probes. As a result of the wide detection window and the superior discriminatory ability, as many as 12 chiral analytes can be simultaneously identified. Notably, chiral aliphatic amines that are difficult to resolve using chiral chromatography are differentiable with these 19F-labeled pincer complexes.269,270 Owing to the strong metal-anion coordination, the palladium pincer complexes also display favorable sensing properties for anions. Upon the addition of a mixture of five anions, including I−, Br−, Cl−, AcO−, and N3−, five new 19F NMR peaks appeared, which demonstrated the capability of sensor 126 to simultaneously identify multiple closely related anions.269 Organoboronic acids have long been recognized as effective receptors for diol-containing analytes.271−274 The ability to bind diols through the formation of boronic esters/boronate in water or aqueous solution makes them appealing candidates for the creation of sensors for some biologically relevant analytes, such as carbohydrates, nucleotides, and catechol derivatives.275,276 The dynamic interconversion between boronic acids and the corresponding boronic esters/boronates is usually slow on the NMR time scale such that each species involved in the equilibrium can be monitored through NMR spectroscopy. 19F-labels are often introduced into boronic acids to probe the hybridization change of boron during the recognition of diol-containing analytes.277,278 When the boronic acid is positioned in a chiral environment, the enantiomeric excess value of nonracemic diols can be evaluated through the formation of a pair of diastereoisomeric boronic esters (Figure 54).279 These studies illustrated the favorable binding property of boronic acids and its potential usage in diol detection. Micouin and co-workers attempted a series of 19F-labeled boronic acids to probe the interactions between boronic acid

Figure 52. 19F-labeled calixarene tungsten complex for the differentiation of structurally similar nitriles.

sensing data produces unique 19F NMR signatures, which were used to distinguish nitriles with tiny structural differences. Compared to the approach to constructing a sensing array with many structurally diverse sensors, the use of a single sensor bearing multiple fluorine probes is more economical and operationally simpler.268 The methods to detect amines and N-heterocycles are of great interest as a result of their ubiquitous occurrence in natural products. 19F-labeled palladium pincer complexes were employed to bind and identify amines and N-heterocycles. The binding of analytes induces distinct NMR shifts of the fluorine atoms appended on the molecular sidewalls that define a pocket around the palladium center (Figure 53). These sensors allow for the simultaneous identification of multiple biogenic amines with structural differences several carbons away from the bonding site. In addition, various N-heterocycles, such as nicotine, pyridine, quinoline, and caffeine are easily differentiated with 19F-labeled palladium complexes. The quantification of caffeine content in regular and decaffeinated coffee without pretreatment was demonstrated, which illustrated the robustness of the method in the analysis of complex mixtures. The differentiation between chiral analytes is achieved by the use of chiral palladium pincer complexes (Figure 53B, 125). In this case, a chiral environment is created to host the analytes, wherein subtle interactions between the ligand and the chiral P

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Figure 54. 19F-labeled boronic acids for the evaluation of enantiomeric excess of chiral diols.

and diols in aqueous solutions. Among various boronic acids tested, the benzoxaborole-based cyclic boronic acid (131) was found to readily associate with various diols. The detection of full-length RNA with 19F-labeled boronic acids was demonstrated for the first time at physiologically relevant conditions (Figure 55).280 The differentiation between adenosine

Figure 56. 19F-labeled boronic acids for the detection of various diols.

analyte. Bullvalenes have been exploited for the design of dynamic sensors because they have hundreds or thousands of interconverting isomers resulting from the facile Cope rearrangement.283−287 A dynamic mixture of structurally varied sensors is thus facilely obtained through the incorporation of binding moieties onto the bullvalene scaffold, which behaves like a sensing array but alleviates the tedious synthesis. The 13 C-labeled bullvalenes with appended porphyrin moiety were developed by Bode and co-workers for the differentiation of fullerenes. A recognizable change in the 13C resonance was observed in the presence of fullerenes. The unique NMR pattern generated based on the 13C resonances and intensities of the 13C peaks allows the differentiation between C60 and C70 (Figure 57).288,289

Figure 55. 19F-labeled boronic acids for the monitoring of reversible boronic-acid-diol interactions.

derivatives may be challenging with this approach, as these analytes all produced a uniformed 19F NMR resonance at −116.9 ppm upon the association with sensor 131. Notably, a large excess amount of boronic acids (ca. 10 equiv) is needed to achieve sufficient binding of the analyte, which may limit the use of this approach for in vivo detection. 19 F-labeled diboronic acids with appended bipyridinium salts were developed by Alexander and co-workers for the diol recognition. The bipyridinium moiety enables water solubility and allows the detection to be performed under physiologically relevant conditions. By varying the position of fluorine substituent on the boronic acid, a sensing array was created. Characteristics barcodes were produced based on the 19F NMR signals produced upon the addition of a certain analyte (Figure 56). In this way, structurally similar analytes are differentiable. Importantly, the 19F NMR resonances of the formed complexes are not significantly affected by the pH between 6−8, which makes the method well-suited for biological applications. Very recently, the authors found that monoboronic acids (135) with appended pyridinium moiety are more robust sensors for various diols. The detection of glucose in synthetic urine sample at 1 mM using a 188 MHz NMR spectrometer was achieved, illustrating the potential application of the method for medical diagnosis.281,282 The structure of the above-mentioned sensors for the detection of diols/polyols is static. An array of sensors with orthogonal discriminatory ability are often needed for the differentiation of closely related analytes. Alternative to this strategy, multidimensional information can be easily obtained if the sensor is structurally dynamic and adaptable to the target

Figure 57. 13C-labeled bullvalenes for the detection of fullerenes.

By varying the recognizing moieties appended on the bullvalene scaffold, sensors targeting diverse analytes can be constructed. Structurally dynamic sensors for polyols were created through decorating the bullvalene core with boronic acids. The distribution of interconverting isomers of the bullvalene is influenced by the identity of the polyol analyte engaged in the formation of boronic acid esters. This process is accompanied by the production of distinct 13C resonance patterns that are uniquely assignable to the corresponding polyols. The conversion of the 13C resonance pattern to an easily interpretable barcode allows the rapid determination of the identity of the polyol analytes (Figure 58). A static sensor with similar scaffold is not competent to pin down the identity of the analytes, which highlights the importance of the shapeshifting behavior.290 It is noteworthy that 19F-labeled enzymes with fluorine probe in proximity to the binding site have been used as Q

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biomacromolecules, such as peptides, proteins, and nucleotides is beyond the scope of this review and will not be discussed in detail.29,292,294−299 Another application of heteronuclearlabeled small-molecule ligand is to probe the structural and conformational change of biomacromolecules and we would like to refer the interested readers to relevant literatures.300−307

3. SENSORS RELYING ON THE MODULATION OF RELAXATION AND CHEMICAL EXCHANGE PROPERTIES 3.1. Background

In addition to the perturbation of the heteronuclear-NMR resonances, the modulation of the relaxation property of the interested nucleus is also a versatile strategy for the design of NMR-based sensors. Generally, the relaxation rate is closely related to the intensity and the broadness of the NMR signals. The NMR signal is attenuated and becomes less visible when the transverse relaxation time (T2) of the nucleus is reduced. As the measurement of changes in signal intensity is easier than the integration, relaxation-based sensors have the potential to provide higher sensitivity. The coupling between the relaxation time and reaction/recognition events thus allows the construction of an on/off-typed sensing system. These strategies have found wide application in MR imaging targeting diverse analytes. The relaxation time T2 is the most frequently used parameter to create relaxation-based sensors, the amplitude of which is influenced by the presence of paramagnetic metal and the molecular mobility of the labeled segment. By coupling the change of relaxation property with enzymatic reactions and recognition events, a wide spectrum of NMR-based sensors have been constructed.

Figure 58. (A) 13C-labeled shapeshifting sensor for the detection of polyols. (B) Conversion of 13C NMR spectrum to a barcode. Panel B reproduced with permission from ref 290. Copyright 2013 American Chemical Society.

3.2. Detection of Enzyme and Enzymatic Activity

3.2.1. Modulation of the Relaxation Properties Based on PRE Effect. The presence of a paramagnetic metal has a profound influence on the relaxation time of the adjacent nuclei. The modulation of relaxation time through the change of the distance between the paramagnetic metal and the nucleus for NMR analysis is often used as a transduction mechanism for detection of ions, binding interactions, and recognition events. If a paramagnetic metal and a 19F-label were tethered together through an enzymatically cleavable linkage with an appropriate length, the NMR signal of the 19F will be masked as a result of the reduced T2 caused by the PRE effect.308 The cleavage of the linker sets the paramagnetic metal apart from the 19F label, thereby restoring the 19F NMR signals. This interesting transduction mechanism was first exploited by Kikuchi and co-workers, where they designed a 19 F MR imaging probe (139) to detect protease activity.309,310 In their design, the carboxylic acid bearing a cyclen ligand was connected to the 19F-label through a peptide linkage, the sequence of which is specifically recognized by caspase-3. The chelated Gd3+ is used to induce PRE effect, owing to its large spin quantum numbers.311,312 Upon the treatment with caspase-3, the 19F NMR signals of the probe became sharper and higher in a time-dependent manner, which suggested the PRE effect was removed through the enzymatic reaction (Figure 60). The visualization of caspase-3 activity by MR imaging was demonstrated with this sensing scheme.309 The fluorescence and 19F MR imaging dual functional probe can be further constructed by the use of a 19F-labeled fluorescent moiety as the end group of the peptide.313

biosensors for the detection of potential inhibitors for the enzyme. For instance, Hamachi and co-workers reported a ligand-directed tosyl chemistry for selective modification of target protein with a fluorinated probe. The conformational dynamic and the binding behavior of the protein are readily investigated with the incorporated 19 F probe (Figure 59).291−293 The investigation of biological events with labeled

Figure 59. LDT-mediated labeling for investigation of protein activities. R

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Gd conjugate for monitoring of the single-electron reduction. The cytochrome:P450 reductase-mediated reduction of the quinone moiety induces the release of DTPA-Gd fragment, which restores the 13C NMR signal.316 Multifunctional MR imaging agents were designed by Zhou and co-workers by coupling the self-immolative reaction with changes in optical and self-assembled properties of the probe.317 In addition to paramagnetic metal ions, the PRE effect of stabilized nitroxide radical has also been exploited for the detection of gene expression. A molecular beacon with a 19F label at one end and nitroxide on the other end was developed by Darling and co-workers for targeting nucleotide sequences. The 19F NMR signal of the beacon is initially quenched in its hairpin conformation as a result of the spatial proximity between fluorine atom and the nitroxide radical. Upon beacon hybridization with its specific complementary nucleotide sequence, the beacon is linearized and thereby positions the radical far away from the fluorine probes (Figure 62). The use

Figure 60. Paramagnetic relaxation-based 19F-labeled sensor for the monitoring of enzymatic reaction. Panel A reprinted with permission from ref 309. Copyright 2008 American Chemical Society.

In the above-mentioned PRE-based sensing system, the paramagnetic metal ion and the 19F-labels are attached to each end of the substrate. This probe design strategy sometimes results in a substrate with significantly reduced activity if the enzyme recognizes the substrate with a confined binding pocket. In order to address this limitation, self-immolative sensors were designed by Kikuchi and co-workers for the detection of β-gal activity.309,313−315 In this new strategy, the enzymatic cleavage of the β-galactoside bond releases a selfimmolative species. The subsequent fragmentation separates Gd3+ from the 19F-label and turns on the 19F NMR signal (Figure 61).314 With this new strategy, the activity of a wide range of enzymes can be evaluated.315 Based on a similar principle, Nishimoto and co-workers developed a 13C-labeled indolequinone-diethylene triamine pentaacetic acid (DTPA)-

Figure 62. Paramagnetic relaxation-based 19F-labeled molecular beacon for the detection of nucleotides. Reprinted with permission from ref 318. Copyright 2018 American Chemical Society.

of nitroxide alleviates the synthetic endeavor, which potentially promotes the wide adoption of this approach for the investigation of complex biological systems.318 The theoretical limit of detection of the matched target was determined to be 2.7 μM when 12 μM of the 19F-labeled beacon was used. Similar to sensing methods relying on chemical-shift change, the PRE-based MR imaging is often not sensitive enough for in vivo applications. The nonafluoro-tert-butyl moiety was used by Chen and co-workers to develop PRE-based sensors for the highly sensitive detection of metalloprotease-2 activity (Figure 63, 142). Upon the cleavage of the peptide connecting the 19F label and the Gd3+-containing moiety, a 8.5-fold increase of the 19 F NMR signal was observed. The attempt to use dendronlike 19F-labels with 27 magnetically equivalent fluorine atoms is

Figure 61. (A and B) Paramagnetic relaxation-based 19F-labeled sensor with self-immolative properties. (C) The density weighted 19F MR phantom images of Gd-DFP-Gal after β-gal was added. Panel C reproduced with permission from ref 314. Copyright 2011 Royal Society of Chemistry.

Figure 63. Paramagnetic relaxation-based 19F-labeled sensor for the detection of matrix metalloprotease-2 activity. S

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carbonic anhydrase I (hCAI), trypsin (TPS), and avidin were selectively detected by varying the recognition units of the self-assembled monomers, suggesting the generality of this approach. As usual, the sensitivity of the detection can be increased by designing sensors bearing multiple magnetically equivalent fluorine atoms.322 By finely tuning the structure of the probe, hCAl at concentration as low as 2.5 μM can be detected. In addition to a binding event, the enzymatic reaction that alters the structure of the substrates was also used for devising biosensensing systems through modulating the aggregation state. Along the line, nitroreductase and matrix metalloprotein were successfully detected by a reaction-driven disassemble mechanism.323 Through a similar transduction mechanism, the detection of tyrosinase and Legumain activity with self-assembled peptides was achieved by the Yang and Liang groups.324,325 Alternative to the formation of self-assembled nanoparticles with monomeric probe molecules, the attachment of 19Flabeled sensing units onto the nanoparticles is also an effective strategy for the modulation of the relaxation time. Polyhedron oligomeric silesesquioxanes (POSS) were used as a valuable scaffold to achieve water-soluble 19F-NMR based sensors. When POSS carrying fluorinated moiety and responsive units were attached to the surface of silica NPs, the mobility of the POSS on silica NPs becomes restricted, which results in a shortened T2 and accordingly suppressed 19F NMR signals. By using different responsive linkers between silica NP and POSS, many biological processes can be monitored. (Figure 66).326,327 The activity of alkaline phosphatase, and glutathione

not successful due to the high hydrophobicity, which prevents the dissolution of the substrate in aqueous solution.319 Hyperpolarized 129Xe has also been exploited to increase the sensitivity of the relaxivity-based detection. The tether of paramagnetic Gd3+−DOTA complex on cryptophane cage increases the relaxivity of the encapsulated xenon by 8-fold. The relaxation of xenon in solution is also accelerated due to the rapid exchange between xenon in cages and in solution. As the removal of enhancement in relaxivity can be achieved through the spatial separation between Gd3+ and the caged xenon (Figure 64), the use of cleavable linker between Gd3+ and the cryptophane cage will lead to sensors targeting various enzymes.320

Figure 64. Paramagnetic relaxation-based sensor utilizing hyperpolarized 129Xe and chemical exchange relaxation transfer.

3.2.2. Modulation of the Relaxation Properties Based on Restriction of Molecular Motions. Compact structures are often generated during the formation of nanoparticles, which potentially restricts the mobility of the inner shell segment of the nanoparticle. The recognition-driven disassembly of nanoparticles by an enzyme is exploited by Hamachi and co-workers for the protein imaging. In this system, 19F-labeled monomeric probe bearing recognition end groups were self-assembled into nanoparticles.321 The mobility of 19F-labeled species is significantly reduced, which turns off the 19F NMR signals. The binding between the end group and the corresponding protein induces the disassembly of the aggregate and restores 19F NMR signals (Figure 65). A variety of biologically relevant macromolecules, such as human

Figure 66. Self-assembling detection.

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reductase328 were successfully measured with this sensing scheme. Owing to the synthetic versatility of POSS to incorporate multiple diversified side chains, fluorescence/ MRI bimodal sensors can be readily constructed.329 The strategy to modulate T2 through restriction of molecular motion has been implemented in 129Xe-based NMR sensors. The binding of avidin, a macromolecular target, to the biotin moiety appended on the xenon cage (144) significantly altered the T2 of the encapsulated xenon by increasing the rotational correlation time. This dramatic change in T2 is then transferred to the bulk 129Xe through a rapid in-and-out chemical exchange, leading to the attenuation of bulk xenon signals (Figure 67).330 Upon the binding of the biotin-containing sensor to avidin at 1.5 μM, the T2 of the free xenon was reduced by a factor of 4. The Gd3+-containing sensor was utilized to enhance the relaxation; however, the relaxivities of xenon in Gd3+-chelated and Gd3+-free sensors are similar.

Figure 65. Self-assembling 19F NMR off/on probe for protein detection. Reprinted with permission from ref 322. Copyright 2011 American Chemical Society. T

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and tunable redox properties, the detection of the reductive environment in live cells was demonstrated.333 Based on the same principle, Que and co-workers described a 19F-labeled CoII complex (147) for the detection of ROS. The oxidation of paramagnetic CoII to diamagnetic CoIII increases the T2 of 19F nucleus, whose NMR signal was initially invisible due to the PRE effect of CoII (Figure 69). The resulting turn-on response was observed in the 19F MR imaging of ROS with a 2−3 fold enhancement in signal intensity.334

Figure 67. Relaxation-based sensor for the detection of biomacromolecules.

Figure 69. ROS.

3.3. Detection of Reactive Oxygen Species (ROS) and Reductive Environment

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F-labeled relaxation-based sensor for the detection of

This on/off-typed relaxation-based sensing system can be also achieved with EuII complexes using the switch between paramagnetic EuII and diamagnetic EuIII (Figure 70). The

Hypoxia is a condition experienced in solid cancer cells, which results in an increased reductive stress. This phenomenon is related to tumor proliferation, and the increased reductive capability of the hypoxic cell has been targeted for diagnosis. Cu2+ complex has been used for the positron emission tomography (PET) imaging of hypoxia.331 In this technique, the cell permeable Cu(II)ATSM (ATSM = diacetyl-bis(4methylthiosemicarbazonato)) is preferentially accumulated in the hypoxic cell through the conversion of Cu2+ to Cu+, which is immobilized by the cellular thiols. This redox behavior to convert the paramagnetic Cu2+ to diamagnetic Cu+ was utilized by Que and co-workers to devise the relaxation-based MR imaging probe (145).332 The 19F NMR signal is initially attenuated in the Cu2+-containing complex. Reduction of Cu2+ to Cu+ and the subsequent ligand dissociation lengthen the T2, thereby turning on the 19F signals. Polyethylene glycol (PEG) linkers with variable length were used to connect the chelated Cu2+ and the fluorine probe (Figure 68), which allows the finetuning of the relaxation properties and solubility of the MR imaging probe. As a result of the enhanced biocompatibility

Figure 70. hypoxia.

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incorporation of 12 magnetically equivalent fluorine atoms on the C3 symmetrical EuII complex (149) significantly lowered the detection limits. A cage-like structure was formed with the aid of intramolecular fluorous interactions, which was found to modulate the accessibility of water to Eu through temperaturedependent conformational change. Despite of the increased fluorine content, the complex is still water-soluble, which allows its usage as a redox-responsive agent for the in vivo 19FMR imaging.335 Nitric oxide (NO•) is a vasodilator molecule that plays an important role in regulating blood pressure. The 19F NMR spin-trapping technique was used for the study of in vivo production of NO•, wherein a fluorinated hydroxylamine of nitroxyl nitroxide (151) is used to scavenge NO•. When applying a reducing environment, the NMR-silent nitroxides (151 and 152) were converted into the corresponding hydroxylamines (153 and 154; Figure 71), which allows the in vivo evaluation of NO• production by 19F NMR.336,337 An ingenious system to enhance the sensitivity of relaxationbased NMR sensing method was proposed by Kikuchi and coworkers. In their system, perfluoro[15]crown-5-ether (PFCE) was encapsulated in silica nanoparticles, the surface of which is modified with chelated paramagnetic metal ion through a disulfide linkage. Although the PFCE at the center of the nanoparticle core is about 250 Å away from the Gd3+

Figure 68. (A) 19F-labeled paramagnetic relaxation-based sensor for the detection of hypoxia. (B) 19F MR images of solvent blank and DMSO solutions containing 146, 145, and 146 plus 145. Panel B reproduced with permission from ref 333. Copyright 2017 American Chemical Society. U

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Figure 73. 19F-labeled relaxation-based sensor for the detection of HOCl and MPO.

synthesized by Whittaker and co-workers through atom transfer radical polymerization (ATRP). The polymer selfassembles into nanoparticle with compact hydrophobic cores, in which the mobility of the fluorinated segment is restricted. The oxidation of the thioether group with H2O2 increases the hydrophilicity of the polymer and induces the disassembly of the aggregation. The increased mobility of the fluorine segment results in an increased T2, thereby turning on 19F NMR signals (Figure 74).341 It is noteworthy that a high

Figure 71. 19F-labeled sensors for the detection of NO•.

complexes on the surface, the PRE effect is still observed due to the motion of PFCE to reach the inner shell of the nanoparticles. Upon the treatment with a reducing agent such as tris(2-carboxyethyl)-phosphine (TCEP), the chelated Gd3+ is removed from the surface of the nanoparticle, thereby turning on the 19F NMR signals of PFCE (Figure 72).

Figure 74. Polymeric oxygen species.

Figure 72. Relaxation-based sensing system utilizing silica nanoparticle with encapsulated PFCE. Reprinted with permission from ref 338. Copyright 2015 John Wiley and Sons.

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concentration of H2O2 (ca. 1 M) was used in this sensing system. Further optimization is needed to make it amenable for biological applications. A similar “off-to-on” strategy was utilized by Kong and co-workers for the noninvasive of biothiols, where disassembly of the 19F nanoprobe occurs upon a sulfydryl-induced aromatic nucleophilic substitution.342

Compared to sensitivity enhancement achieved by the incorporation of many magnetically equivalent fluorine atoms, this novel strategy retains the high water solubility of the sensor. The high sensitivity and biocompatibility make this sensing system very promising for various in vivo applications.338 Temporary adherence of small molecules to endogenous biomacromolecules often reduces mobility of the adherent small molecules, which leads to a shortened T2 value. As a consequence, the NMR signals of hydrophobic compounds are often attenuated in blood sample due to their high affinity with the abundant serum albumin. This effect was exploited by Sando and co-workers for the design of on/off-typed 19F MRI probes to sense hypochlorous acid (HOCl) and the activity of enzyme myeloperoxidase (MPO). In their sensing system, the fluoroalkoxyaniline (155) reacts with HOCl to produce a fluorinated alcohol (55), whose NMR signals are less influenced by the serum albumin due to the increased hydrophilicity. Thus, the enhancement of the 19F resonance of the trifluoroethanol (55) can be used to indicate the presence of HOCl or MPO (Figure 73).339 Polymeric agents have also been used to generate redoxresponsive contrast for 19F MR imaging. The ability to incorporate diverse functional units through copolymerization and the multivariate assembly states provide rich opportunities to tune the sensing properties of polymeric agents.340 A thioether- and 19F-containing methacrylate-based polymer was

3.4. Detection of Ions and Neutral Organic Analytes

When the metal ion of interest is paramagnetic in nature, its detection and quantification can be easily performed through monitoring the T1 and T2 values of an NMR-active nucleus on the metal chelator. As the PRE effect can induce severe line broadening, optimization of the distance between the paramagnetic metal ion and the nuclei of interest is often needed. Datta and co-workers developed a macrocyclic 19F-MR probe for the detection of Mn2+ ion (Figure 75). The distance between MnII and the 19F label on the sensor is about 9.25 Å in

Figure 75. Relaxation-based sensing system for the detection of Mn2+. V

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moieties. Only two of the thiouredio moieties were found to engage in the hydrogen-bonding interactions in crystal structures, while in chloroform the hydrogen bonding partners can switch between all three thioureido moieties, which enabled NMR chemical exchange between geminal hydrogens (Figure 77). The addition of chloride interrupts the intra-

the optimized conformation as determined by DFT calculation. This distance is found to be sufficient to minimize the broadening effect while maintaining the PRE effect. A linear increase in longitudinal and transverse relaxation rates was afforded when the concentration of MnII increased from 100 μM to 1 mM (Figure 75). The mapping of the distribution of MnII through MR imaging was achieved by the concentrationdependent relaxation change.343 Indicator displacement assay (IDA), a strategy developed by Anslyn and co-workers, found wide application in the design of chemical sensors.344,345 In contrast to the extensive usage in optical-based sensing schemes, the implementation of this strategy in NMR-based detection is less explored. Smith and co-workers reported a relaxation-based sensing system for the detection of phosphates. The sensing system was constructed with a zinc(II)-bis(dipicolylamine) (ZnBDPA) complex (160) bearing a paramagnetic moiety combined with a reversible bound 19F-labeled phosphate as a competitor. Initially, the 19F resonance of the phosphate is attenuated due to the PRE effect induced by the Gd3+ ion in proximity. The replacement of the 19 F-labeled phosphate by the target phosphorylated analytes reduces the PRE effect, thereby turning on the 19F signals. The rapid exchange of the phosphate between bound/free states allowed for the signal amplification since all the fluorinated indicators interacting with the zinc complex during the NMR detection time scale were influenced by the PRE effect (Figure 76). As a demonstration of the ability of this system to

Figure 77. Detection of chloride based on the modulation of chemical exchange properties.

molecular hydrogen bonding, which results in an increase in the conformation flexibility and exchange rate. This tremendous effect of the anion to decrease the activation barrier of conformational interconversion through weakening the HB allows ultrasensitive detection of anions through observing the peak broadening (Figure 77). A detectable peak broadening was observed in the presence of Cl− as low as 120 nM.347 The modulation of relaxation property of the paramagnetic metal complexes through the control of aggregation/dispersion state was exploited for the detection of the small neutral organic molecules. Chujo and co-workers found that paramagnetic Ni-porphyrin complexes could be absorbed by the 19 F-labeled POSS as a result of the hydrophobic interactions. The moderate PRE effect of the monomeric paramagnetic complex was greatly enhanced by an amine-induced aggregation, which was accompanied by the attenuation of the 19F NMR signals (Figure 78). Based on the signal reduction induced by the self-assembly, amines at concentrations 10,000 Times in Liquid-State NMR. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 10158−10163. AC

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DOI: 10.1021/acs.chemrev.8b00202 Chem. Rev. XXXX, XXX, XXX−XXX