A clinically-translatable ros / rns molecular imaging agent using a radiolabeled derivative of edaravone (EDV)

Abstract

The present disclosure relates to compounds, pharmaceutical compositions, and methods of using the compounds and compositions to image reactive oxygen and nitrogen species (RONS). The disclosed compounds and pharmaceutical compositions can also be useful in treating diseases or disorders due to oxidative stress or otherwise based on RONS pathophysiology such as, for example, neurological diseases, cancer, cardiovascular diseases, and ischemia reperfusion injury (IRI). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

A CLINICALLY-TRANSLATABLE ROS / RNS MOLECULAR IMAGING AGENT USING A RADIOLABELED DERIVATIVE OF EDARAVONE (EDV) CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 530,889, filed on August 04, 2023, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant number EB028338 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] Reactive oxygen species (ROS) and reactive nitrogen species (RNS) (together, RONS) play significant roles in the pathogenesis and exacerbation of various diseases, including cancer (Ishikawa, K. et al. (2008) Science 320, 661–664 and Park, L. et al. (2008) Proc National Acad Sci 105, 1347–1352), neurodegeneration (Huang, Y. & Mucke, L. (2012) Cell 148, 1204–1222; Mattson, M. P. (2004) Nature 430, 631–639; and Lin, M. T. & Beal, M. F. (2006) Nature 443, 787–795 ), chronic inflammation (Salvemini, D., Doyle, T. M. & Cuzzocrea, S. (2006) Biochem Soc T 34, 965–70 and Rubartelli, A. & Lotze, M. T. (2007) Trends Immunol 28, 429–436), and diabetes (Houstis, N., et al. (2006) Nature 440, 944–948 ). Unsurprisingly, antioxidants have long been investigated as an effective therapeutic intervention strategy (Uno, M. et al. (2005) Free Radical Bio Med 39, 1109–1116, Aizawa, H. et al. (2006) Internal Med 45, 1–4, Yoshino, H. & Kimura, A. (2006) Amyotroph Lateral Sc 7, 247–251, Knapp, L. T. & Klann, E. J. (2002) Neurosci. Res.70, 1–7, Zhuo, M., et al. (1993) Science 260, 1946–1950, and Barzilai, A. & Yamamoto, K.-I. (2004) DNA Repair 3, 1109–1115) in many central nervous system (CNS) diseases, including stroke, addiction, depression, bipolar disorder, traumatic brain injury, and amyotrophic lateral sclerosis (ALS). The efficacy of antioxidant therapies against CNS diseases is difficult to quantify, as detecting biomarkers of oxidative stress relies on indirect measurements, such as plasma concentrations of monounsaturated fatty acids and oxidized low- density lipoproteins (Uno, M. et al. (2005) Free Radical Bio Med 39, 1109–1116), circulating neutrophils (Aizawa, H. et al. (2006) Internal Med 45, 1–4), and 3-nitrotyrosine ormalondialdehyde (MDA) levels in cerebrospinal fluid(Yoshino, H. & Kimura, (2006) Amyotroph Lateral Sc 7, 247–251). Not only are some of these assays highly invasive but also the systemically circulating biomarkers may or may not correlate with the microenvironment status of inaccessible CNS regions (e.g., hippocampus, amygdala, and prefrontal cortex), which research suggests are most susceptible to oxidative stress and subsequent functional decline (Knapp, L. T. & Klann, E. J. (2002) Neurosci. Res.70, 1–7, Zhuo, M., et al. (1993) Science 260, 1946–1950 Wang, X. & Michaelis, E. K. (2010) Front Aging Neurosci 2, 12). Furthermore, it is difficult, if not practically impossible, to quantify whether an antioxidant is trafficking to the intended target within the CNS. Consequently, while antioxidants remain a plausible frontline therapeutic strategy for many CNS disorders, the inability to elucidate optimal therapeutic windows for neutralizing RONS continues to impede the objective evaluation of treatment outcomes, such as identifying relevant secondary biomarkers of CNS disease, monitoring disease progression, and predicting symptom onset or resolution.

[0004] Oxidative phosphorylation, which occurs in mitochondria, is the body’s major source of ATP; however, it concomitantly produces free radicals, RONS, and various other carbon- and sulfur-derived radicals (Barzilai, A. & Yamamoto, K.-I. (2004) DNA Repair 3, 1109–1115). Under normal physiological conditions, RONS are important chemical modulators that provide efficient, essential signal transduction and an electron shuttle pathway for normal metabolism. However, when endogenous regulating cellular antioxidant pathways are overwhelmed or saturated, which is collectively referred to as “oxidative stress,” the normally short-lived, low- concentration RONS initiate a cascade of radical chain reactions with the cellular environment, including nucleic acids, proteins, carbohydrates, and lipids.

[0005] Among the principal cellular components, lipids comprise the cellular membrane and are most easily oxidized by excessive RONS (Yamamoto, Y., et al. (1985) Biochimica Et Biophysica Acta Bba - Biomembr 819, 29–36, Burton, G. W. & Ingold, K. U. (1981) J Am Chem Soc 103, 6472–6477). Hydroxyl radicals (OH•) are short-lived intermediates; however, when hydroxyl radical reacts with a lipid or other carbon source in the presence of oxygen, a much longer-lived peroxyl radical (HOO•) is formed. Peroxyl radicals oxidize fatty acids in the plasma membrane (. Burton, G. W. & Ingold, K. U. (1981) J Am Chem Soc 103, 6472–6477)17 and initiate a radical chain reaction in which a single peroxyl radical can generate thousands of molecules of lipid hydrogen peroxide (Yamamoto, Y., et al. (1985) Biochimica Et Biophysica Acta Bba - Biomembr 819, 29–36, Yamamoto, Y. et al. (1986) J Nutr Sci Vitaminol 32, 475– 479). The resultant cascade damages the plasma membrane, causing cell death and potentiallyimpairs the function of surrounding cells, tissue, and organ. High concentrations of nitric oxide react with superoxide (O2•–) to produce peroxynitrite (ONOO–) (Radi, R. (2013) J Biol Chem 288, 26464–26472), which is primarily responsible for nitrating tyrosine residues in proteins and eliciting aberrant enzyme activity (Kummer, M. P. et al. (2011) Neuron 71, 833–844 ). Extensive evidence also supports the importance of peroxyl radicals and peroxynitrite in injury after cerebral ischemia. Ischemia (and / or ischemia followed by re-perfusion) dramatically increases RONS through peroxyl radical or peroxynitrite chain reactions with cell membranes. The resulting chain reaction leads to ischemic brain injury, manifested as edema, infarction, and neuronopathy (Rodrigo, J., et al. (2005) Free Radical Bio Med 39, 26–50, Yoshida, S. et al. (1982) Brain Res 245, 307–316, and Crimi, E., et al. (2007) Free Radical Res 41, 1364–1375). In summary, peroxyl radicals and peroxynitrite are attractive targets for antioxidant and radical scavenger drug development.

[0006] Despite these implications, precise, accurate quantification of RONS within the CNS of a living organism remains a practical challenge and limits the ability to design clinical studies evaluating antioxidant efficacy. Radiopharmaceuticals that react rapidly with a broad spectrum of RONS would enable longitudinal studies of RONS-based disease pathophysiology and improve the design of antioxidant-based therapeutic clinical studies. Thus, there remains a need for compounds and compositions that facilitate ROS and RNS molecular imaging, and methods of making and using same. SUMMARY

[0007] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds, pharmaceutical compositions, and methods of using the compounds and compositions to image reactive oxygen and nitrogen species (RONS). In various aspects, the disclosed compounds and pharmaceutical compositions can also be useful in treating diseases or disorders due to oxidative stress or otherwise based on RONS pathophysiology such as, for example, neurological diseases (e.g., Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), multiple sclerosis, cortical cavernous malformation (CCM), ischemic stroke), cancer, cardiovascular diseases, and ischemia reperfusion injury (IRI).

[0008] Thus, disclosed are methods of imaging reactive oxygen and nitrogen species (RONS) in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0009] Also disclosed are methods of imaging reactive oxygen and nitrogen species (RONS) in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0010] Also disclosed are kits comprising a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a mixing agent; and (b) instructions for imaging a radiotracer.

[0011] Also disclosed are methods of treating a disease or disorder due to oxidative stress in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0012] Also disclosed are kits comprising a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically salt thereof, and one or more selected from: (a) an agent associated with the treatment of a disease or disorder due to oxidative stress; (b) instructions for administering the compound in connection with treating a disease or disorder due to oxidative stress; and (c) instructions for treating a disease or disorder due to oxidative stress.

[0013] Also disclosed are compounds having a structure represented by a formula:, wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when R1is ‒F, then Ar1is not phenyl, or a pharmaceutically acceptable salt thereof.

[0014] Also disclosed are compounds having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R4is selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar3is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are compounds having a structure represented by a formula:,,or a pharmaceutically acceptable salt thereof.

[0016] Also disclosed are pharmaceutical compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in thespecification. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0019] FIG.1A-G show representative data illustrating that ROS are key components of homeostasis and pathology.

[0020] FIG.2A-E show representative data illustrating the imaging of oxidative stress in vivo.

[0021] FIG.3A-F show representative data illustrating the imaging of pathology-derived oxidative stress in vivo in a murine model of stroke.

[0022] FIG.4A-D show representative data illustrating that dynamic PET imaging with [18F]FEDV significantly increases sensitivity to RONS pathophysiology.

[0023] FIG.5 shows a representative mechanism of action of edaravone with ROS / RNS.

[0024] FIG.6 shows representative proposed EDV RPs and their corresponding biological characteristics. Superscripts indicate the site of isotopic labeling.

[0025] FIG.7 shows comparison of ROS imaging agents with proposed edaravone PET analogs.

[0026] FIG.8A-C shows representative radio synthesis of [18F]edaravone and reactivity wth ROS in vitro.

[0027] FIG.9 shows representative radio synthesis of [11C]edaravone.

[0028] FIG.10 shows representative radio synthesis of [18F]Ph-edaravone.

[0029] FIG.11A-C show representative data illustrating ROS resulting from photothrombic stroke.

[0030] FIG.12 shows representative data illustrating that the increased [18F]EDV-PET signals in PT mice is not due to BBB-extravasation.

[0031] FIG.13A-D show representative data illustrating that [18F]FEDV-PET imaging detects increased RONS in the P301S (PS19) mouse brain.

[0032] FIG.14 shows representative data illustrating that [18F]FDG-PET / CT imaging is unable to differentiate significant differences in the P301S (PS19) mouse brain. See also FIG.2E.

[0033] FIG.15A-C shows representative data for the characterization of 2-(4-fluorophenyl)-5- methyl-2,4-dihydro-3H-pyrazol-3-one (FEDV).

[0034] FIG.16 shows a representative semi-preparative HPLC chromatogram from purification of [18F]FEDV.

[0035] FIG.17 shows a representative semi-preparative HPLC chromatogram from purification of [18F]FEDV with standard coinjection.

[0036] FIG.18 shows a representative analytical quality control HPLC chromatogram of [18F]FEDV.

[0037] FIG.19 shows a representative analytical quality control HPLC chromatogram of [18F]FEDV confirmed with coinjection of a fully characterized standard.

[0038] FIG.20 shows a representative semi-preparative HPLC chromatogram from purification of [18F]FN.

[0039] FIG.21 shows representative data illustrating an analytical quality control HPLC chromatogram of [18F]FN.

[0040] FIG.22 shows representative data illustrating an analytical quality control HPLC chromatogram of [18F]FN confirmed with coinjection of a fully characterized standard.

[0041] FIG.23A-D show representative data illustrating that [18F]FEDV-PET imaging detects increased RONS in the P301S (PS19) mouse brain. Specifically, FIG.23A shows representative data illustrating that [18F]FN-PET / MRI is unable to differentiate significant differences in signal follow photothrombosis induced stroke. FIG.23B shows illustrative data that dynamic time activity curves (SUVavg) of [18F]FN are unable to quantify differences in PET signal following photothrombosis induced stroke. FIG.23C shows illustrative data that static (SUVavg) of [18F]FN are unable to quantify differences in regional PET signal in mouse brain following photothrombosis induced stroke. FIG.23D shows illustrative data that gamma counts from extracted brain tissue following [18F]FN PET / MRI are unable to quantify differences in regional radioactive signal in mouse brain following photothrombosis induced stroke ex vivo compared to [18F]FEDV.

[0042] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in thespecification. DETAILED DESCRIPTION

[0043] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0044] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0045] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0046] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.A. DEFINITIONS

[0047] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0048] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0049] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0050] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0051] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a partby weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0052] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0053] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0054] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0055] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat,guinea pig, fruit fly, etc.).

[0056] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0057] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0058] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0059] As used herein, the term “imaging” refers to a procedure that can make detailed pictures of areas inside a human body. Imaging procedures use different forms of energy such as x-rays (high-energy radiation), ultrasound (high-energy sound waves), radio waves, and radioactive substances. Imaging procedures can be used to help diagnose disease, to plan treatment, or to determine how well treatment is working. Exemplary imaging procedures include, but are not limited to, computed tomography (CT), mammography, ultrasonography, magnetic resonance imaging (MRI), nuclear medicine tests, positron emission tomography (PET), PET / MRI, and PET / CT.

[0060] The terms “radioactive isotope” and “radioisotope,” as used herein, refers to an isotope whose nuclei is unstable and, as such, the isotope can dissipate excess energy by spontaneously emitting radiation in the form of alpha, beta, and / or gamma rays. Examples of radioisotopes include, but are not limited to,2H,3H,11C,13C,14C,13N,15N,15O,17O,18F,35S,36Cl,82Br,76Br,77Br,123I,124I,125I, and131I.

[0061] As used herein, the phrase “a subject in need of RONS imaging” refers to a subject who has been diagnosed as having, or is otherwise suspected of having, a disorder or disease caused by or otherwise attributable to oxidative stress as detailed elsewhere herein. For example, in various aspects, where a subject is suspected of having a disorder or disease caused by or exacerbated by oxidative stress (e.g., a subject in need of RONS imaging), the subject can undergo an imaging procedure to assess whether they demonstrate an increased signal (e.g., an increased PET signal) in a region of interest. If the imaging procedure reveals that the subject does, indeed, have an increased signal in the region of interest, they would then be identified as being in need of therapeutic treatment.

[0062] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0063] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorphthereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha- tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0064] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0065] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0066] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to anorganism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body;or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0067] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0068] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0069] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through abacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0070] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0071] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0072] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0073] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moietythat may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1- 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0074] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo- oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0075] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0076] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0077] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. For example, the cycloalkyl group and heterocycloalkyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, −NH2, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, −OH, C1-C4 hydroxyalkyl, −NO2, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein.

[0078] The term “polyalkylene group” as used herein is a group having two or more CH2groups linked to one another. The polyalkylene group can be represented by the formula —(CH2)a—, where “a” is an integer of from 2 to 500.

[0079] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0080] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0081] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. For example, the cycloalkenyl group and heterocycloalkenyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldeyhyde, −NH2, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, −OH, C1-C4 hydroxyalkyl, ketone, azide, −NO2, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein.

[0082] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0083] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0084] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0085] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0086] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” or “CO” is a short hand notation for a carbonyl group, i.e., C=O.

[0087] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0088] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0089] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylaminogroup and the like.

[0090] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0091] The term “ester” as used herein is represented by the formula —OC(O)A1or —C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0092] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0093] The terms “halo,” “halogen,” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I. As would be understood by one of skill in the art, isoptically-labeled halogens are also envisioned. The isotopically labeled halogens also include the radioactive isotopes such as ‒18F, ‒76Br, ‒123I, and ‒124I.

[0094] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0095] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0096] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted orunsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0097] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0098] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H- pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0099] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0100] The term “hydroxy” or “hydroxyl” as used herein is represented by the formula —OH.

[0101] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0102] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0103] The term “nitro” as used herein is represented by the formula —NO2.

[0104] The term “nitrile” or “cyano” as used herein is represented by the formula —CN or —C≡N.

[0105] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0106] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0107] The term “thiol” as used herein is represented by the formula —SH.

[0108] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0109] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0110] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certainaspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0111] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R °; –(CH2)0–4OR °; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR °)2; –(CH2)0–4SR °; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R °)2; –(CH2)0–4N(R °)C(O)R °; –N(R °)C(S)R °; –(CH2)0– 4N(R °)C(O)NR °2; -N(R °)C(S)NR °2; –(CH2)0–4N(R °)C(O)OR °; – N(R °)N(R °)C(O)R °; -N(R °)N(R °)C(O)NR °2; -N(R °)N(R °)C(O)OR °; –(CH2)0–4C(O)R °; – C(S)R °; –(CH2)0–4C(O)OR °; –(CH2)0–4C(O)SR °; -(CH2)0–4C(O)OSiR °3; –(CH2)0–4OC(O)R °; – OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R °; –(CH2)0–4C(O)NR °2; –C(S)NR °2; – C(S)SR°; -(CH2)0–4OC(O)NR °2; -C(O)N(OR °)R °; –C(O)C(O)R °; –C(O)CH2C(O)R °; – C(NOR °)R °; -(CH2)0–4SSR °; –(CH2)0–4S(O)2R °; –(CH2)0–4S(O)2OR °; –(CH2)0–4OS(O)2R °; – S(O)2NR °2; -(CH2)0–4S(O)R °; -N(R °)S(O)2NR °2; –N(R °)S(O)2R °; –N(OR °)R °; –C(NH)NR °2; – P(O)2R °; -P(O)R °2; -OP(O)R °2; –OP(O)(OR °)2; SiR °3; –(C1–4 straight or branched alkylene)O– N(R °)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R °)2, wherein each R ° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0– 1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R °, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0112] Suitable monovalent substituents on R ° (or the ring formed by taking two independent occurrences of R ° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, – (CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, – OSiR●3, -C(O)SR●,–(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ° include =O and =S.

[0113] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0114] Suitable substituents on the aliphatic group of R*include halogen, – R●, -(haloR●), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0115] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0116] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

[0117] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0118] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0119] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0120] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: ,regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0121] “Organic radicals,” as the term is defined and used herein, contain one or morecarbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2- 8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0122] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0123] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unlessstated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0124] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0125] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0126] Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0127] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0128] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co- crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acidand benzenesulfonic acid.

[0129] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[0130] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1-unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below.Unless stated to the contrary, the invention includes all such possible tautomers.

[0131] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0132] In some aspects, a structure of a compound can be represented by a formula: ,which is understood to be equivalent to a formula: ,wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0133] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0134] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0135] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated iseach and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0136] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B. COMPOUNDS

[0137] In one aspect, disclosed are compounds and compositions useful in imaging reactive oxygen and nitrogen species (RONS). Also disclosed are compounds and compositions useful in treating diseases or disorders due to oxidative stress such as, for example, neurological diseases, cancer, cardiovascular diseases, and ischemia reperfusion injury (IRI).

[0138] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0139] In one aspect, disclosed are compounds having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0140] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when R1is ‒F, then Ar1is not phenyl, or a pharmaceutically acceptable salt thereof.

[0141] In one aspect, disclosed are compounds having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0142] In one aspect, disclosed are compounds having a structure represented by a formula:wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R4is selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar3is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0143] In one aspect, disclosed are compounds selected from:or a pharmaceutically acceptable salt thereof.

[0144] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0145] In various aspects, the compound has a structure represented by a formula: ,wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptable salt thereof. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a still further aspect, four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0146] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or apharmaceutically acceptable salt thereof.

[0147] In various aspects, the compound has a structure represented by a formula:, wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. In a further aspect, one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a still further aspect, three of R10b, R10c, R10d, and R10eare hydrogen.

[0148] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0149] In various aspects, the compound is selected from: O ,or a pharmaceutically acceptable salt thereof.

[0150] In various aspects, the compound is selected from: ,or a pharmaceutically acceptable salt thereof.

[0151] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0152] In various aspects, the compound is:, or a pharmaceutically acceptable salt thereof.

[0153] In various aspects, the compound is not: O, or a pharmaceutically acceptable salt thereof.

[0154] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0155] In various aspects, the compound has a structure represented by a formula: ,wherein one of R11a, R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, R11d, and R11eis hydrogen, or a pharmaceutically acceptable salt thereof. In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis halogen. In a still further aspect, four of R11a, R11b, R11c, R11d, and R11eare hydrogen.

[0156] In various aspects, the compound has a structure represented by a formula:, wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

[0157] In various aspects, the compound has a structure represented by a formula:, wherein one of R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. In a further aspect, one of R11b, R11c, R11d, and R11eis halogen. In a still further aspect, three of R11b, R11c, R11d, and R11eare hydrogen.

[0158] In various aspects, the compound has a structure represented by a formula: ,wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

[0159] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0160] In various aspects, the compound is selected from: Oor a pharmaceutically acceptable salt thereof.

[0161] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0162] In various aspects, the compound has a structure represented by a formula: ,wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptablesalt thereof. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a still further aspect, four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0163] In various aspects, the compound has a structure represented by a formula:, wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0164] In various aspects, the compound has a structure represented by a formula: ,wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. In a further aspect, one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a still further aspect, three of R10b, R10c, R10d, and R10eare hydrogen.

[0165] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0166] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0167] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0168] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0169] In various aspects, compound has a structure represented by a formula:, wherein one of R12b, R12c, R12d, and R12eis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. In a further aspect, three of R12b, R12c, R12d, and R12eare hydrogen. In a still further aspect, the compound has a structure represented by a formula: ,wherein R12cis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

[0170] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof. a. R1GROUP

[0171] In one aspect, R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope. Examples of radioactive isotopes include, but are not limited to, ‒18F, ‒76Br, ‒123I, and ‒124I. Thus, in various aspects, the radioactive isotope is ‒18F. In a still further aspect, the radioactive isotope is ‒76Br. In a yet further aspect, the radioactive isotope is ‒123I. In an even further aspect, the radioactive isotope is ‒124I.

[0172] In various aspects, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒ OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒ SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒ NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒ NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒ N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒ N(CH3)CH2CH2CH2I. In a still further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒ OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒ NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0173] In various aspects, R1is selected from halogen and ‒O(C1-C4 haloalkyl). In a further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, and ‒OCH2I.

[0174] In various aspects, R1is selected from halogen and ‒S(C1-C4 haloalkyl). In a further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, and ‒SCH2CH2CH2I. In a still further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, and ‒SCH2CH2I. In a still further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, and ‒SCH2I.

[0175] In various aspects, R1is selected from halogen, ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒ NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒ N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒ NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R1is selected from ‒F, ‒Br, ‒I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0176] In various aspects, R1is halogen. In a further aspect, R1is ‒F, ‒Br, or ‒I. In a still further aspect, R1is ‒F. In yet a further aspect, R1is ‒18F. In an even further aspect, R1is Br. In a still further aspect, R1is ‒76Br. In yet a further aspect, R1is I. In an even further aspsect, R1is ‒123I or ‒124I. In a further aspect, R1is ‒123I. In a yet further aspect, R1is ‒124I.

[0177] In various aspects, R1is ‒O(C1-C4 haloalkyl). In a further aspect, R1is selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, R1is selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R1is selected from ‒ OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0178] In various aspects, R1is ‒O(C1-C4 fluoroalkyl). In a further aspect, R1is selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R1is selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, R1is ‒OCH2F.

[0179] In various aspects R1is ‒O(C2 haloalkyl). In a further aspect, R1is selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, R1is ‒OCH2CH2F. In yet a further aspect, R1is ‒OCH2CH218F. b. R2GROUP

[0180] In one aspect, R2is selected from hydrogen and C1-C4 alkyl. In a further aspect, R2is selected from hydrogen, ‒CH3, ‒CH2CH3, ‒CH2CH2CH3, and ‒CH(CH3)2. In a still further aspect, R2is selected from hydrogen, ‒CH3, and ‒CH2CH3. In a yet further aspect, R2is selected from hydrogen and ‒CH3.

[0181] In various aspects, R2is C1-C4 alkyl. In a further aspect, R2is selected from ‒ CH3, ‒CH2CH3, ‒CH2CH2CH3, and ‒CH(CH3)2. In a still further aspect, R2is selected from ‒CH3and ‒CH2CH3.In a yet further aspect, R2is ‒CH3.

[0182] In various aspects, R2is hydrogen. c. R3GROUP

[0183] In one aspect, R3is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒ SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒ SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒ NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH2F)CH3, ‒ N(CH2Br)CH3, ‒N(CH2I)CH3, ‒N(CH2CH2F)CH3, ‒N(CH2CH2Br)CH3, ‒N(CH2CH2I)CH3, ‒ N(CH2CH2CH2F)CH3, ‒N(CH2CH2CH2Br)CH3, and ‒N(CH2CH2CH2I)CH3. In a still further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒ SCH2CH2I, ‒NH(CH2F), ‒NHCH2Br, -‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒ NHCH2CH2I, ‒NCH3(CH2F), ‒N(CH2Br)CH3, ‒N(CH2I)CH3, ‒N(CH2CH2F)CH3, ‒ N(CH2CH2Br)CH3, and ‒N(CH2CH2I)CH3. In a yet further aspect, R3is selected from ‒F, ‒Br, ‒ I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒N(CH2F)CH3, ‒N(CH2Br)CH3, and ‒N(CH2I)CH3.

[0184] In various aspects, R3is selected from halogen and ‒O(C1-C4 haloalkyl). In a further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, and ‒OCH2I.

[0185] In various aspects, R3is selected from halogen and ‒S(C1-C4 haloalkyl). In a further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, and ‒SCH2CH2CH2I. In a still further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, and ‒SCH2CH2I. In a still further aspect, R3is selected from ‒F, ‒Br, ‒I, ‒SCH2F, ‒SCH2Br, and ‒SCH2I.

[0186] In various aspects, R3is selected from halogen, ‒NH(C1-C4 haloalkyl), and ‒ N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R3is selected from ‒F, ‒Cl, ‒Br, I, ‒NHCH2F, ‒NHCH2Cl, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Cl, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Cl, ‒NHCH2CH2CH2Br, ‒ NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Cl, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F‒N(CH3)CH2CH2Cl, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F‒N(CH3)CH2CH2CH2Cl, ‒N(CH3)CH2CH2CH2Br, and ‒ N(CH3)CH2CH2CH2I. In a still further aspect, R3is selected from ‒F, ‒Cl, ‒Br, ‒I, ‒NHCH2F, ‒ NHCH2Cl, ‒NHCH2Br, -NH(CH2I), ‒NHCH2CH2F, ‒NHCH2CH2Cl, ‒NHCH2CH2Br, ‒ NHCH2CH2I, ‒‒N(CH3)CH2F, ‒N(CH3)CH2Cl, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Cl, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R3is selected from a F, Cl, Br, I, ‒NH(CH2F), -NH(CH2Cl), -NH(CH2Br), - NH(CH2I), ‒NCH3(CH2F), -NCH3(CH2Cl), -NCH3(CH2Br), and -NCH3(CH2I).

[0187] In various aspects, R3is halogen. In a further aspect, R3is ‒F, ‒Br, or ‒I. In a still further aspect, R3is ‒F. In yet a further aspect, R3is ‒Br. In a still further aspect, R3is ‒I. In an even further aspsect, R3is ‒Cl.

[0188] In various aspects, R3is ‒O(C1-C4 haloalkyl). In a further aspect, R3is selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, R3is selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R3is selected from ‒ OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0189] In various aspects, R3is ‒O(C1-C4 fluoroalkyl). In a further aspect, R3is selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R3is selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, R3is ‒OCH2F.

[0190] In various aspects R3is ‒O(C2 haloalkyl). In a further aspect, R3is selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, R3is ‒OCH2CH2F. d. R4GROUP

[0191] In one aspect, R4is selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒ NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒ NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒ NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I) ‒N(CH3)CH2F, ‒ N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒ SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0192] In various aspects, R4is a ‒O(C1-C4 haloalkyl). In a further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ OCH2CH2CH2F, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R4is selected from ‒OCH2F, ‒OCH2Br, and ‒OCH2I.

[0193] In various aspects, R4is ‒S(C1-C4 haloalkyl). In a further aspect, R4is selected from ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒ SCH2CH2CH2Br, and ‒SCH2CH2CH2I. In a still further aspect, R4is selected from ‒SCH2F, ‒ SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, and ‒SCH2CH2I. In a still further aspect, R4is selected from ‒SCH2F, ‒SCH2Br, and ‒SCH2I.

[0194] In various aspects, R4is selected from ‒NH(C1-C4 haloalkyl) and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R4is selected from ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒ NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒ N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, R4is selected from ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I) ‒ N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒ N(CH3)CH2CH2I. In a yet further aspect, R4is selected from ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0195] In various aspects, R4is ‒O(C1-C4 fluoroalkyl). In a further aspect, R4is selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R4is selected from ‒OCH2F and ‒OCH2CH2F. In an even further aspect, R4is ‒OCH2F. In a still further aspect, R4is ‒OCH2CH2F.

[0196] In various aspects, R4is ‒O(C2 haloalkyl). In a further aspect, R4is selected from‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R4is ‒ OCH2CH2F. In a still further aspect, R4is ‒OCH2CH2Cl. In an even further aspect, R4is ‒ OCH2CH2Br. In a yet further aspect, R4is ‒OCH2CH2I.

[0197] In various aspects, R4is ‒OCH2CH2F. e. R10A, R10B, R10C, R10D, AND R10EGROUPS

[0198] In one aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, and four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen.

[0199] In one aspect, one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1- C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, and three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and is labeled with a radioactive isotope.

[0200] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1- C4 haloalkyl), and is labeled with a radioactive isotope. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒ OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒ OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒ SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒ NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒ NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒ N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒ N(CH3)CH2CH2CH2I. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒ OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒ N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0201] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis halogen. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒F, ‒Br, or ‒I. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒F. In yet a further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒18F. In an even further aspect, one of R10a, R10b, R10c, R10d, and R10eis Br. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒76Br. In yet a further aspect, one of R10a, R10b, R10c, R10d, and R10eis I. In an even further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒123I or ‒124I. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒123I. In a yet further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒124I.

[0202] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis ‒O(C1-C4 haloalkyl). In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒ OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒ OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0203] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis ‒O(C1-C4 fluoroalkyl). In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒OCH2F.

[0204] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis ‒O(C2 haloalkyl). In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒OCH2CH2F, ‒ OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒ OCH2CH2F. In yet a further aspect, one of R10a, R10b, R10c, R10d, and R10eis ‒OCH2CH218F.

[0205] In various aspects, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n- propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, –OCH3, –OCH2CH3, – OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), – CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,– CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, and –CH2NH2.

[0206] In various aspects, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0207] In various aspects, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen and C1-C4 alkyl. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, methyl, and ethyl. In a still further aspect, four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen and methyl.

[0208] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, one of R10a, R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, and ‒I.

[0209] In various aspects, four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0210] In various aspects, R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope. In a further aspect, R10cis selected from selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒ OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒ SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒ NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒ N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, R10cis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒ SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R10cis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0211] In various aspects, R10cis halogen. In a further aspect, R10cis ‒F, ‒Br, or ‒I. In a still further aspect, R10cis ‒F. In yet a further aspect, R10cis ‒18F. In an even further aspect, R10cis Br. In a still further aspect, R10cis is ‒76Br. In yet a further aspect, R10cis I. In an even further aspect, R10cis ‒123I or ‒124I. In a further aspect, R10cis ‒123I. In a yet further aspect, R10cis ‒124I.

[0212] In various aspects, R10cis ‒O(C1-C4 haloalkyl). In a further aspect, R10cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒ OCH2CH2CH2I. In a still further aspect, R10cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R10cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0213] In various aspects, R10cis ‒O(C1-C4 fluoroalkyl). In a further aspect, R10cis selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R10cis selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, R10cis ‒OCH2F.

[0214] In various aspects, R10cis ‒O(C2 haloalkyl). In a further aspect, R10cis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, R10cis ‒ OCH2CH2F. In yet a further aspect, R10cis ‒OCH2CH218F.

[0215] In various aspects, one of R10b, R10c, R10d, and R10eis selected from halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope. In a further aspect, one of R10b, R10c, R10d, and R10eis selected from selected ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒ SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒ SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒ NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒ N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒ N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒ OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒ NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒ SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒ N(CH3)CH2I

[0216] In various aspects, one of R10b, R10c, R10d, and R10eis halogen. In a further aspect, one of R10b, R10c, R10d, and R10eis ‒F, ‒Br, or ‒I. In a still further aspect, one of R10b, R10c, R10d, and R10eis ‒F. In yet a further aspect, one of R10b, R10c, R10d, and R10eis ‒18F. In an even further aspect, one of R10b, R10c, R10d, and R10eis ‒Br. In a still further aspect, one of R10b, R10c, R10d, and R10eis ‒76Br. In yet a further aspect, one of R10b, R10c, R10d, and R10eis ‒I. In an even further aspect, one of R10b, R10c, R10d, and R10eis ‒123I or ‒124I. In a further aspect, one of R10b, R10c, R10d, and R10eis ‒123I. In a yet further aspect, one of R10b, R10c, R10d, and R10eis ‒124I.

[0217] In various aspects, one of R10b, R10c, R10d, and R10eis ‒O(C1-C4 haloalkyl). In a further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒ OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0218] In various aspects, one of R10b, R10c, R10d, and R10eis ‒O(C1-C4 fluoroalkyl). In afurther aspect, one of R10b, R10c, R10d, and R10eis selected from ‒OCH2F, ‒OCH2CH2F, and ‒ OCH2CH2CH2F. In a still further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒ OCH2F and ‒OCH2CH2F. In a yet further aspect, one of R10b, R10c, R10d, and R10eis ‒OCH2F.

[0219] In various aspects, one of R10b, R10c, R10d, and R10eis ‒O(C2 haloalkyl). In a further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, one of R10b, R10c, R10d, and R10eis ‒OCH2CH2F. In yet a further aspect, one of R10b, R10c, R10d, and R10eis ‒OCH2CH218F.

[0220] In various aspects, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and is labeled with a radioactive isotope. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, – CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, – OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, – CH2CH2NH2, –CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, – CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCF3, –OCH2CF3, – OCH3, –NHCH3, –N(CH3)2, and –CH2NH2.

[0221] In various aspects, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, three of R10b,R10c, R10d, and R10eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0222] In various aspects, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen and C1-C4 alkyl. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, methyl, and ethyl. In a still further aspect, three of R10b, R10c, R10d, and R10eare independently selected from hydrogen and methyl.

[0223] In various aspects, one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, one of R10b, R10c, R10d, and R10eis selected from ‒F, ‒Br, and ‒I.

[0224] In various aspects, three of R10b, R10c, R10d, and R10eare hydrogen. f. R11A, R11B, R11C, R11D, AND R11EGROUPS

[0225] In one aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl and four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, R11d, and R11eis hydrogen.

[0226] In one aspect, one of R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1- C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl) and three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

[0227] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1- C4 haloalkyl. In a further aspsect, one of R11a, R11b, R11c, R11d, and R11eis selected from selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒ N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒ N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0228] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis halogen. In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis ‒F, ‒Br, or ‒I. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis ‒F. In yet a further aspect, one of R11a, R11b, R11c, R11d, and R11eis Br. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis I.

[0229] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis ‒O(C1-C4 haloalkyl). In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒ OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒ OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0230] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis ‒O(C1-C4 fluoroalkyl). In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, one of R11a, R11b, R11c, R11d, and R11eis ‒OCH2F.

[0231] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis ‒O(C2 haloalkyl). In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒OCH2CH2F, ‒ OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, one of R11a, R11b, R11c, R11d, and R11eis ‒ OCH2CH2F.

[0232] In various aspects, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, R11d, and R11eis hydrogen. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, –OCH3, –OCH2CH3, – OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), – CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,– CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, and –CH2NH2.

[0233] In various aspects, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0234] In various aspects, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen and C1-C4 alkyl. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, methyl, and ethyl. In a still further aspect, four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen and methyl.

[0235] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis halogen. In a further aspect, one of R11a, R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, and ‒I.

[0236] In various aspects, four of R11a, R11b, R11c, R11d, and R11eare hydrogen.

[0237] In various aspects, R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R11cis selected from selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒ SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒ SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒ NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒ N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒ N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, R11cis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒ OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒ N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, R11cis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0238] In various aspects, R11cis halogen. In a further aspect, R11cis ‒F, ‒Br, or ‒I. In a still further aspect, R11cis ‒F. In yet a further aspect, R11cis Br. In a still further aspect, R11cis I.

[0239] In various aspects, R11cis ‒O(C1-C4 haloalkyl). In a further aspect, R11cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒ OCH2CH2CH2I. In a still further aspect, R11cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R11cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0240] In various aspects, R11cis ‒O(C1-C4 fluoroalkyl). In a further aspect, R11cis selected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R11cis selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, R11cis ‒OCH2F.

[0241] In various aspects, R11cis ‒O(C2 haloalkyl). In a further aspect, R11cis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, R11cis ‒ OCH2CH2F.

[0242] In various aspects, one of R11b, R11c, R11d, and R11eis selected from is selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, one of R11b, R11c, R11d, and R11eselected from ‒ F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒ NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒ N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒ SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒ N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, ‒I, ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0243] In various aspects, one of R11b, R11c, R11d, and R11eis halogen. In a further aspect, one of R11b, R11c, R11d, and R11eis ‒F, ‒Br, or ‒I. In a still further aspect, one of R11b, R11c, R11d, and R11eis ‒F. In yet a further aspect, one of R11b, R11c, R11d, and R11eis ‒Br. In a still further aspect, one of R11b, R11c, R11d, and R11eis ‒I.

[0244] In various aspects, one of R11b, R11c, R11d, and R11eis ‒O(C1-C4 haloalkyl). In a further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒ OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒ OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0245] In various aspects, one of R11b, R11c, R11d, and R11eis ‒O(C1-C4 fluoroalkyl). In a further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒OCH2F, ‒OCH2CH2F, and ‒ OCH2CH2CH2F. In a still further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒ OCH2F and ‒OCH2CH2F. In a yet further aspect, one of R11b, R11c, R11d, and R11eis ‒OCH2F.

[0246] In various aspects, one of R11b, R11c, R11d, and R11eis ‒O(C2 haloalkyl). In a further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, one of R11b, R11c, R11d, and R11eis ‒OCH2CH2F.

[0247] In various aspects, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a futher aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒ NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, – CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, and – CH(CH3)CH2NH2. In a further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, – OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, and –CH2NH2.

[0248] In various aspects, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0249] In various aspects, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen and C1-C4 alkyl. In a further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, methyl, and ethyl. In a still further aspect, three of R11b, R11c, R11d, and R11eare independently selected fromhydrogen and methyl.

[0250] In various aspects, one of R11b, R11c, R11d, and R11eis halogen. In a further aspect, one of R11b, R11c, R11d, and R11eis selected from ‒F, ‒Br, and ‒I.

[0251] In various aspects, three of R11b, R11c, R11d, and R11eare hydrogen. g. R12B, R12C, R12D, AND R12EGROUPS

[0252] In one aspect, one of R12b, R12c, R12d, and R12eis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl) and three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.

[0253] In various aspects, one of R12b, R12c, R12d, and R12eis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒ OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒ OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒ SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒NHCH2CH2CH2F, ‒ NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒N(CH3)CH2I, ‒ N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒N(CH3)CH2CH2CH2F, ‒ N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒ NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒ N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I. In a yet further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2Br, ‒ OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒ N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0254] In various aspects, one of R12b, R12c, R12d, and R12eis ‒O(C1-C4 haloalkyl). In a further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒ OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒OCH2CH2CH2I. In a still further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0255] In various aspects, one of R12b, R12c, R12d, and R12eis ‒O(C1-C4 fluoroalkyl). In a further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2F, ‒OCH2CH2F, and ‒ OCH2CH2CH2F. In a still further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒ OCH2F and ‒OCH2CH2F. In a yet further aspect, one of R12b, R12c, R12d, and R12eis ‒OCH2F.

[0256] In various aspects, one of R12b, R12c, R12d, and R12eis ‒O(C2 haloalkyl). In a further aspect, one of R12b, R12c, R12d, and R12eis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, one of R12b, R12c, R12d, and R12eis ‒OCH2CH2F.

[0257] In various aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒ NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, – CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, and – CH(CH3)CH2NH2. In a further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, – OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, and –CH2NH2.

[0258] In various aspects, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. Ina further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0259] In various aspects, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen and C1-C4 alkyl. In a further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, methyl, and ethyl. In a still further aspect, three of R12b, R12c, R12d, and R12eare independently selected from hydrogen and methyl.

[0260] In various aspects, three of R12b, R12c, R12d, and R12eare hydrogen.

[0261] In various aspects, R12cis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl). In a further aspect, R12cis selected from selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒ OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Br, ‒OCH2CH2CH2I, ‒SCH2F, ‒SCH2Br, ‒ SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒SCH2CH2CH2F, ‒SCH2CH2CH2Br, ‒ SCH2CH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒ NHCH2CH2I, ‒NHCH2CH2CH2F, ‒NHCH2CH2CH2Br, ‒NHCH2CH2CH2I, ‒N(CH3)CH2F, ‒ N(CH3)CH2Br, ‒N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, ‒N(CH3)CH2CH2I, ‒ N(CH3)CH2CH2CH2F, ‒N(CH3)CH2CH2CH2Br, and ‒N(CH3)CH2CH2CH2I. In a still further R12cis selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Br, ‒OCH2CH2I, ‒ SCH2F, ‒SCH2Br, ‒SCH2I, ‒SCH2CH2F, ‒SCH2CH2Br, ‒SCH2CH2I, ‒NHCH2F, ‒NHCH2Br, ‒ NHCH2I, ‒NHCH2CH2F, ‒NHCH2CH2Br, ‒NHCH2CH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, ‒ N(CH3)CH2I, ‒N(CH3)CH2CH2F, ‒N(CH3)CH2CH2Br, and ‒N(CH3)CH2CH2I.. In a yet further aspect, R12cis selected from ‒OCH2F, ‒OCH2Br, ‒OCH2I, ‒SCH2F, ‒SCH2Br, ‒SCH2I, ‒ NHCH2F, ‒NHCH2Br, ‒NHCH2I, ‒N(CH3)CH2F, ‒N(CH3)CH2Br, and ‒N(CH3)CH2I.

[0262] In various aspects, R12cis ‒O(C1-C4 haloalkyl). In a further aspect, R12cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒ OCH2CH2Br, ‒OCH2CH2I, ‒OCH2CH2CH2F, ‒OCH2CH2CH2Cl, ‒OCH2CH2CH2Br, and ‒ OCH2CH2CH2I. In a still further aspect, R12cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, ‒ OCH2I, ‒OCH2CH2F, ‒OCH2CH2Cl, ‒OCH2CH2Br, and ‒OCH2CH2I. In a yet further aspect, R12cis selected from ‒OCH2F, ‒OCH2Cl, ‒OCH2Br, and ‒OCH2I.

[0263] In various aspects, R12cis ‒O(C1-C4 fluoroalkyl). In a further aspect, R12cisselected from ‒OCH2F, ‒OCH2CH2F, and ‒OCH2CH2CH2F. In a still further aspect, R12cis selected from ‒OCH2F and ‒OCH2CH2F. In a yet further aspect, R12cis ‒OCH2F.

[0264] In various aspects, R12cis ‒O(C2 haloalkyl). In a further aspect, R12cis selected from ‒OCH2CH2F, ‒OCH2CH2Br, and ‒OCH2CH2I. In a still further aspect, R12cis ‒ OCH2CH2F. In yet a further aspect, R12cis ‒OCH2CH218F. h. AR1GROUP

[0265] In one aspect, Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 additional groups.

[0266] In various aspects, Ar1is a C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C14 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar1is a C6-C14 aryl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒ CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is a C6-C14 aryl substitutedwith 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is a C6-C14 aryl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is a C6-C14 aryl substituted with 0 additional groups.

[0267] In various aspects, Ar1is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is phenylsubstituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is phenyl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is phenyl monosubstituted with an additional group selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is phenyl substituted with 0 additional groups.

[0268] In various aspects, Ar1is a C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C10 heteroaryl include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar1is a C2-C10 heteroaryl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is a C2-C10 heteroaryl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is a C2-C10 heteroaryl monosubstituted with an additional group selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is a C2-C10 heteroaryl substituted with 0 additional groups.

[0269] In various aspects, Ar1is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is pyridinyl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is pyridinyl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is pyridinyl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is pyridinyl substituted with 0 additional groups. i. AR2GROUP

[0270] In one aspect, Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 additional groups independently selectedfrom halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 additional.

[0271] In various aspects, Ar2is a C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C14 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar2is a C6-C14 aryl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒ CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is a C6-C14 aryl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is a C6-C14 aryl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is a C6-C14 aryl substituted with 0 additional groups.

[0272] In various aspects, Ar2is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar2isphenyl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is phenyl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is phenyl monosubstituted with an additional group selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is phenyl substituted with 0 additional groups.

[0273] In various aspects, Ar2is a C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C10 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar2is a C2-C10 heteroaryl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is a C2-C10 heteroaryl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is a C2-C10 heteroaryl monosubstituted with an additional group selected from halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is a C2-C10 heteroaryl substituted with 0 additional groups. In various aspects, Ar2is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar2is pyridinyl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is pyridinyl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is pyridinyl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is pyridinyl substituted with 0 additional groups. j. AR3GROUP

[0274] In one aspect, Ar3is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C10 heteroaryl include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar3is C2-C10 heteroaryl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar3is C2-C10 heteroaryl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar3is C2-C10 heteroaryl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar3is C2-C10 heteroaryl substituted with 0 additional groups.

[0275] In various aspects, Ar3is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar3is pyridinyl substituted with 0, 1, or 2 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar3is pyridinyl substituted with 0 or 1 additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar3is pyridinyl monosubstituted with an additional group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar3is pyridinyl substituted with 0 additional groups. 2. EXAMPLE COMPOUNDS

[0276] In one aspect, a compound can be present as one or more of the following structures: Oor a pharmaceutically acceptable salt thereof.

[0277] In a further aspect, a compound can be present as the following structure: ,or a pharmaceutically acceptable salt thereof.

[0278] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.

[0279] In one aspect, a compound can be present as the following structure:or a pharmaceutically acceptable salt thereof. 3. PROPHETIC EXAMPLE COMPOUNDS

[0280] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as agents to image reactive oxygen and nitrogen species (RONS) and / or agents to treat a disease or disorder due to oxidative stress, as further detailed herein, and such activity can be determined using the assay methods described herein below.

[0281] Thus, in one aspect, a compound is:or a pharmaceutically acceptable salt thereof.

[0282] In a further aspect, a compound is:or a pharmaceutically acceptable salt thereof.

[0283] In one aspect, a compound is:or a pharmaceutically acceptable salt thereof.

[0284] In a further aspect, a compound is:or a pharmaceutically acceptable salt thereof.

[0285] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0286] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0287] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like. C. METHODS OF MAKING A COMPOUND

[0288] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0289] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-IV, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE 1

[0290] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 1A.

[0291] Compounds are represented in generic form, wherein PG is an amine protecting group (e.g., carbobenzyloxy, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9- fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4- dimethoxybenzyl, p-methoxyphenyl, tosyl, 4-nitrobenzenesulfonyl), Z is a suitable leaving group (e.g., ‒N(CH3)3, triflate, tosylate, mesylate, halogen), and with other substituents as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 1A is provided below. SCHEME 1B.

[0292] In one aspect, compounds of type 1.8, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.7 can be prepared by reacting an appropriate diazene, e.g.1.5 as shown above, and an appropriate radiolabeled nucleophile, e.g., 1.6 as shown above. Appropriate diazenes and appropriate radiolabeled nucleophiles are commercially available or prepared by methods known to one of skill in the art. The reaction is carried out in the presence of an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., acetonitrile, at an appropriate temperature, e.g.85 °C. Compounds of type 1.8 can be prepared by a reduction of an appropriate radiolabeled diazene, e.g., 1.7 as shown above. The reduction reaction can be carried out in the presence of an appropriate reducing agent, e.g., metallic zinc, in an appropriate solvent, e.g., acetic acid, at an appropriate temperature, e.g., 85 °C. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 1.1, 1.2, and 1.3) can be substituted in thereaction to provide compounds similar to Formula 1.4. 2. ROUTE II

[0293] In one aspect, the disclosed edaravone derivatives can be prepared as shown below. SCHEME 2A.

[0294] Compounds are represented in generic form, wherein PG is an amine protecting group (e.g., carbobenzyloxy, p-methoxybenzyl carbonyl, t-butyloxycarbonyl, 9- fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4- dimethoxybenzyl, p-methoxyphenyl, tosyl, 4-nitrobenzenesulfonyl), R is a C1-C4 alkyl, and with other substituents as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Schemes 2A-C is provided below.SCHEME 2D.

[0295] In one aspect, compounds of type 2.10, and similar compounds, can be prepared according to reaction Scheme 2D above. Thus, compounds of type 2.10 can be prepared by cyclization of an appropriate diazene, e.g., 1.8 as shown above. Appropriate diazenes are commercially available, prepared by methods known to one of skill in the art, or prepared by methods described elsewhere herein (e.g., Route I). The cyclization can be carried out in the presence of an appropriate acetoacetate derivative, e.g., 2.9 as shown above, and an appropriate acid, e.g., conc HCl. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7) can be substituted in the reaction to provide edaravone derivatives similar to Formula 2.8. 3. ROUTE III

[0296] In one aspect, the disclosed compounds can be prepared as shown below. SCHEME 3A.

[0297] Compounds are represented in generic form, wherein each occurrence of the substituents are as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 3B is provided below. SCHEME 3B.

[0298] In one aspect, compounds of type 3.4, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 3.4 can be prepared by rearrangement of an appropriate acetate, e.g., 3.3 as shown above. Appropriate acetates are commercially available or prepared by methods known to one of skill in the art. The rearrangement is carried out in the presence of an appropriate carbon dioxide source, e.g., carbon dioxide gas, and an appropriate base, e.g., methyl lithium, in an appropriate solvent, e.g., tetyrahydrofuran (THF). As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 3.1) can be substituted in the reaction to provide compounds similar to Formula 3.2. 4. ROUTE 4

[0299] In one aspect, the disclosed edaravone derivatives can be prepared as shown below. SCHEME 4A.SCHEME 4C.

[0300] Compounds are represented in generic form, wherein each occurrence of the substituents are as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Schemes 4A-C is provided below. SCHEME 4D.

[0301] In one aspect, compounds of type 4.10, and similar compounds, can be prepared according to reaction Scheme 4D above. Thus, compounds of type 4.10 can be prepared by cyclization of an aryl hydrazine, e.g., 4.9 as shown above, in the presence of an appropriate acetate, 4.8 as shown above. Appropirate aryl hydrazines and appropriate acetates are commercially available or prepared by methods known to one of skill in the art. The cyclization reaction can be carried out in an appropriate solvent, e.g., ethanol, in the presence of an appropriate acid, e.g. hydrogen chloride. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 4.1, 4.2, 4.3, 4.5, and 4.6) can be substituted in the reaction to provide edaravone derivatives similar to Formula 4.7. D. PHARMACEUTICAL COMPOSITIONS

[0302] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound useful in treating diseases or disorders due to oxidative stress such as, for example, neurological diseases (e.g., Alzheimer’s disease, Parkinson’s disease,Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), multiple sclerosis, cortical cavernous malformation (CCM), ischemic stroke), cancer, cardiovascular diseases, andischemia reperfusion injury (IRI).

[0303] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compounds having a structure represented by a formula:, wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R4is selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar3is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0304] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from: Oor a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0305] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.

[0306] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0307] In various aspects, the disclosed pharmaceutical compositions comprise thedisclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0308] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0309] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0310] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0311] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0312] The pharmaceutical compositions of the present invention comprise a compoundof the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0313] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0314] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0315] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0316] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0317] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0318] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0319] In a further aspect, the pharmaceutical composition is used to treat a disease or disorder due to oxidative stress or otherwise based on RONS pathophysiology. In a further aspect, the disease or disorder is a neurological disease. Examples of neurological diseases include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), multiple sclerosis, cortical cavernous malformation (CCM), and ischemic stroke.

[0320] In various aspects, the pharmaceutical composition is used to treat a disease or disorder selected from cancer, a cardiovascular disease, and ischemia reperfusion injury (IRI).

[0321] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. E. METHODS OF IMAGING REACTIVE OXYGEN AND NITROGEN SPECIES (RONS) IN A SUBJECT

[0322] In one aspect, disclosed are methods of imaging reactive oxygen and nitrogen species (RONS) in a subject using a disclosed compound. Thus, in various aspect, the method comprises administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selectedfrom C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0323] In various aspects, the radioactive isotope is selected from ‒18F, ‒76Br, ‒123I, and ‒124I.

[0324] In various aspects, R1is a halogen. In a further aspect, R1is ‒F. In a still further aspect, R1is ‒18F. In yet a further aspect, R1is ‒Br. In an even further aspect, R1is ‒76Br. In a still further aspect, R1is ‒I. In yet a further aspect, R1is ‒123I or ‒124I.

[0325] In various aspects, R1is ‒O(C1-C4 haloalkyl). In a further aspect, R1is ‒O(C1- C4 fluoroalkyl). In a still further aspect, R1is ‒O(C2 haloalkyl). In yet a further aspect, R1is ‒ OCH2CH2F. In an even further aspect, R1is ‒OCH2CH218F.

[0326] In various aspects, R2is hydrogen.

[0327] In various aspects, R2is C1-C4 alkyl. In a further aspect, R2is methyl.

[0328] In various aspects, Ar1is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is phenyl substituted with 0 additional groups.

[0329] In various aspects, Ar1is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is C2-C10 heteroaryl substituted with 0 additional groups. In a still further aspect, Ar1is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is pyridinylsubstituted with 0 additional groups.

[0330] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0331] In various aspects, the compound has a structure represented by a formula:, wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptable salt thereof.

[0332] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0333] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0334] In various aspects, the compound has a structure represented by a formula:, wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0335] In various aspects, one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, three of R10b, R10c, R10d, and R10eare hydrogen.

[0336] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0337] In various aspects, the compound is selected from: O ,,,or a pharmaceutically acceptable salt thereof.

[0338] In various aspects, the compound is selected from: Oor a pharmaceutically acceptable salt thereof.

[0339] In various aspects, the compound is: O ,or a pharmaceutically acceptable salt thereof.

[0340] In various aspects, the compound is not: ,or a pharmaceutically acceptable salt thereof.

[0341] In various aspects, imaging is positron emission tomography (PET) imaging. In a further aspect, imaging is positron emission tomography / magnetic resonance imaging(PET / MRI) imaging or positron emission tomography / computerized tomography (PET / CT) imaging. In a further aspect, imaging is positron emission tomography / magnetic resonance imaging (PET / MRI). In a still further aspect, imaging is positron emission tomography / computerized tomography (PET / CT) imaging.

[0342] In various aspects, imaging is single-photon emission computerized tomography (SPECT) imaging. In a further aspect, imaging is single-photon emission computerized tomography / computerized tomography (SPECT / CT) imaging.

[0343] In various aspects, RONS are central nervous system-derived (CNS-derived) RONS. In a further aspect, RONS are peripheral nervous system-derived (PNS-derived) RONS.

[0344] In various aspects, RONS comprise one or more of superoxide, hydrogen peroxide, hydroxyl radicals, singlet oxygen, peroxyl radicals, hypochlorous acid, and peroxynitrite.

[0345] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[0346] In various aspects, administering is oral administration, intranasal administration, intramuscular administration, or intravenous administration. In a further aspect, administering is intravenous administration.

[0347] In various aspects, the subject has been diagnosed with a need for imaging RONS prior to the administering step. In a further aspect, the method further comprises identifying a subject in need of RONS imaging.

[0348] In various aspects, imaging serves to evaluate efficacy of a treatment, such as, for example, Focused Ultrasound (FUS) treatment. F. METHODS OF IMAGING REACTIVE OXYGEN AND NITROGEN SPECIES (RONS) IN A CELL

[0349] In one aspect, disclosed are methods of imaging reactive oxygen and nitrogen species (RONS) in a cell using a disclosed compound. Thus, in various aspect, the method comprises contacting the cell with an effective amount of a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0350] In various aspects, the radioactive isotope is selected from ‒18F, ‒76Br, ‒123I, and ‒124I.

[0351] In various aspects, R1is a halogen. In a further aspect, R1is ‒F. In a still further aspect, R1is ‒18F. In yet a further aspect, R1is ‒Br. In an even further aspect, R1is ‒76Br. In a still further aspect, R1is ‒I. In yet a further aspect, R1is ‒123I or ‒124I.

[0352] In various aspects, R1is ‒O(C1-C4 haloalkyl). In a further aspect, R1is ‒O(C1- C4 fluoroalkyl). In a still further aspect, R1is ‒O(C2 haloalkyl). In yet a further aspect, R1is ‒ OCH2CH2F. In an even further aspect, R1is ‒OCH2CH218F.

[0353] In various aspects, R2is hydrogen.

[0354] In various aspects, R2is C1-C4 alkyl. In a further aspect, R2is methyl.

[0355] In various aspects, Ar1is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar1is phenyl substituted with 0 additional groups.

[0356] In various aspects, Ar1is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar1is C2-C10 heteroaryl substituted with 0 additional groups. In a still further aspect, Ar1is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar1is pyridinyl substituted with 0 additional groups.

[0357] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0358] In various aspects, the compound has a structure represented by a formula:, wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptable salt thereof.

[0359] In various aspects, one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0360] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0361] In various aspects, the compound has a structure represented by a formula:, wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0362] In various aspects, one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope. In a further aspect, three of R10b, R10c, R10d, and R10eare hydrogen.

[0363] In various aspects, the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

[0364] In various aspects, the compound is selected from:,or a pharmaceutically acceptable salt thereof.

[0365] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0366] In various aspects, the compound is: or a pharmaceutically acceptablesalt thereof.

[0367] In various aspects, the compound is not: ,or a pharmaceutically acceptable salt thereof.

[0368] In various aspects, the cell is a prokaryotic cell.

[0369] In various aspects, the cell is mammalian. In a further aspect, the cell is human.

[0370] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0371] In various aspects, contacting is in vitro. In a further aspect, contacting is ex vivo.

[0372] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for RONS imaging prior to the administering step. G. METHODS OF TREATING A DISEASE OR DISORDER DUE TO OXIDATIVE STRESS IN A SUBJECT

[0373] In one aspect, disclosed are methods of treating a disease or disorder due to oxidative stress or otherwise due to RONS pathophysiology in a subject in need thereof using a disclosed compound. Thus, in various aspects, the method comprises administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0374] In various aspects, R2is hydrogen.

[0375] In various aspects, R2is C1-C4 alkyl. In a further aspect, R2is methyl.

[0376] In various aspects, R3is a halogen. In a further aspect, R3is selected from ‒F, ‒ Br, and ‒I.

[0377] In various aspects, R3is ‒O(C1-C4 haloalkyl). In a further aspect, R3is ‒O(C1- C4 fluoroalkyl). In a still further aspect, R3is ‒O(C2 haloalkyl). In yet a further aspect, R3is ‒ OCH2CH2F.

[0378] In various aspects, Ar2is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar2is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is phenyl substituted with 0 additional groups.

[0379] In various aspects, Ar2is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar2is C2-C10 heteroaryl substituted with 0 additional groups. In a still further aspect, Ar2is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is pyridinyl substituted with 0 additional groups.

[0380] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0381] In various aspects, the compound has a structure represented by a formula: ,wherein one of R11a, R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, R11d, and R11eis hydrogen, or a pharmaceutically acceptable salt thereof.

[0382] In various aspects, one of R11a, R11b, R11c, R11d, and R11eis halogen. In a further aspect, four of R11a, R11b, R11c, R11d, and R11eare hydrogen.

[0383] In various aspects, the compound has a structure represented by a formula:, wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

[0384] In various aspects, the compound has a structure represented by a formula: ,wherein one of R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1- C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒ NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0385] In various aspects, one of R11b, R11c, R11d, and R11eis halogen. In a further aspect, three of R11b, R11c, R11d, and R11eare hydrogen.

[0386] In various aspects, the compound has a structure represented by a formula: ,wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

[0387] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0388] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0389] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[0390] In various aspects, the effective amount is a therapeutically effective amount.

[0391] In various aspects, the effective amount is a prophylactically effective amount.

[0392] In various aspects, the disease or disorder is a neurological disease. In a further aspect, the neurological disease is selected from Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), multiple sclerosis, cortical cavernous malformation (CCM), and ischemic stroke.

[0393] In various aspects, the disease or disorder is cancer, a cardiovascular disease, or ischemia reperfusion injury (IRI).

[0394] In various aspects, the subject has been diagnosed with the disease or disorder prior to the administering step. In a further aspect, the method further comprises the step of identifying a subject in need of treatment of the disease or disorder.

[0395] In various aspects, the method further comprises administering to the subject an agent known for treating a neurological disease. In a further aspect, the agent is an anticonvulsant. Examples of anticonvulsants include, but are not limited to, levetiracetam, topiramate, lamotrigine, oxcarbazepine, and divalproex sodium. H. METHODS OF USING THE COMPOSITIONS

[0396] Provided herein are methods of using of a disclosed compound or composition as a medicament. In one aspect, the method of use is directed to imaging reactive oxygen and nitrogen species (RONS). In a further aspect, the method of use is directed to the treatment of a disorder. In a further aspect, the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of the aforementioned diseases, disorders, and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.

[0397] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. 1. MANUFACTURE OF A MEDICAMENT

[0398] In one aspect, the invention relates to a method for the manufacture of a medicament for imaging reactive oxygen and nitrogen species (RONS) in subject or in a cell. The invention, in another aspect, relates to a method for the manufacture of a medicament for treating diseases or disorders due to oxidative stress such as, for example, neurological diseases, cancer, cardiovascular diseases, andischemia reperfusion injury (IRI).

[0399] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in treatment of a disease or disorder due to oxidative stress, such as, for example, neurodegenerative diseases, cancer, cardiovascular diseases, and ischemiareperfusion injury (IRI) as further disclosed herein. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the disease or disorder.

[0400] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising compounds for imaging reactive oxygen and nitrogen species (RONS) or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, by admixing with a pharmaceutically acceptable carrier or diluent.. In a further aspect, the invention relates to the manufacture of a medicament comprising compounds for treating diseases or disorders due to oxidative stress such as, for example, neurological diseases, cancer, cardiovascular diseases, and ischemia reperfusion injury (IRI), or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, by admixing with a pharmaceutically acceptable carrier or diluent. 2. USE OF COMPOUNDS AND COMPOSITIONS

[0401] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, the use relates to the manufacture of a medicament for imaging reactive oxygen and nitrogen species (RONS) in a subject. In a still further aspect, the use relates to the manufacture of a medicament for the treatment of disease or disorder due to oxidative stress in a subject.

[0402] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0403] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0404] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0405] In various aspects, the use relates to imaging of reactive oxygen and nitrogen species (RONS) in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the imaging is positron emission tomography (PET) imaging, positron emission tomography / magnetic resonance imaging (PET / MRI) imaging, positron emission tomography / computerized tomography (PET / CT) imaging, or single-photon emission computerized tomography (SPECT) imaging (e.g., single- photon emission computerized tomography / computerized tomography (SPECT / CT) imaging).

[0406] In various aspects, the use relates to a treatment of disease or disorder due to oxidative stress in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the disease or disorder is a neurological disease, cancer, carcinoma cardiovascular disease, or ischemia reperfusion injury (IRI).

[0407] In a further aspect, the use relates to the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a subject.

[0408] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for imaging reactive oxygen and nitrogen species (RONS) in a mammal. In a still further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a mammal. 3. SUBJECTS

[0409] In various aspects, the subject of the disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0410] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for imaging of reactive oxygen and nitrogen species (RONS) prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a disease or disorder due to oxidative stress prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need fortreatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a. DOSAGE

[0411] Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50 (the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50.

[0412] Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agents used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50(that is, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.

[0413] The formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human. Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment. The dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.

[0414] In various aspects, the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation, or allergic response. Although individual needs may vary, the determination of optimal ranges for effective amountsof formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA). In general, the dosage required to provide an effective amount of a formulation, which can be adjusted by one skilled in the art, will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY). b. ROUTES OF ADMINISTRATION

[0415] Also provided are routes of administering the disclosed compounds and compositions. The compounds and compositions of the present invention can be administered by direct therapy using systemic administration and / or local administration. In various aspects, the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient. In various aspects, an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized. Alternatively, therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration.

[0416] Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays).

[0417] In various aspects, the modes of administration described above may be combined in any order. 4. KITS

[0418] In one aspect, disclosed are kits comprising a compound having a structure represented by a formula:, wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a mixing agent; and (b) instructions for imaging a radiotracer.

[0419] In one aspect, disclosed are kits comprising a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒ O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically salt thereof, and one or more selected from: (a) an agent associated with the treatment of a disease or disorder due to oxidative stress; (b) instructions for administering the compound in connection with treating a disease or disorder due to oxidative stress; and (c) instructions for treating a disease or disorder due to oxidative stress.

[0420] In various aspects, the kit comprises the mixing agent. Examples of mixing agents include, but are not limited to, saline, ethanol, and dimethylsulfoxide (DMSO).

[0421] In various aspects, the kit comprises the agent associated with the treatment of a disease or disorder due to oxidative stress. In a further aspect, the agent is an anticonvulsant.Examples of anticonvulsants include, but are not limited to, levetiracetam, topiramate, lamotrigine, oxcarbazepine, and divalproex sodium.

[0422] In various aspects, the compound and agent are co-packaged. In a further aspect, the compound and the agent are co-formulated. I. EXAMPLES

[0423] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0424] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. IMAGING PATHOLOGIC OXIDATIVE STRESS IN THE CENTRAL NERVOUS SYSTEM IN VIVO WITH A NOVEL PET REPORTER a. GENERAL METHODS

[0425] All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under anatmosphere of dry N2. All reagents and solvents were obtained from Millipore Sigma unless otherwise noted and were used without further purification.4-(4,4,5,5- tetramethyl1,3,2-dioxaborolan-2-yl)naphthalen-1-ol was purchased from Chembridge (San Diego, CA). [18F]FDG was purchased from Cardinal Health (Dublin, OH).

[0426] EMT6 cells were commercially available from ATCC (Manassas, VA). All mice were acquired from the same source; all husbandry was identical across cohorts; and each mouse was randomly assigned to its respective study cohort (injured vs. control). Construction of volumes-of-interest (VOIs) from positron emission tomography / computed tomography (PET / CT) images and subsequent analyses of these VOIs were performed by multiple individuals to maximize rigor. All animal protocols were approved by the University of Virginia Animal Care and Use Committee, Radiation Safety Committee, and Biosafety Committee.i. SYNTHETIC METHODS (a) RADIOSYNTHESIS OF [18F]FEDV

[0427] To synthesize [18F]Fluoride ion, a Siemens RDS 11 cyclotron (Siemens, Princeton, NJ) was used to complete the nuclear reaction of18O(p,n)18F in a target of [18O]OH2. An anion-exchange resin (Myja Scientific, O’Neill, NE) preconditioned with 12 mL deionized water was used to capture [18F]fluoride, which was then eluted with a 1 mL solution of 9:1 acetonitrile-water containing 1 mg potassium carbonate and 6 mg Kryptofix 222 (Sigma-Aldrich, St. Louis, MO). Argon flow with reduced pressure and heating (90 °C) was performed to remove the solvents. The residue was then dried via azeotropic distillation that included two aliquots (1 mL) of anhydrous acetonitrile under argon flow, with reduced pressure and heating (90 °C). Next, 2.5 mg 4-((tert-butoxycarbonyl)diazenyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate was dissolved in 400 μL anhydrous acetonitrile and then added to the reactor vial. The vial was sealed and heated to 85 °C for 60 s. The solvent was then diluted in 3 mL deionized water and passed through a tC18 Plus Light Sep Pak (Waters Corp, Milford, MA). The cartridge was washed with 3 mL water, followed by >6 mL nitrogen gas to purge it. Next, the product was eluted from the cartridge with 1 mL glacial acetic acid into a clean reactor vial that was previously charged with 20 mg zinc dust and a teflon-coated magnetic stir bar. The reactor vial was sealed and heated to 85 °C for 60 s with stirring. The vial was then removed from the heat and 100 μL ethyl acetoacetate was added, followed by 100 μL concentrated HCl. The vial was left to stand uncapped for 60 s, until the evolution of hydrogen gas had ceased. Next, the vial was sealed and heated at 85 °C for 20 min with stirring and then cooled for 60 s. A 2 mL solution of water containing 200 mg sodium acetate was then added to the vial, and the solution was transferred through a 13-mm, 0.45- μm PVDF syringe filter and purified by semi- prep HPLC using a Synergi Hydro-RP C18 column (10 μm, 250 × 10 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 35:65 ethanol:acetate buffer (0.2 M acetic acid / 0.05 M sodium acetate) at 4.7 mL / min. The product was collected from 11 to 13 min into 20 mL deionized water. The entire solution was transferred through an Oasis HLB Plus light cartridge (Waters Corp), which was subsequently washed with 5 mL deionized water. Finally, 500 μL ethanol was passed through the HLB cartridge and diluted with 9.5 mL saline to yield 2-(4-[18F]fluorophenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one in a 12% ± 1% radiochemical yield (EOS) with an estimated molar activity of 9.2 ± 1.4 curies / micromole (n = 8). Chemical and radiochemical purity were determined by analytical HPLC using a SynergiHydro-RP C18 column (4 μm, 4.6 × 250 mm, 80 Å) under isocratic flow of a mobile phase consisting of 30:70 ethanol:acetate buffer (0.2 M acetic acid / 0.05 M sodium acetate) at 1.5 mL / min ([18F]FEDV Rt = 12 ± 0.5 min).

[0428] The identity of [18F]FEDV was verified by HPLC co-injection with a fully characterized fluorine-19 standard (FIG.15A-C). A semi-preparative HPLC chromatogram from purification of [18F]FEDV (6.3 – 7.3 minutes) is shown in FIG.16. Progress was monitored by UV absorbance at 254 nm, 210 nm, and radioactivity using HPLC column: Synergi Hydro-RP C18 column (10 μm, 250 × 10 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 65:35 acetonitrile:acetate buffer (0.2 M acetic acid / 0.05 M sodium acetate) at 4.7 mL / min. A semi-preparative HPLC chromatogram from purification of [18F]FEDV with standard coinjection to confirm product identity (6.3 – 7 minutes) is shown in FIG.17. Progress was monitored by UV absorbance at 254 nm, 210 nm, and radioactivity using HPLC column: Synergi Hydro-RP C18 column (10 μm, 250 × 10 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 65:35 acetonitrile:acetate buffer (0.2 M acetic acid / 0.05 M sodium acetate) at 4.7 mL / min. An analytical quality control HPLC chromatogram of [18F]FEDV used in all studies is shown in FIG.18. Chemical purity was determined by UV absorbance at 254nm (top) and radioactivity using a gamma detector (bottom) using HPLC column: Synergi Hydro-RP C18 column (4 μm, 250 × 4.6 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 65:35 acetonitrile:formate buffer (0.2 M formic acid / 0.05 M sodium formate) at 1 mL / min. An analytical quality control HPLC chromatogram of [18F]FEDV as used in all studies, and confirmed with coinjection of a fully characterized standard, is shown in FIG.19. Chemical purity was determined by UV absorbance at 254nm (top) and radioactivity using a gamma detector (bottom). HPLC column: Synergi Hydro-RP C18 column (4 μm, 250 × 4.6 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 65:35 acetonitrile:formate buffer (0.2 M formic acid / 0.05 M sodium formate) at 1 mL / min. (b) SYNTHESIS OF TERT-BUTYL (4-(4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-YL)NAPHTHALEN-1-YL) CARBONATE (8)

[0429] tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) carbonate (8) was synthesized as previously described (Pisaneschi, F., et al. (2022) Nat. Biotechnol.40, 965–973) with slight modifications.4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2- yl)naphthalen-1-ol (ChemBridge) (7, 200 mg, 0.75 mmol) was dissolved in anhydrous dichloromethane (3.0 ml), and Boc2O (165 mg, 0.75 mmol) and DMAP (90 mg, 0.75 mmol) were added in sequential order. The mixture was stirred at room temperature for 18 hours and progress was monitored by silica TLC (Rf product = 0.8, 20% ethyl acetate:hexanes). The reaction mixture was diluted with 25 mL of methylene chloride and 2 g of deactivated silica (10% triethylamine / hexanes) was added with stirring. The solvent was removed by rotary evaporation and the crude residue was was dry loaded into an empty CombiFlash syringe cartridge. The mixture was purified on a CombiFlash system using 12 g of silica and a gradient solvent system consisting of hexanes:ethyl acetate (% AcOEt in hexanes: 0% for 4 minutes, 0%→20% from 4 – 13 minutes, 20% hold from 13 – 20 minutes. tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl) carbonate (8) was isolated in an 82% yield (225 mg) as a white solid, which was dried over dynamic vacuum for 24 hours prior to use. (c) RADIOSYNTHESIS OF [18F]FN (10)

[0430] The radiosynthesis was performed on a commercially available automated radiosynthesizer, Elixys Flex / Chem (Sofie Biosciences – Dulles, VA). All purifications and reformulations were performed on a custom-built purification / reformulation system (RICO). Briefly, [18F]Fluoride was captured on an anion-exchange resin (Myja Scientific-O’Neill, NE) (previously conditioned with 5 mL of 0.5 M K2CO3, followed by 10 mL of water) and then eluted with a solution containing 20 mg of Kryptofix (K222) in 0.9 mL of anhydrous acetonitrile (MeCN) and 2 mg of K2CO3in 0.1 mL of sterile water. Water was removed by azeotropic distillation at 100 °C under negative pressure. Anhydrous acetonitrile (0.7 mL x 2) was added to the residue to azeotropically remove water at 100 °C. Next, 7 mg of tert-butyl (4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) carbonate (8), along with Cu(OTf)2(Py)4(15 mg) were added as a dissolved solution in 600 μL of anhydrous DMF. The reaction mixture was stirred with a glass coated magnetic stir bar and heated at 120 °C for 25 minutes. After allowing to cool to 40 °C, the solution was diluted with 1 mL of 1 M HCl and heated at 100 °C for 10 minutes. The reaction was cooled to 30 °C, diluted with 3 mL of deionized water, then transferred through a non-vented syringe filter and subsequently sent to a semi-prep HPLC for purification (Phenomenex Synergi Hydro-RP, 250 X 10 mm, 10 μm; flow rate = 4.0 mL / min, isocratic mobile phase of 50% CH3CN: 50% aqueous H3PO4(0.085% v / v); tR= 14-16 mins) with a recording wavelength of 254 nm (FIG.20). The desired product (10) was collected in a gross dilution vial containing 25 mL of water and transferred through an HLB Light Sep Pak. The HLB cartridge was rinsed with 10 mL of sterile water, followed by 0.5 mL USP EtOH to recover the product. The final product was reconstituted with 4.5 sterile saline and terminally sterilized through a 0.22 μm filter for imaging studies. Analytical quality control HPLC chromatogram of [18F]FN used in all studies was performed as shown in FIG.21. Chemical purity was determined by UV absorbance at 254nm (top) and radioactivity using a gamma detector (top). HPLC column: Synergi Hydro-RP C18 column (4 μm, 150 × 4.6 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 50:50 acetonitrile:formate buffer (0.2 M formic acid / 0.05 M sodium formate) at 1 mL / min. Furthermore, analytical quality control HPLC chromatogram of [18F]FN was confirmed with coinjection of a fully characterized standard as shown in FIG.22. Chemical purity was determined by UV absorbance at 254nm (bottom) and radioactivity using a gamma detector (top). HPLC column: Synergi Hydro-RP C18 column (4 μm, 150 × 4.6 mm, 80 Å) (Phenomenex, Torrance, CA) under isocratic flow of a mobile phase consisting of 50:50 acetonitrile:formate buffer (0.2 M formic acid / 0.05 M sodium formate) at 1 mL / min.ii. [18F]FEDVCHEMICAL REACTIVITY ASSAYS WITH VARIOUSRONS IN SOLUTION

[0431] All RONS chemical reactivity assays were performed as previously described (Alexander et al. (2011) Journal of the American Chemical Society 133 (11): 3776-3779). All RONS species were tested with specific concentrations of each RONS, as indicated, and reacted with 50 μM [18F]FEDV. All samples were quenched with 15 μL 500 mM ascorbic acid prior to HPLC analysis, at each indicated time point. Concentrations of [18F]FEDV were calculated by integrating areas and comparing to a standard mass curve of [18F]FEDV. All specific assay conditions are provided below.

[0432] [18F]FEDV chemical reactivity assays with various RONS in solution: Chemical reactivity of FEDV with various RONS was measured by analytical HPLC using an Agilent 1200 Series HPLC System equipped with a multi-wavelength detector and a Phenomenex Synergi Hydro-RP C18 Column (10 μm particle size, 4.6 x 250 mm). Concentrations of FEDV were calibrated by measuring the integrated peak intensities at 254 nm of samples containing 0, 25, 50, 75, and 100 μM (20 μL aliquots were injected into the HPLC). The reaction with RONS was measured as follows:

[0433] H2O2: 10 μL of 1 M H2O2(for a final concentration of 5 mM) was added to 1990 μL of 50 μM FEDV in 20 mM HEPES buffered at pH 7.4.400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0434] tBuOOH: A 70%tBuOOH in H2O solution was diluted 10-fold and 12.9 μL was added to 1987 μL of 50 μM FEDV in 20 mM HEPES buffered at pH 7.4 (final concentration oftBuOOH was 5 mM).400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0435] NO: A 10 mM NaOH solution was degassed for ~20 min by bubbling N2 through the solution. A stock solution of PROLInonoate (5.48 mg / mL, 25 mM) was prepared in degassed 10 mM NaOH and stored on ice. At the same time, 1800 μL 50 μM FEDV in 20 mM HEPES buffered at pH 7.4 was degassed for ~20 min by bubbling N2through the solution. 200 μL of the PROLInonoate solution (for a final concentration of 5 mM) was added to the FEDV solution. 400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0436] OCl–: 12 μL of a 6.15% NaOCl solution was added to 1988 μL of 50 μM FEDV in 20 mM HEPES buffered at pH 7.4 (final concentration of NaOCl was 5 mM).400 μLaliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0437] OH•: 2 mL of a 50 μM FEDV solution in 20 mM HEPES buffered at pH 7.4 was degassed for ~5 min by bubbling N2.8 mg ammonium iron(II) sulfate (10 mM) was added and the solution was degassed for ~30 min by bubbling N2.10 μL of 1 M H2O2was added (for a final concentration of 5 mM).400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0438] tBuO•: 3 mL of a 50 μM FEDV solution in 20 mM HEPES buffered at pH 7.4 was degassed for ~5 min by bubbling N2.11.2 mg ammonium iron(II) sulfate (9.52 mM) was added and the solution was degassed for ~30 min by bubbling N2. A 70%tBuOOH in H2O solution was diluted 10-fold and 19.4 μL was added to the BFA solution (for a final concentration of 5 mM).400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes.

[0439] ONOO–: A 30% aqueous solution of H2O2(0.24 mL, 2.4 mmol) followed by n- amyl nitrite (0.27 mL, 2.0 mmol) was added to 4.5 mL 0.55 M NaOH and 5 mL isopropyl alcohol. The reaction was stirred for 15 min and washed with10 mL CH2Cl2. MnO2 was added to the aqueous layer to scavenge unreacted H2O2with visible bubbling. The solution was filtered and stored on ice. The solution was diluted 200-fold in 0.1 M NaOH and the concentration of the stock solution was determined to by measuring the absorbance at 302 nm (ε =1670 M–1). 90 μL of ONOO–(for a final concentration of 5 mM) was added to 2410 μL of a 50 μM FEDV solution in 20 mM HEPES buffered at pH 7.4.400 μL aliquots were quenched with 15 μL 500 mM ascorbic acid (for a final concentration of 18 mM), and analyzed by analytical HPLC at 5, 10, 15, and 20 minutes. iii. [18F]FEDVIN VITRO ASSAYS

[0440] In vitro assays of [18F]FEDV were performed using EMT6 cells, as previously described (Wenhua et al. (2014) Org. Biomol. Chem.12: 4421-4431). Briefly, EMT6 cells were maintained in DMEM / F12 and seeded in 96-well culture plates 48 h before the uptake assays to achieve log-growth phase with approximately 70% confluence at the time of the uptake assay (approximately 10,000 cells per well). Cell culture medium was removed, and freshly prepared cell culture medium containing 5.6 ± 1.8 × 10-2MBq of [18F]FEDV was added to each well. After 30-, 60-, 120-, or 180-min incubation at 37 °C, cells were rinsed twice with 1 mL ice-cold 1× PBS. Then the cells were lysed by incubating them in 100 μL 2 M KOH at 37 °C for 10 min.The cell-associated radioactivity was measured by transferring 80 μL of the supernatant from each well into 1.5-mL microcentrifuge tubes and assaying radioactive counts using a Hidex AMG automated gamma counter (Hidex, Turku, Finland). iv. SNP MOUSE MODEL

[0441] Cerebral oxidative stress was induced by intrastriatal microinjection of sodium nitroprusside (SNP, Sigma-Aldrich). Briefly, mice were anesthetized with 2% isoflurane and placed in a stereotatic apparatus. A scalp incision was made along the midline of skull. A hole was drilled for the intrastriatal microinjection at the coordinates: anterior-posterior (AP) +0.5 mm, medial-lateral (ML) -2 mm, dorsal-ventral (DV) −3.5 mm from the bregma. The 1 μL of SNP (10, 20, or 50 nM in saline) was injected into the left striatum at a speed of 0.2 μL / min for 5 mins using a microinjection syringe pump (MICRO2T SMARTouch, World Precision Instruments Inc.). After the microinjection, the glass micropipette was kept in place for an additional 5 min allowing the maximal volume of SNP diffusion. Subsequently, the animals were subjected to PET / CT imaging or oxHET measurement at one hour after SNP-injection. v. PHOTOTHROMBOSIS STROKE MODEL

[0442] The photothrombosis (PT) stroke model was performed as previously described (Sun et al. (2020) Blood Adv.4(7): 1222-1231). Briefly, mice were anesthetized with 2% isoflurane, and fur was shaved above the temporalis muscle to visualize the ispilateral common carotid artery (CCA). Mice underwent permanent ligation of the ipsilateral CCA, and the chest opening was closed. An incision in the skin was made from the corner of the eye to the ear, exposing the temporalis muscle, followed by a 50- μL injection of bupivacaine (0.25%) into the temporalis muscle. After 1 min, an incision was made in the temporalis muscle, along the temporal line, and the temporalis muscle was gently retracted to expose the skull. A 1-mm- diameter area of skull, over the proximal branch of the middle cerebral artery (MCA), was thinned using an electric drill. Next, an intravenous injection of Rose bengal dye (50 mg / kg; Sigma-Aldrich) was delivered into the retroorbital sinus, and the 1-mm window was illuminated by a 543-nm laser beam (5 mW) 1 mm in diameter for 20 min. vi. PET / CT IMAGING

[0443] A tail vein catheter was placed in mice under isoflurane anesthesia. For all studies, approximately 150 μCi were injected via the catheter. Two types of scans, dynamic and static, were used for this study. For dynamic-scan studies, a Bruker AlbiraSi PET-CT system(Bruker, Billerica, MA) was used. Immediately after the radiotracer was inject, a 60-min PET scan was initiated. Dynamic frames were binned as follows [frames, time(s)]: 15 × 5 s, 5 × 15 s, 5 × 30 s, 3 × 60 s, 4 × 180 s, and 8 × 300 s. For static-scan studies, animals were allowed to recover and micturate after the radiotracer was injected. At 35 min post injection, they were anesthetized again with isoflurane. At 45 min postinjection, the mice were transferred to the PET / CT system for 15 min to acquire a single PET image. Both types of PET scans were immediately followed by a 10-min CT scan to ensure attenuation correction and anatomical co- registration. Anesthesia was maintained during imaging by using isofluorane. Upon completion of the study, mice were euthanized for biodistribution, where applicable, and γ counting of harvested tissue was performed using a Hidex AMG Automatic Gamma Counter (Hidex). vii. COMPUTATION OF PARAMETRIC PET MAPS

[0444] To generate parametric total-body PET maps of rodents, a blood input model was computed. Image-derived input function was optimized using data derived from the inferior vena cava and accounts for partial volume recovery of the blood input. This model was developed to study rodent hearts, as previously described (Huang, Q., et. al., (2019) Phys Medicine Biology 64, 165010). Data from the model and that from whole-body dynamic PET (160 ×160 pixels × 300 slices) were entered into a graphical Patlak model (Patlak, C. S. and Blasberg, R. G. (1985) J Cereb Blood Flow Metabolism 5, 584–590) in Matlab (Mathworks Inc., Natick, MA). The Patlak model performed linear regression analysis, starting at 6.5 min to ≥8 min, when the image data are linear and where the slope indicates the Ki at that voxel. A 12-core Linux workstation was used to compute the parametric total-body Ki maps. viii. PET / CTIMAGE REGISTRATION AND QUANTIFICATION

[0445] Ki maps were computed using the same image dimensions as one frame of the raw PET 4-dimension volume and generated as NiFtis by using the same header information (i.e., voxel size and centering transform as the raw image) that is used by Matlab. Next, CT images that were obtained simultaneously were center-padded until their dimensions were consistent with that of their Ki map image. Finally, header information was replaced with the Ki maps, and the CT data were brought to the same image space, ensuring direct registration. Isotropic VOIs (2 mm) were delineated on the fused Ki map–CT images by using PMOD (version 3.9, PMOD Technologies Ltd., Zurich, Switzerland). The regional average Ki was quantified as a function of colony-forming units. After bringing the Ki map to the same image header space in Matlab, it was upscaled by four fold (a factor of their relative initial voxel size)for registration to the high-resolution CT. Volume rendering of the co-registered image was performed using PMOD. ix. CONFOCAL MICROSCOPIC IMAGING OF OXIDIZED HYDROETHIDINE IN MOUSE BRAIN

[0446] To prepare a 1 mg / mL solution of dihydroethidium (DHE D11347; ThermoFisher Scientific, Waltham, MA), 1 mg DHE was dissolved in 100 μL DMSO and diluted with 900 μL warm PBS. Each mouse received 300 μL of the resultant DHE solution via tail vein injection. After 60 min, mice were perfused with 10 mL saline followed by 10 mL PFA (4%). Brains were carefully removed and postfixed overnight in 4% PFA at 4 °C in the dark. The next day, the PFA was discarded and brains were placed in 15 mL sucrose (30%) at 4 °C in the dark overnight. After 24 h, the first round of sucrose was discarded, and brains were placed in 15 mL fresh sucrose (30%) at 4 °C in the dark overnight. After 24 h, the second round of sucrose was discarded, and brains were embedded for cryosectioning. Embedded brains were stored at -80 °C and sectioned at 20- μm thickness at -25 °C. Tissue slices were placed on glass microscope slides. Oxidized DHE (oxHET) was excited at 514 nm and detected at an emission of 590 to 620 nm. Quantification of oxidative stress was calculated as the ratio of oxHET to DAPI+nuclei in four randomly selected visual fields (40×). x. PATHOLOGY

[0447] Tissues were fixed in 10% neutral-buffered formalin and processed as paraffin embedded samples. Tissues were sectioned at a 4-μm thickness and mounted onto positively charged glass slides (Superfrost Plus; ThermoFisher Scientific, Waltham, MA) then HE stained and coverslipped using the HistoCore SPECTRA Workstain (Lecia Biosystems). Serial sections were immunolabeled with Phospho-Tau (Ser202, Thr205) Monoclonal Antibody (Clone AT8, Invitrogen, #MN1020, 1:20,000) using a Ventana Discovery Ultra autostainer (Roche, Indianapolis, IN) and the following conditions: Heat-induced epitope retrieval, Cell Conditioning Solution ULTRA CC1 (950-224, Roche) and visualization with DISCOVERY OmniMap anti- Rb HRP (760-4311, Roche), Hematoxylin II (790-2208, Roche), and Bluing reagent (760-2021, Roche). Morphologic assessments and interpretation of immunohistochemistry were conducted by a board-certified veterinary pathologist and in a manner that was blinded to the experimental condition of each mouse. Whole slide images to a 20x scalable magnification were created using a PANNORAMIC 250 Flash III digital slide scanner (3DHISTECH Ltd, Budapest, Hungary).Images were taken using the HALO v3.6.4134.137 software program (Indica Labs). xi. STATISTICAL ANALYSES

[0448] Quantitative data are expressed as the mean ± standard error of the mean, unless otherwise indicated. One-way or two-way ANOVA were used to compare means for a single or multiple comparisons, respectively. The Mann-Whitney U test was used to assess dynamic-scan PET data, specifically the differences in SUV comparisons over time. P-values smaller than 0.05 were considered statistically significant. b. RESULTS

[0449] Edaravone, which was approved for the treatment of ALS by the U.S. Food and Drug Administration in 2017 and for the treatment of acute ischemic stroke in Japan in 2001, has a well-defined mechanism of reactivity with RONS and pharmacokinetics in humans. By adding the isotope fluorine-18 [18F] to edaravone, the bioisostere [18F]FEDV was radiosynthesized to identify pathologic oxidative stress in the CNS when imaged via positron emission tomography / computed tomography (PET / CT) or PET / magnetic resonance imaging (PET / MRI). It was hypothesized that [18F]FEDV would freely diffuse through the plasma membrane and rapidly react with intracellular RONS at a physiological pH (FIG.1A), thereby creating an unstable intermediate that rapidly decomposes to generate the carboxylate anion [18F]F-OPB, which cannot pass through the plasma membrane. In turn, the [18F]F-OPB retained in the cell could promote contrast on PET / CT or PET / MRI images. Accordingly, without wishing to be bound by theory, [18F]FEDV can provide a robust and translatable theranostic agent capable of detecting CNS-derived oxidative stress with PET / CT or PET / MRI to facilitate follow-up therapy with edaravone.

[0450] Here, the ability of [18F]FEDV to identify oxidative stress within the CNS was investigated by using PET / CT or PET / MRI. This imaging tool may provide a noninvasive, quantitative measure of CNS-derived oxidative stress, which is desperately needed in the clinic to define therapeutic windows to optimize antioxidant strategies in a myriad of diseases. i. RADIOSYNTHESIS OF [18F]FEDV

[0451] The boc-protected trimethylammonium diazo precursor (1) was synthesized from 4-fluorophenylhydrazine through four straightforward, high-yielding steps (FIG.1C) (Nebel, N. et al. (2017) Acs Omega 2: 8649–8659; Latli, B. et al. (2018) J Label Compd Radiopharm 61: 764–772). The probe [18F]FEDV was synthesized in a three-step, two-pot radiochemicalreaction (see FIG.1A). The first step proceeded through nucleophilic aromatic substitution of (1) with [18F]fluoride to produce (2) in nearly quantitative yield in 60 s. The reaction was briefly purified via intermediate-cartridge purification, and then (2) was transferred into a new reactor vial previously charged with zinc dust, using acetic acid as the eluent. Again, this reaction proceeded in nearly quantitative yield (correcting for decay) and was complete within 60 s. The final product (3), [18F]FEDV, was generated by concomitant deprotection and condensation after adding ethyl acetotacetate and HCl directly to the reactor vial and heating for 20 min. After HPLC purification and reformulation, [18F]FEDV was synthesized in 12% ± 1% activity yield (n = 8) within 60 min. This robust, straightforward, high-yielding radiosynthesis produced [18F]FEDV with >99% radiochemical purity, the identity of which was confirmed by HPLC co- injection with a fully characterized fluorine-19 standard. ii. CHARACTERIZATION OF [18F]FEDV RONS REACTIVITY IN VITRO

[0452] Edaravone is thought to possess lipophilic and hydrophilic properties resembling those of antioxidants vitamin E and vitamin C, respectively (Ohara, K. et al. (2006) B Chem Soc Jpn 79, 1501–1508 and Hata, K. et al. (2011) J Radiat Res 52, 15–23). It also possesses broad chemical reactivity with various oxidants in solution. The chemical reactivity of [18F]FEDV was characterized with various lipophilic and hydrophilic oxidants. The RONS that are most associated with CNS pathogenesis and disease exacerbation (FIG.1C) are superoxide, hydrogen peroxide, hydroxyl radical, singlet oxygen, peroxyl radicals, hypochlorous acid, and peroxynitrite. [18F]FEDV (50 μM) was incubated in buffer with an oxidant (FIG.1C), and the rate of conversion of [18F]FEDV to [18F]F-OPB (FIG.1A) was measured by HPLC integration. [18F]FEDV demonstrated favorably high reactivity with both hydrophilic and lipophilic sources of oxidants; [18F]FEDV nearly completely converted to [18F]F-OPB wtihin 5 min. In addition, [18F]FEDV displayed high reaction specificity for peroxyl radical sources of oxidants, rather than peroxides.

[0453] To determine the suitability of [18F]FEDV as a PET agent, whether[18F]FEDV would react with intracellular sources of RONS, and whether those reactions would promote intracellular retention of the agent , was investigated (FIG.1A). EMT6 mouse mammary adenocarcinoma cells were treated with doxorubicin (DOX) (Chu, W. et al. (2014) Org Biomol Chem 12, 4421–4431, Luanpitpong, S. et al. (2012) Biochem Pharmacol 83, 1643–1654) to create an in vitro model system of intracellular oxidative stress. After DOX treatment, cells wereincubated with [18F]FEDV and assayed 30–180 min post-treatment to quantify cell-associated radioactivity (FIG.1D). [18F]FEDV rapidly accumulated within DOX-treated EMT6 cells, showing peak uptake within 2 h post-treatment. To confirm specificity, DOX-treated EMT6 cells were co-incubated with [18F]FEDV and 10 mM FEDV (FIG.1E), which showed intracellular accumulation of [18F]FEDV could be effectively blocked. [18F]FEDV stability and suitability for imaging RONS-associated pathology in vivo was confirmed by incubating [18F]FEDV in 5% ethanol / saline (reformulation solution) or human plasma (FIG.1F). In the reformulation solution, [18F]FEDV demonstrated high solution stability; >99% of [18F]FEDV was unchanged after 8 h. In human plasma, parent [18F]FEDV was measured to be >90% intact after 3 h, indicating high plasma stability of [18F]FEDV. Together, these results confirm the favorable reactivity of [18F]FEDV with RONS and suggest the suitability of this agent to detect oxidative stress in vivo.Referring to FIG.1A-F, under homeostasis, RONS production and antioxidant- mediated elimination are tightly regulated. The drug edaravone freely diffuses through the plasma membrane and rapidly reacts with intracellular RONS at physiological pH. The unstable intermediate rapidly decomposes to generate a carboxylate anion, [18F]F-OPB, which is unable to pass through the plasma membrane and is retained within the cell. Disruption of redox homeostasis, oxidative stress, results in high levels of RONS that damage proteins, lipids, carbohydrates, and nucleic acids. FIG.1A shows the radiosynthesis of [18F]F-EDV, a radiopharmaceutical analogue of edaravone. FIG.1B shows the presumed mechanism of intracellular retention of [18F]FEDV upon RONS reaction. Quantification of [18F]FEDV with various sources of oxidants over time is shown in FIG.1C; n = 3 replicates. Quantification of [18F]FEDV accumulation in EMT6 cells exposed to 3 µM doxorubicin (DOX) over time is shown in FIG.1D; n = 6 replicates.

[0454] To test the suitability of [18F]FEDV for imaging RONS in vivo, the stability of [18F]FEDV in the final product reformulation solvent (5% ethanol (v / v) in saline) and in human plasma was compared (see FIG.1E). In the reformulation solution, [18F]FEDV showed remarkable stability, with >99% of [18F]FEDV unchanged after 8 h. The probe also remained >90% intact after 3 h in human plasma, suggesting high stability and minimal radiolysis of [18F]FEDV (Fig.1e). Without wishing to be bound by theory, these results, when taken together, suggest that [18F]FEDV has a broad reactivity spectrum to RONS and favorable stability for in vivo imaging. Referring to FIG.1E, cellular accumulation of [18F]FEDV in EMT6 mammary carcinoma cells mediated by doxorubicin- induced oxidative stress, shown are means ± SEM; ***p <0.001, one-way is shown in FIG.1F.iii. INITIAL CHARACTERIZATION OF [18F]FEDV DETECTION OF RONS AFTER STRIATAL SNP INJECTION

[0455] The specificity of [18F]FEDV to identify CNS-derived RONS was assessed by utilizing a sodium nitroprusside (SNP) model (Hosoi, R. et al. (2019) Mol Imaging 18, 1536012118820421). To generate RONS in the brain, SNP was injected into the striatum, where SNP reacted with glutathione (FIG.2A). Mice were injected with either 20 nmol SNP or saline (control) and allowed to recover for 60 min prior to imaging. When compared to saline-injected mice, SNP-injected mice demonstrated increased PET signal at the site of injection (FIG.2B). To confirm the increased PET signal was due to a reaction with RONS, mice were injected with dihydroethidine (DHE) via the lateral tail vein 30 min prior to the conclusion of PET scanning and allowed it to react for 60 min (Sun, Y.-Y. et al. (2020) Blood Adv 4, 1222–1231, Sun, Y.-Y. et al. (2015) Stroke 46, 1947–1955, and Sun, Y.-Y. et al. (2014) Plos One 9, e98807). Postmortem confocal microscopy of mouse striatum confirmed that the increased [18F]FEDV PET signal was due to site-specific reaction with RONS. Focused time activity curves comparing SNP-injected vs saline-injected striata showed enhanced retention of [18F]FEDV- derived PET signal (FIG.2C P < 0.001). To model typical clinical workflows for PET scans, we also performed static PET imaging of SNP-injected vs saline-injected mice at 45–60 min postinjection of [18F]FEDV. Static imaging yielded a significantly higher standard uptake value (SUV) in SNP-injected mice than in saline-injected mice (FIG.2D, P < 0.001).

[0456] [18F]FN, a recently reported redox-tuned PET reporter (Massey, J.C., et al. (2021) Frontiers Medicine 8, 618645), in the SNP model was also studied as a model comparison for [18F]FEDV imaging data. The SNP-injected mouse showed very little difference in PET signal (FIG.2B) between brain hemispheres. Accordingly, SUV of [18F]FN showed no significant differences (FIG.2D, p = 0.921, n=4 for each treatment) between SNP-treated vs saline-injected mice at 45-60 minutes post-[18F]FN injection. Whether [18F]FDG could differentiate SNP-treated vs saline-treated mouse brain was also tested. Robust PET signal in both SNP-treated and saline- treated mice was observed (FIG.2E); however, no significant differences in SUV were observed (FIG.2D, p = 0.168, n =4 for each treatment) between saline-treated and SNP-treated mice. Without wishing to be bound by theory, these results indicated that [18F]FEDV–PET imaging is sufficient to detect SNP-induced oxidative stress in vivo.

[0457] Referring to FIG.2A-E, [18F]FEDV accumulated in the striata of C57BL / 6 mice injected with 20 nmol sodium nitroprusside (SNP) but not in those injected with saline (n = 4 per treatment). At 1 h postinjection of SNP or saline, mice were imaged with [18F]FEDV for 60 minusing PET / CT to quantify CNS-derived RONS. FIG.2A shows that intrastriatal injection of SNP stimulates RONS generation by releasing nitric oxide (NO). This was confirmed by confocal microscopic imaging (bottom) of oxidized hydroethidine (oxHET) from the mouse striatum. Referring to FIG.2B, axial (top) and coronal (bottom) PET / CT images of [18F]FEDV in mice treated with saline (left) or 20 nmol SNP (right) to generate RONS are shown. Referring to FIG.2C and FIG.2D, [18F]FEDV time activity curves (TACs) were quantified for SNP- treated mice and saline-treated mice in striatum (top panel; n = 4 each; P < 0.0001, two-way ANOVA with subject matching in time and treatment repeated measures, two tailed t-test), which were summed 45–60 min post-treatment to generate the standard uptake values (SUV) (P < 0.0001, one-way ANOVA with Bonferroni post hoc test for significance; error bars = SEM). Refering to FIG.2E, [18F]FDG PET / CT imaging of sodium nitroprusside-induced ROS in mouse brain in vivo is shown. Adult male C57BL / 6 mice were subjected to intrastriatal injections of saline or 20 nmol sodium nitroprusside (SNP; Na2[Fe(CN)5NO]), followed by [18F]FDG- PET / CT imaging 1 h later (n = 4 for each). Axial (top) and coronal (bottom) [18F]FDG-PET / CT images of mice that received intra-striatal injection of saline (left) or SNP (right). iv. IMAGING RONS CAUSED BY ACUTE ISCHEMIC STROKE WITH [18F]FEDV PET

[0458] To test whether [18F]FEDV can quantify RONS-mediated pathology in a more clinically relevant model, a photothrombotic (PT) mouse model of acute ischemic stroke was utilized (Sun, Y.-Y. et al. (2020) Blood Adv 4, 1222–1231). The PT model utilizes a combination of Rose-Bengal dye injection, followed by laser treatment of the middle cerebral artery (MCA) to generate an occlusion with consistent location and size of infarct with well-characterized RONS pathology. Mice were retro-orbitally injected with Rose-Bengal dye (PT) or saline (sham) and imaged at 4 and 24 h after laser treatment by using [18F]FEDV PET. At 4 h post-PT, no observable SUV differences between the site of laser ablation and the contralateral hemisphere in mouse brain were seen; however, at 24 h post-PT, enhanced uptake of [18F]FEDV was clearly evident at the site of focused laser ablation of the MCA (FIG.3A). Focused time activity curves were generated to compare the sites of laser treatment of the MCA to contralateal uninjured sites within the brain at 4 hand 24 h post-PT (FIG.3B). These dynamic data revealed rapid wash- in / wash-out kinetics of [18F]FEDV in brain regions contralateral to PT, which did not generate a significantly different SUV in regions of interest measured at 4 h post-PT. However, at 24 h post-PT, the TAC demonstrated a steadily increasing, sustained [18F]FEDV-derived SUV, compared to 4 hours post-PT and contralateral hemispheres to 4 h and 24 h post-PT regions ofinterest. Static PET imaging 45–60 min post-[18F]FEDV injection yielded a significantly higher SUV in mice at 24 h post-PT vs 4 h post-PT or sham mice (FIG.3C, P < 0.001). Importantly, [18F]FEDV PET detection of PT-derived RONS was compared to the gold-standard MDA assay detection of RONS reaction products ex vivo (FIG.3D). The sensitivity of the [18F]FEDV PET to detect PT-derived RONS was similar to that of the MDA assay. [18F]FN in the PT model was also studied; however, no differences were observed in PET signal or SUV in ipsilateral:contralateral ROIs drawn in the PT mouse brain, which was also verified ex vivo with gamma counting of harvested brain tissue (FIG.23A-D, p = 0.913, n=3). Without wishing to be bound by theory, these data suggest that the sensitivity of static [18F]FEDV–PET imaging to detect in vivo RONS is similar to that of the MDA assay, a standard biochemical assay of oxidative injury.

[0459] Ischemic stroke can compromise the integrity of the BBB (Nian, K., et al. (2020) Front Physiol 11, 605398 and Okada, T., et al. (2020) Curr Neuropharmacol 18, 1187–1212); thus, it was also important to demonstrate that the increased [18F]FEDV PET signal was a function of the specific reaction of [18F]FEDV with PT-derived RONS, rather than nonspecific signal accumulation caused by edema or other biological process facilitated by a compromised BBB. A modified procedure of Kessler (Kessler, R. M. et al. (1984) J Cereb Blood Flow Metabolism 4, 323–328) was utilized to catheterize the carotid arteries of mice 24 h after the onset of PT to inject [68Ga]EDTA, a nonspecific PET agent that accumulates in the CNS of rodents that have a compromised BBB. As anticipated, the PET signal was significantly increased in mice injected with [18F]FEDV at 24 h post-PT, compared to mice injected with [68Ga]EDTA (FIG.3E). The PET data were also validated postmortem by using harvested brain tissues after PET scan completion and quantifying total radioactivity counts in each hemisphere ex vivo (FIG.3F, (P < 0.001)). Thus, the increased PET signal observed at 24 h post-PT was a function of [18F]FEDV reaction with RONS. Without wishing to be bound by theory, these results suggest that the increased [18F]FEDV-PET signal at 24 h post-PT is not caused by extravasation alone.

[0460] Referring to FIG.3A-F, [18F]FEDV accumulated in the striata of mice in a photothrombosis (PT) model of stroke. C57BL / 6 mice were injected with Rose bengal dye or saline and then exposed to 543-nm laser stimulation to induce thromboembolism (n = 4 per treatment) and imaged with [18F]FEDV for 60 min using PET / CT to quantify CNS-derived RONS. Specifically, FIG.3A shows axial (top) and coronal (bottom) PET / CT images of [18F]FEDV in mice treated with saline (left) or Rose bengal dye (middle, right), followed byproximal middle cerebral artery (MCA) laser stimulation to generate RONS after platelet aggregation. Mice were imaged at 4 h (middle) or 24 h (right) post-laser stimulation. Dynamic imaging with [18F]FEDV revealed significant differences in PET signal at the site of infarct 24 h after the induction of stroke (left) (FIG.3B). PET imaging of arterially infused [68Ga]EDTA (left) or [18F]FEDV (right) following laser stimulation of the proximal MCA in mice injected with saline (Sham) or Rose bengal dye (PT) revealed that increased PET signal after a stroke is a function of increased RONS and not of the disrupted blood–brain barrier (BBB) (FIG.3E). Ex vivo gamma counting in mouse brain after PT revealed significant differences between the ipsilateral (Ipsi; injured) and contralateral (Cont; uninjured) brain hemispheres of [18F]FEDV- injected mice (FIG 3F).***P = 0.0077. Ex vivo quantification of CNS-derived RONS showed significant differences in malondialdehyde (MDA) concentrations 24 h post-stroke in the ipsilateral (injured) hemisphere (FIG 3D).

[0461] Referring to FIG.23A-D, [18F]FN is unable to differentiate RONS in a murine model of stroke. Adult male C57BL / 6 mice were subjected to unilateral middle cerebral artery (MCA)-targeted photothrombosis (PT), followed by [18F]FN-PET / CT imaging 24 h later to detect stroke-induced RONS in vivo (n = 4 for each time point). FIG.23A shows axial (top) and coronal (bottom) PET / CT images of [18F]FN in mice treated with rose bengal dye, followed by 543-nm laser stimulation at the proximal MCA branch. Mice were imaged at 24 h post-PT. FIG. 23B shows the SUVAVGcurves and quantifications showed no significant differences of [18F]FN- PET signal in the ipsilateral cortex at 24 h, compared to the contralateral hemisphere after stroke. Shown are the means ± SEMs; ns, one-way ANOVA with Bonferroni post-hoc test for significance. FIG.23C shows mouse [18F]FN PET data were summed 45–60 minutes post- injection to generate SUVavg(n = 3 each; ns, two-way ANOVA with tukey post-hoc test for significance; shown are the means ± SEMs). FIG.23D shows ex vivo quantification of [18F]FEDV (left) vs [18F]FN (right) in the ipsilateral and contralateral hemispheres at 24 h. (n = 3 for each group; ***p <0.001, two-way ANOVA). v. DYNAMIC PET IMAGING WITH [18F]FDV DRAMATICALLY INCREASES THE SENSITIVITY TO DETECT RONS PATHOPHYSIOLOGY IN VIVO (FIG 4A).

[0462] Mouse models of ischemia have demonstrated an early pathophysiological role of oxidative stress toward the development of subsequent infarct (Sun, Y.-Y. et al. (2020) Blood Adv 4, 1222–1231, Sun, Y.-Y. et al. (2015) Stroke 46, 1947–1955, and Sun, Y.-Y. et al. (2014)Plos One 9, e98807). Accordingly, early therapeutic intervention with edaravone in mouse models of ischemia directly reduced the infarct (Sun, Y.-Y. et al. (2015) Stroke 46, 1947–1955 and Sun, Y.-Y. et al. (2014) Plos One 9, e98807). Thus, the PT mouse model of ischemia was pursued to determine the sensitivity of [18F]FEDV for quantifying RONS-induced pathophysiology as a result of stroke. [18F]FEDV was intravenously administered in mice and dynamically imaged with PET at 4 h and 24 h post-PT for 60 min. After completion of the PET scan, mice were immediately imaged with T2 MRI to determine the anatomical localization of the brain infarct. To quantify the PET signal, volumes of interest (VOIs) in the brain were delineated by using MRI to define the size of the infarct and by comparing this VOI to the contralateral, noninjured region, as well as the ipsilateral and contralateral VOIs in sham-treated mice. Using parametric mapping (Huang, Q., et al. (2019) Phys Medicine Biology 64, 165010– 165018 ), whether the rate of [18F]FEDV uptake in tissue (Ki)(Patlak, C. S. & Blasberg, R. G. (1985) J Cereb Blood Flow Metab 5, 584–590 ) could increase PET sensitivity for pathologically derived RONS in the CNS was investigated , rather than SUV, which is semiquantitative and cannot discern the PET signal of blood pool contamination from that of tissue. Dynamic PET / MRI with [18F]FEDV showed enhanced uptake at the site of infarct at 4 h and 24 h post-PT (FIG.4A). As a result, parametric mapping showed significant differences in Ki at the site of infarct at 4 h and 24 h (P < 0.001), compared to the ipsilateal and contralateral VOIs in sham- treated mice (FIG.4B). Ki was significantly different between the site of infarct and the contralateral VOI at 4 h post-PT (P < 0.01); however, this comparison was not significant (P = 0.055) at 24 h post-PT (FIG.4B). As is visually evident by PET / MRI, the differences in Ki at 4 h and 24 h were most likely due to the temporal spread of untreated infarct and subsequently RONS within the brain. After imaging, the brain tissue was harvested and made slices for autoradiography (FIG.4C), which revealed radioactive counts localized to the site of infarct (red arrows). Adjacent slices were examined via confocal microscopy to quantify RONS-positive cells (FIG.4D). Significantly more RONS-positive cells at the site of injury were found compared to that in control mice at both time points (P < 0.01).

[0463] Referring to FIG.4A-D, in a photothrombotic (PT) model of acute ischemic stroke, [18F]FEDV demonstrated increased retention in regions of interest (ROIs) with confirmed reactive oxygen and nitrogen species (RONS), as a result of ischemia. [18F]FEDV PET signal detected significant ischemia-induced RONS signatures in the mouse brain that were not detected by the gold-standard malondialdehyde (MDA) assay ex vivo. C57Bl6 / N mice (n = 4 per imaging time point) were injected with Rose bengal dye or saline retro-orbitally and then treatedwith laser of the middle cerebral artery (MCA) to induce occlusion. Mice were then imaged 4 h or 24 h later with [18F]FEDV using dynamic PET for 60 min. Mice were immediately transferred and imaged by 9.4 T MRI to visualize stroke injury by T2. PET / MRI images were co-registered to calculate ROIs as the rate of tracer uptake (Ki). FIG.4A shows [18F]FEDV PET / MRI images of mice 4 h (left) and 24 h (right) post-PT, which reveal enhanced uptake at sites of stroke injury (yellow arrows). FIG.4B shows that the Ki of [18F]FEDV uptake in brain tissue revealed significant increases in PET at the site of ischemia (blue) compared to the contralateral volume of interest (VOI; orange) or sham (gray and yellow) (**P <0.01, ***P <0.001, two-way ANOVA, two-tailed, ns P = 0.055). FIG.4C shows representative autoradiography of mouse brain at 4 h (left, black) and 24 h (right, blue) post-PT, which shows spatial specificity of [18F]FEDV-associated radioactive counts, relative to the site of ischemia. Brains were harvested after completion of PET / MRI. Representative confocal microscopic images (top) of harvested mouse brains 4 h post-PT with DAPI (blue, left) and hydroethidine (red, right) are shown in FIG.4D. Fluorescence was significantly increased in ischemic tissue (bottom) at 4 h and 24 h post-PT. Data are presented as means ± SEM. vi. DETECTION OF OXIDATIVE STRESS IN THE PS19 TAUOPATHY MODEL WITH [18F]FEDV–PET IMAGING

[0464] [18F]FEDV–PET was used to compare the brains of heterozygous PS19 and wild- type (WT) mice, because oxidative stress has been implicated as a pathogenic mechanism of AD (Butterfield and Halliwell (2019) Nature Reviews Neuroscience 20: 148-160). PS19 mice express the human P301S mutant tau with evident protein carbonyls in the cortical mitochondrial fraction from 10 months of age, but to-date, no in vivo imaging studies quantifying RONS in PS19 mice have been reported. [18F]FEDV–PET / MRI imaging showed markedly increased PET signal in 12-month-old male heterozygous PS19 mice, when compared to age-matched male WT mice (FIG.13A, n = 6 for each group). SUV analysis showed a marked increase of [18F]FEDV uptake in most brain regions, including the hippocampus, striatum, thalamus, hypothalamus, amygdala, midbrain, cerebellum, and brainstem (FIG.13B, n = 6; *p <0.05, **p <0.01, ***p <0.001). Whether [18F]FDG could detect regional differences in the PS19 mouse brain compared to age- matched control mice was also studied. SUV analysis of identical brain regions, as studied with [18F]FEDV, showed no statistically significant differences (FIG 14, n = 4 for each group) between the PS19 mouse brain and the age-matched control mouse brain.

[0465] oxHET labeling after [18F]FEDV–PET / MRI imaging to validate RONS PET signal ex vivo was also performed. This analysis showed a significant increase of oxHET+cellsin the hippocampus of PS19 mice compared to WT mice on postmortem fluorescence microscopy (FIG.13C; p <0.01, n = 4 per group). Similarly, PS19 mice showed a higher level of phosphorylated tau (AT8) staining in the hippocampus than did WT mice (FIG.13D; p <0.05, n = 4 per group). Without wishing to be bound by theory, together, these results suggest that [18F]FEDV imaging via the clinical standard static PET is sufficient to detect greater oxidative stress in the brains of 12-month-old PS19 tauopathy mice.

[0466] Refering to FIG.13A-D, [18F]FEDV-PET imaging detects increased RONS in the P301S (PS19) mouse brain. [18F]FEDV–PET / MRI was used to compare male P301S (PS19) mice and wild-type (WT) mice (both at 12 months of age, n = 6 for each group). Dynamic imaging of the mice was performed with [18F]FEDV–PET for 60 min and then immediately transferred and imaged by 9.4 T MRI for anatomical identification. FIG.13A shows that summed [18F]FEDV–PET / MRIs (45–60 min) reveal widespread enhanced uptake in PS19 mice, compared to that in age-matched WT mice. FIG.13B reveals that SUV analysis shows significantly higher [18F]FEDV–PET signal in nearly all regions of interest (ROIs) in PS19 mice (red) than in age-matched WT mice (gray). ROIs were generated using the Ma-Benveniste- Mirrione atlas on MRI, and PET signal in ROIs was quantified (n = 6 for each group; *p <0.05, **p <0.01, ***p <0.001, two-way ANOVA). FIG.13C shows representative microscopy images of oxHET fluorescence and quantification of oxHET+cells in the hippocampus of PS19 mice and age-matched WT mice (n = 4 for each group, **p <0.01, two-way ANOVA). FIG.13D shows representative immunohistochemical staining and quantification of phosphorylated tau (AT8) in the hippocampus of PS19 mice and WT mice (n = 4 for each group, *p <0.05, two-way ANOVA). Shown are mean ± SEM.

[0467] Referring to FIG.14, [18F]FDG-PET / CT imaging is unable to differentiate significant differences in the P301S (PS19) mouse brain. FIG.14A shows summed [18F]FEDV– PET / MRIs (45–60 min) SUVAVGanalysis shows slightly increased [18F]FDG–PET signal in all regions of interest (ROIs) in PS19 mice (red) than in age-matched WT mice (gray). ROIs were generated using the Ma-Benveniste-Mirrione atlas on MRI, and PET signal in ROIs was quantified (n = 4 for each group; ns, two-way ANOVA with Šídák’s multiple comparison). FIG. 14B shows summary of all p values calculated for [18F]FDG-PET comparison in PS19 vs WT mice. c. DISCUSSION

[0468] Oxidative stress and RONS have demonstrated a major pathophysiological role infunctional decline in a myriad of CNS diseases, including ALS, stoke, depression, schizophrenia, multiple sclerosis, Alzheimer disease, and Parkinson disease. The current gold standard for measuring RONS in the CNS involves ex vivo processing of harvested tissue, which poses major technical and practical challenges, particularly in the clinical setting. These challenges hamper clinical research of CNS-targeted antioxidant therapeutic strategies, such as evaluating the efficacy of novel and repurposed antioxidants, stratifying treatments based on response, identifying therapeutic windows, and quantifying target engagement of the antioxidant in the CNS. In this report, we showed that [18F]FEDV freely crosses the intact BBB and reacts with RONS in high chemical and spatial specificity in vivo. Thus, [18F]FEDV PET is a noninvasive approach to spatially and temporally quantify CNS-derived RONS, to study the pathologic contributions of RONS to disease, and to evaluate the efficacy of novel antioxidant strategies for treating diseases in preclinical and clinical studies.

[0469] Several practical considerations led us to develop the novel radiopharmaceutical [18F]FEDV to quantify RONS in the CNS via PET imaging. First, radiosynthesis is a straightforward nucleophilic aromatic substitution reaction followed by acid-catalyzed hydrogenation, deprotection, and condensation. This robust, high-yielding radiosynthesis affords [18F]FEDV in high radiochemical yield, purity, and molar activity. In addition, the incorporation of [18F]fluorine engenders an extended half-life without abrogating the radiopharmaceutical’s biological or chemical reactivity with RONS. One major concern about high-energy radiopharmaceuticals is solution stability resulting from radiolysis. Radiolysis is derived from the nuclear decay of high-energy particles reacting with solvent, such as water, to generate radicals (Neumann, K. D. et al. (2020) Curr Chem Biology 14, 289–303 ), which subsequently can degrade the radiopharmaceutical product. Radiolysis is typically countered by adding excipients, such as antioxidants, which would be incompatible for a RONS imaging agent. [18F]FEDV demonstrated a unique solution stability; it remained >99% intact in solution up to 8 h post-synthesis. Together, these features promote robust access to [18F]FEDV for translational imaging studies.

[0470] A unique feature of edaravone is its reaction specificity toward peroxyl radicals of both hydrophilic and lipophilic sources. Many antioxidants and radical scavengers (e.g., tirilazad, nicaraven, ebselen, disufenton sodium, vitamin E, coenzyme Q10, vitamin C) have been tested in a plethora of clinical trials to evaluate their efficacy in CNS disorders. The therapeutic strategies are generally limited to targeting hydrophilic- or liphophilic-derived RONS, which may or may not have the ability to traverse the plasma membrane or BBB and calls into question the efficacyof these antioxidants. Herein it has been shown that [18F]FEDV rapidly reacts with various sources of hydrophilic and lipophilic RONS and shows complete reactivity in as little as 5 min after RONS exposure. Importantly, [18F]FEDV reacted with RONS with variable biological half- life, including nitric oxide (t1 / 2 = 1-10 s)(Radi, R. (2018) Proc National Acad Sci 115, 5839– 5848) and lipid peroxyl radicals (t1 / 2= 20 min to >10 h) (Qian, S. Y., et al. (2000) Free Radical Bio Med 29, 568–579). It has also been shown that [18F]FEDV reacts with intracellularly derived RONS, and that the rate of plasma membrane diffusion, reaction, and retention occurs on a timescale compatible with PET-imaging protocols. Thus, [18F]FEDV demonstrated the chemical reactivity and biological compatibility to study a myriad of disorders founded in RONS pathophysiology.

[0471] A common pathophysiologic hallmark of neurodegenerative diseases is oxidative stress. The formation of oxidative stress leads to calcium dysregulation, which in turn, promotes neuronal toxicity and death (Barnham, K. J., et al. (2004) Nat Rev Drug Discov 3, 205–214 and Markesbery, W. R. (1999) Arch Neurol-chicago 56, 1449–1452). In addition, the brain is composed of an abundance of polyunsatured fatty acids that are especially prone to oxidation, has a high oxygen-consumption rate, and lacks sufficient endogenous antioxidant-defense mechanisms. Accordingly, antioxidants have been investigated to test their efficacy against neurodegenerative diseases in clinical studies (Sano, M. et al. (1997) New Engl J Medicine 336, 1216–22, Petersen, R. C. et al. (2005) New Engl J Med 352, 2379–2388, and Paganoni, S. et al. (2020) New Engl J Med 383, 919–930), albeit with mixed results. A key challenge for clinical trials implementing antioxidant therapy is the relative unknowns of antioxidant target engagement (Does the therapy cross the BBB?), effective treatment doses (Does the administered dose neutralize RONS?), and identifying relevant therapeutic windows in any given CNS disease. All these unknowns are exacerbated by the practical challenges of gleaning the microenvironment status of RONS in the CNS of a living system. In this study, it has been shown that [18F]FEDV facilitated the quantification of specific RONS signatures in the mouse brain.

[0472] Edaravone has been used to treat patients with acute ischemic stroke in Japan for over 20 years and was recently shown to improve NIHSS scores after an ischemic stroke (Kobayashi, S., et al. (2019) Stroke 50, 1805–1811). Although edaravone is approved for use within 24 h of stroke onset, it is most effective if administered within 3 h (Furuya, D. et al. (2006) Nosotchu 28, 291–296). Recent preclinical evidence has shown that, relative to the onset of stroke, early administration or even prophylactic use of edaravone confers the greatestphyiologic benefit and neuroprotection (Sun, Y.-Y. et al. (2015) Stroke 46, 1947–1955, and Sun, Y.-Y. et al. (2014) Plos One 9, e98807). The imaging results herein align with the suggested use of edaravone therapy for stroke and suggest [18F]FEDV is an ideal PET reporter for studying RONS-associated pathophysiology in the CNS.

[0473] Current RONS-sensing techniques in living systems are largely limited to in vitro studies. Advances toward in vivo RONS detection include electron spin trapping (Dikalov, S., Jiang, J. & Mason, R. P. (2005) Free Radical Res 39, 825–836), near-infrared optical (Karton- Lifshin, N. et al. (2011) J Am Chem Soc 133, 10960–10965), bioluminescence (Bittner, G. C. V. de, et al. (2010) Proc National Acad Sci 107, 21316–21321 ), [13C] MRI (Lippert, A. R., et al. (2011) J Am Chem Soc 133, 3776–3779 and Keshari, K. R. et al. (2011) Proc National Acad Sci 108, 18606–18611), chemiluminescent probes (Cowan, E. A. et al. (2013) Enzyme Microb Tech 53, 373–377), fluorescent probes (Dickinson, B. C. & Chang, C. J. A (2008) J Am Chem Soc 130, 11561–11561 and Albers, A. E., et al. (2008) Bioorg Med Chem Lett 18, 5948–5950), and PET (Carroll, V. et al. (2014) J Am Chem Soc 136, 14742–14745 and Pisaneschi, F., et al. (2022) Nat Biotechnol 40, 965–973). Among these techniques, PET possesses superior sensitivity, high spatial resolution, and is essentially nontoxic, as it requires very little contrast agent to acquire an image. PET also has the greatest potential for detecting RONS in a living system in a clinical setting. As a testament to the unmet need for an in vivo sensor for RONS, several PET radiopharmaceuticals have been investigated as possible imaging agents of oxidative stress, including [11C]DHA (Carroll, V. N. et al. (2016) Chem Commun 52, 4888– 4890), [18F]ROSTrace (Hsieh, C.-J. et al. (2022) Ejnmmi Res 12, 43 and Hou, C. et al. (2018) Acs Chem Neurosci 9, 578–586), DHQ1 (Okamura, T., et al. (2015) J Cereb Blood Flow Metabolism 35, 1930–1936 ), [11C]DHM (Wilson, A. A. et al. (2017) Nucl Med Biol 53, 14–20 ), and [18F]4FN (Pisaneschi, F., et al. (2022)Nat Biotechnol 40, 965–973). Unfortunately, these agents are limited by a combination of RONS reactivity, biological stability, and / or BBB permeability. For example, although [18F]ROSTrace demonstrates high brain uptake, it is limited to reactivity with the short-lived superoxide radical (t1 / 2= 1–4 μs). Recently, [18F]4FN was reported as a novel PET agent for imaging high-redox-potential RONS produced by the activated innate immune system. The RONS reactivity of [18F]4FN beyond hydrogen peroxide, particularly in the CNS, suggests this agent is limited in its translational potential. [18F]FEDV readily crossed the BBB and reacted to various RONS species. [18F]FEDV PET may inform a clinician when to use edaravone therapy. Therefore, [18F]FEDV may be the ideal PET-imaging agent for quantifying (and subsequently treating) oxidative stress, particularly in CNS diseases.Furthermore, although this study focused on quantifying CNS-derived RONS, [18F]FEDV could enable the study of RONS in other conditions, such as ischemia and reperfusion after myocardial infarction, reperfusion injury following organ transplant, monitoring / predicting drug resistance in cancer, or respiratory bursts of the innate immune system.

[0474] [18F]FEDV–PET imaging was tested in three in vivo models of acute and chronic neurodegeneration. First, [18F]FEDV demonstrated markedly increased PET signal in the ipsilateral hemisphere after intrastriatal injection of SNP, a popular model for chemical-induced CNS oxidative stress (Wilson, A.A. et al. (2017) Nucl Med Biol 53, 14-20). Meanwhile, neither [18F]FN or [18F]FDG were able to differentiate sites of oxidative stress from saline-injected or healthy contralateral brain tissue. As [18F]FDG measures glucose uptake in cells, high nonspecific signal is typical in mammalian brain and limits the biological specificity in which [18F]FDG can be applied for disease interpretation. Meanwhile, [18F]FN was recently reported (Pisaneschi, F., et al., (2022) Nat Biotechnol 40, 965-973) to react with endogenous RONS and showed sufficiently high brain:blood ratios; however, significant differences in SNP-associated PET signal were not observed (FIG.2B) or SUV (FIG.2D) or stroke-induced PET signal, SUV, or ex vivo brain tissue (FIG.2E). Without wishing to be bound by theory, these results suggest more limited application for [18F]FN, while [18F]FEDV-PET imaging has a broader application for detecting RONS in various brain injuries.

[0475] Next, SUVs of [18F]FEDV in T2 MRI–defined VOIs of injury were significantly elevated in the ipsilateral hemisphere at 24 h after unilateral MCA-targeted PT, which produced limited BBB destruction (Sun, Y.Y. et al. (2020) Blood Adv 4, 1222-1231). Without wishing to be bound by theory, these results suggest that the increased [18F]FEDV signal 24 h after PT was not solely due to extravasation of the radiopharmaceutical but indicated a rise in oxidative stress. This notion was supported by the concomitant increase of MDA, a lipid peroxidation marker. Hence, the acute stroke model was utilized to compare the sensitivity of [18F]FEDV–PET imaging based on SUV analysis versus dynamic parametric mapping (Quigg, M. & Kundu, B. (2022) Ann Clin Transl Neurol 9, 1487-1497, Li, Y. & Kundu, B.K. (2018) Phys Med Biol 63, 055003, Massey, J.C. et al. (2021) Front Med (Lausanne) 8, 618645). Similar to Statistical Parametric Mapping (Gallivanone, F., et al., (2016)Curr Alzheimer Res 13, 682-694), dynamic parametric mapping uses a VOI-based method to calculate the blood-to-tissue uptake (Ki) of a radiopharmaceutical and improves the sensitivity of [18F]FDG–PET in humans (Quigg, M. &Kundu, B. (2022) Ann Clin Transl Neurol 9, 1487-1497). Dynamic parametric mapping increased the sensitivity of [18F]FEDV–PET imaging to RONS at 4 h post-stroke, which was more sensitivethan the MDA assay but similar to oxHET labeling and ex vivo autoradiography in postmortem brains. Together, these results suggested that dynamic [18F]FEDV–PET with parametric mapping is a sensitive imaging biomarker of RONS in vivo.

[0476] Finally, [18F]FEDV–PET imaging was used to test the purported CNS oxidative stress in the PS19 mouse model of AD (Yoshiyama, Y. et al. (2007) Neuron 53, 337-351). A previous study reported increased protein carbonyls despite normal MDA levels in the brains of 10-month-old PS19 mice, compared to that of age-matched WT mice (Dumont, M. et al. (2011) FASEB J 25, 4063-4072). Here it was shown that at 12 months, postmortem brains of PS19 mice exhibited a widespread increase of [18F]FEDV signals correlated with greater oxHET and AT8 labeling, compared to that in age-matched WT brains. Region-focused SUV analysis revealed a significant increase of [18F]FEDV uptake in multiple subcortical areas and to a lesser degree in the cerebral cortex. [18F]FEDV is the first PET-imaging probe to detect a clear increase in CNS oxidative stress in PS19 mice based on SUV analysis. A recent study of [18F]ROStrace also detected CNS oxidative stress in the APP / PS1 mouse model of AD; however, those results require validation with ex vivo autoradiography and parametric mapping to elucidate the mechanistic basis of the increased [18F]ROStrace signals in those mutant mice (Hsieh, C.J. et al. (2022) EJNMMI Res 12, 43). Future studies are also warranted to compare the sensitivities of [18F]FEDV and [18F]ROStrace in the same mouse model of AD and to correlate the progression of [18F]FEDV–PET imaging with that of cognitive deficits across ages in PS19 mice.

[0477] [18F]FDG is reimbursable by the Centers of Medicare and Medicaid Services (CMS) for the differential diagnosis of fronto-temporal dementia (FTD) and AD and is the most routinely used PET radiopharmaceutical used in nuclear medicine. Therefore, whether [18F]FDG was able to differentiate changes in SUV in the PS19 mouse brain relative to the age-matched control was investigated. It was found that [18F]FDG was unable to demonstrate any SUV differences in any brain region tested, whereas, [18F]FEDV was able to quantify differences in most brain regions tested, but especially in brain regions of known AD susceptibility, like hippocampus. While the limited sample size may have reduced the ability of [18F]FDG to detect SUV changes in the PS19 mouse brain, [18F]FDG is limited by high nonspecific binding in the mouse brain and is merely a measure of glycolytic flux. On the other hand, [18F]FEDV PET signal is associated with areas of RONS and offers the potential to inform of potential therapeutic windows with antioxidants or other therapies that ultimately reduce oxidative stress2.

[0478] In conclusion, a novel PET agent, [18F]FEDV, was developed for imaging R...

Claims

CLAIMS What is claimed is:

1. A method of imaging reactive oxygen and nitrogen species (RONS) in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the radioactive isotope is selected from ‒18F, ‒76Br, ‒123I, and ‒124I.

3. The method of claim 1 or claim 2, wherein R1is a halogen.

4. The method of claim 3, wherein R1is ‒F.

5. The method of claim 3, wherein R1is ‒18F.

6. The method of claim 3, wherein R1is ‒Br.

7. The method of claim 3, wherein R1is ‒76Br.

8. The method of claim 3, wherein R1is ‒I.

9. The method of claim 3, wherein R1is ‒123I or ‒124I.

10. The method of claim 1 or claim 2, wherein R1is ‒O(C1-C4 haloalkyl).

11. The method of claim 10, wherein R1is ‒O(C1-C4 fluoroalkyl).

12. The method of claim 10, wherein R1is ‒O(C2 haloalkyl).

13. The method of claim 10, wherein R1is ‒OCH2CH2F.

14. The method of claim 10, wherein R1is ‒OCH2CH218F.

15. The method of any one of claims 1 to 14, wherein R2is hydrogen.

16. The method of any one of claims 1 to 14, wherein R2is C1-C4 alkyl.

17. The method of claim 16, wherein R2is methyl.

18. The method of any one of claims 1 to 17, wherein Ar1is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

19. The method of claim 18, wherein Ar1is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

20. The method of claim 18, wherein Ar1is phenyl substituted with 0 additional groups.

21. The method of any one of claims 1 to 17, wherein Ar1is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

22. The method of claim 21, wherein Ar1is C2-C10 heteroaryl substituted with 0 additional groups.

23. The method of claim 21, wherein Ar1is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

24. The method of claim 21, wherein Ar1is pyridinyl substituted with 0 additional groups.

25. The method of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

26. The method of claim 1, wherein the compound has a structure represented by a formula: ,wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope.

28. The method of claim 26 or claim 27, wherein four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

29. The method of claim 26, wherein the compound has a structure represented by a formula:, wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

30. The method of claim 1, wherein the compound has a structure represented by a formula: ,wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope.

32. The method of claim 30 or claim 31, wherein three of R10b, R10c, R10d, and R10eare hydrogen.

33. The method of claim 30, wherein the compound has a structure represented by a formula:, wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

34. The method of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

35. The method of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

36. The method of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

37. The method of claim 1, wherein the compound is not: ,or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 1 to 37, wherein imaging is positron emission tomography (PET) imaging.

39. The method of claim 38, wherein imaging is positron emission tomography / magnetic resonance imaging (PET / MRI) imaging or positron emission tomography / computerized tomography (PET / CT) imaging.

40. The method of any one of claims 1 to 37, wherein imaging is single-photon emission computerized tomography (SPECT) imaging.

41. The method of claim 40, wherein imaging is single-photon emission computerized tomography / computerized tomography (SPECT / CT) imaging.

42. The method of any one of claims 1 to 41, wherein RONS are central nervous system- derived (CNS-derived) RONS.

43. The method of any one of claims 1 to 41, wherein RONS are peripheral nervous system- derived (PNS-derived) RONS.

44. The method of any one of claims 1 to 41, wherein RONS comprise one or more of superoxide, hydrogen peroxide, hydroxyl radicals, singlet oxygen, peroxyl radicals, hypochlorous acid, and peroxynitrite.

45. The method of any one of claims 1 to 44, wherein the subject is a mammal.

46. The method of claim 45, wherein the mammal is a human.

47. The method of any one of claims 1 to 46, wherein administering is oral administration, intranasal administration, intramuscular administration, or intravenous administration.

48. The method of any one of claims 1 to 46, wherein administering is intravenous administration.

49. The method of any one of claims 1 to 48, wherein the subject has been diagnosed with a need for imaging RONS prior to the administering step.

50. The method of any one of claims 1 to 49, further comprising identifying a subject in need of RONS imaging.

51. The method of any one of claims 1 to 50, wherein imaging serves to evaluate efficacy of a treatment.

52. The method of claim 51, wherein the treatment is Focused Ultrasound (FUS).

53. A method of imaging reactive oxygen and nitrogen species (RONS) in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the cell is a prokaryotic cell.

55. The method of claim 53, wherein the cell is mammalian.

56. The method of claim 55, wherein the cell is human.

57. The method of claim 53, wherein the cell has been isolated from a mammal prior to the contacting step.

58. The method of any one of claims 53 to 57, wherein contacting is in vitro.

59. The method of any one of claims 53 to 57, wherein contacting is ex vivo.

60. The method of any one of claims 53 to 56, wherein contacting is via administration to a mammal.

61. The method of claim 60, wherein the mammal has been diagnosed with a need for RONS imaging prior to the administering step.

62. A kit comprising a compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a mixing agent; and (b) instructions for imaging a radiotracer.

63. The kit of claim 62, wherein the mixing agent is selected from saline, ethanol, and dimethylsulfoxide (DMSO).

64. A method of treating a disease or disorder due to oxidative stress in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein R2is hydrogen.

66. The method of claim 64, wherein R2is C1-C4 alkyl.

67. The method of claim 64, wherein R2is methyl.

68. The method of any one of claims 64 to 67, wherein R3is a halogen.

69. The method of claim 68, wherein R3is selected from ‒F, ‒Br, and ‒I.

70. The method of any one of claims 64 to 67, wherein R3is ‒O(C1-C4 haloalkyl).

71. The method of claim 70, wherein R3is ‒O(C1-C4 fluoroalkyl).

72. The method of claim 70, wherein R3is ‒O(C2 haloalkyl).

73. The method of claim 70, wherein R3is ‒OCH2CH2F.

74. The method of any one of claims 64 to 73, wherein Ar2is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

75. The method of claim 74, wherein Ar2is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

76. The method of claim 74, wherein Ar2is phenyl substituted with 0 additional groups.

77. The method of any one of claims 64 to 73, wherein Ar2is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

78. The method of claim 77, wherein Ar2is C2-C10 heteroaryl substituted with 0 additional groups.

79. The method of claim 77, wherein Ar2is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

80. The method of claim 77, wherein Ar2is pyridinyl substituted with 0 additional groups.

81. The method of claim 64, wherein the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

82. The method of claim 64, wherein the compound has a structure represented by a formula: ,wherein one of R11a, R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein four of R11a, R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, R11d, and R11eis hydrogen, or a pharmaceutically acceptable salt thereof.

83. The method of claim 82, wherein one of R11a, R11b, R11c, R11d, and R11eis halogen.

84. The method of claim 82, wherein four of R11a, R11b, R11c, R11d, and R11eare hydrogen.

85. The method of claim 82, wherein the compound has a structure represented by a formula:, wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

86. The method of claim 64, wherein the compound has a structure represented by a formula: ,wherein one of R11b, R11c, R11d, and R11eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein three of R11b, R11c, R11d, and R11eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

87. The method of claim 86, wherein one of R11b, R11c, R11d, and R11eis halogen.

88. The method of claim 86, wherein three of R11b, R11c, R11d, and R11eare hydrogen.

89. The method of claim 86, wherein the compound has a structure represented by a formula:, wherein R11cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), or a pharmaceutically acceptable salt thereof.

90. The method of claim 64, wherein the compound is selected from: ,or a pharmaceutically acceptable salt thereof.

91. The method of claim 64, wherein the compound is selected from: Oor a pharmaceutically acceptable salt thereof.

92. The method of any one of claims 64 to 91, wherein the subject is a mammal.

93. The method of claim 92, wherein the mammal is a human.

94. The method of any one of claims 64 to 93, wherein the effective amount is a therapeutically effective amount.

95. The method of any one of claims 64 to 93, wherein the effective amount is a prophylactically effective amount.

96. The method of any one of claims 64 to 95, wherein the disease or disorder is a neurological disease.

97. The method of claim 96, wherein the neurological disease is selected from Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis (ALS / Lou Gehrig’s disease), multiple sclerosis, cortical cavernous malformation (CCM), and ischemic stroke.

98. The method of any one of claims 64 to 95, wherein the disease or disorder is cancer, a cardiovascular disease, or ischemia reperfusion injury (IRI).

99. The method of any one of claims 64 to 98, wherein the subject has been diagnosed with the disease or disorder prior to the administering step.

100. The method of any one of claims 64 to 99, further comprising the step of identifying a subject in need of treatment of the disease or disorder.

101. The method of any one of claims 64 to 99, further comprising administering to the subject an agent known for treating a neurological disease.

102. The method of any one of claims 64 to 101, wherein the agent is an anticonvulsant.

103. The method of claim 102, wherein the anticonvulsant is selected from levetiracetam, topiramate, lamotrigine, oxcarbazepine, and divalproex sodium.

104. A kit comprising a compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R3is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar2is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically salt thereof, and one or more selected from: (a) an agent associated with the treatment of a disease or disorder due to oxidative stress; (b) instructions for administering the compound in connection with treating a disease or disorder due to oxidative stress; and (c) instructions for treating a disease or disorder due to oxidative stress.

105. A compound having a structure represented by a formula: ,wherein R1is selected from a halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), provided that R1is labeled with a radioactive isotope; wherein R2is selected from hydrogen and C1-C4 alkyl; and wherein Ar1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,provided that when R1is ‒F, then Ar1is not phenyl, or a pharmaceutically acceptable salt thereof.

106. The compound of claim 105, wherein the radioactive isotope is selected from ‒18F, ‒76Br, ‒123I, and ‒124I.

107. The compound of claim 105, wherein R1is a halogen.

108. The compound of claim 107, wherein R1is ‒F.

109. The compound of claim 107, wherein R1is ‒18F.

110. The compound of claim 107, wherein R1is ‒Br.

111. The compound of claim 107, wherein R1is ‒76Br.

112. The compound of claim 107, wherein R1is ‒I.

113. The compound of claim 107, wherein R1is ‒123I or ‒124I.

114. The compound of claim 105, wherein R1is ‒O(C1-C4 haloalkyl).

115. The compound of claim 114, wherein R1is ‒O(C1-C4 fluoroalkyl).

116. The compound of claim 114, wherein R1is ‒O(C2 haloalkyl).

117. The compound of claim 114, wherein R1is ‒OCH2CH2F.

118. The compound of claim 114, wherein R1is ‒OCH2CH218F.

119. The compound of any one of claims 106 to 118, wherein R2is hydrogen.

120. The compound of any one of claims 106 to 118, wherein R2is C1-C4 alkyl.

121. The compound of claim 120, wherein R2is methyl.

122. The compound of any one of claims 106 to 121, wherein Ar1is C6-C14 aryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

123. The compound of claim 122, wherein Ar1is phenyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

124. The compound of claim 122, wherein Ar1is phenyl substituted with 0 additional groups.

125. The compound of any one of claims 106 to 124, wherein Ar1is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

126. The compound of claim 125, wherein Ar1is C2-C10 heteroaryl substituted with 0 additional groups.

127. The compound of claim 125, wherein Ar1is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

128. The compound of claim 125, wherein Ar1is pyridinyl substituted with 0 additional groups.

129. The compound of claim 105, wherein the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

130. The compound of claim 105, wherein the compound has a structure represented by a formula:, wherein one of R10a, R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein four of R10a, R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R10a, R10b, R10c, R10d, and R10dis hydrogen, or a pharmaceutically acceptable salt thereof.

131. The compound of claim 130, wherein one of R10a, R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope.

132. The compound of claim 130, wherein four of R10a, R10b, R10c, R10d, and R10eare hydrogen.

133. The compound of claim 130, wherein the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

134. The compound of claim 105, wherein the compound has a structure represented by a formula:, wherein one of R10b, R10c, R10d, and R10eis selected from halogen, ‒O(C1-C4 haloalkyl), ‒ S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope; and wherein three of R10b, R10c, R10d, and R10eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

135. The compound of claim 134, wherein one of R10b, R10c, R10d, and R10eis halogen labeled with a radioactive isotope.

136. The compound of claim 134, wherein three of R10b, R10c, R10d, and R10eare hydrogen.

137. The compound of claim 134, wherein the compound has a structure represented by a formula: ,wherein R10cis selected from halogen, ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1- C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl), and is labeled with a radioactive isotope, or a pharmaceutically acceptable salt thereof.

138. The compound of claim 105, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

139. The compound of claim 105, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

140. A compound having a structure represented by a formula: ,wherein R2is selected from hydrogen and C1-C4 alkyl; wherein R4is selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein Ar3is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

141. The compound of claim 140, wherein R2is hydrogen.

142. The compound of claim 140, wherein R2is C1-C4 alkyl.

143. The compound of claim 142, wherein R2is methyl.

144. The compound of claim 140, wherein R4is ‒O(C1-C4 haloalkyl).

145. The compound of claim 144, wherein R4is ‒O(C1-C4 fluoroalkyl).

146. The compound of claim 144, wherein R4is ‒O(C2 haloalkyl).

147. The compound of claim 144, wherein R4is ‒OCH2CH2F.

148. The compound of any one of claims 140 to 147, wherein Ar3is C2-C10 heteroaryl substituted with 0 additional groups.

149. The compound of any one of claims 140 to 147, wherein Ar3is pyridinyl substituted with 0, 1, 2, or 3 additional groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

150. The compound of any one of claims 140 to 147, wherein Ar3is pyridinyl substituted with 0 additional groups.

151. The compound of claim 140, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

152. The compound of claim 140, wherein the compound has a structure represented by a formula:, wherein one of R12b, R12c, R12d, and R12eis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl); and wherein three of R12b, R12c, R12d, and R12eare independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

153. The compound of claim 152, wherein three of R12b, R12c, R12d, and R12eare hydrogen.

154. The compound of claim 152, wherein the compound has a structure represented by a formula: ,wherein R12cis selected from ‒O(C1-C4 haloalkyl), ‒S(C1-C4 haloalkyl), ‒NH(C1-C4 haloalkyl), and ‒N(C1-C4 alkyl)(C1-C4 haloalkyl),or a pharmaceutically acceptable salt thereof.

155. The compound of claim 140, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

156. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 140 to 155, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

157. A compound selected from:or a pharmaceutically acceptable salt thereof.

158. A pharmaceutical composition comprising an effective amount of the compound of claim 157, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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