Aldehyde binding optical imaging probes methods of use thereof

Abstract

The present disclosure provides compounds having the formula F-L-N(R')H that are useful in imaging tissue remodeling and / or in diagnosing diseases such as myocardial infarction.

Description

[0001]Attorney Docket No.29539-0775WO1 ALDEHYDE BINDING OPTICAL IMAGING PROBES METHODS OF USE THEREOF STATEMENT OF FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. HL155237, awarded by National Institutes of Health. The government has certain rights in the invention. RELATED APPLICATION This application claims priority to U.S. Provisional Application No.63 / 515,380, filed July 25, 2023, the entire content of which is incorporated herein by reference. FIELD The present disclosure relates to compounds useful in imaging tissue remodeling or in diagnosing a disease such as myocardial infarction. BACKGROUND Fibrosis is a result of aberrant wound-healing that leads to pathological scarring. During fibrosis, extracellular matrix (ECM) components accumulate within the tissue, undergo cross-linking to stabilize the ECM, thereby disrupting organ function and eventually leading to organ failure. Fibrosis can affect all major organs and contributes to the pathology of chronic liver diseases like cirrhosis, hepatitis, non-alcoholic steatohepatitis (NASH), chronic kidney diseases, heart diseases like myocardial infarction, heart failure, atrial fibrillation, lung diseases such as idiopathic pulmonary fibrosis (IPF), cancers such as pancreatic ductal adenocarcinoma, and other diseases such as scleroderma and atherosclerosis. With approximately one in four individuals affected, fibrotic diseases account for a staggering 35% to 45% of global deaths. The economic burden of fibrotic disease is equally daunting, and annual costs are in the tens of billions of dollars in the United States alone. A hallmark of all fibrotic disease regardless of organ or disease etiology is the accumulation of collagen-rich scar within the affected tissue. The mechanisms for deposition and stabilization of this collagen-rich ECM is conserved across all vertebrates. The collagen molecules are initially deposited extracellularly as individual triple helix proteins. Once collagen is extracellular, it is oxidized by the enzymes in the Lysyl Oxidase family (LOXs). LOXs convert collagen lysine residues to allysine Attorney Docket No.29539-0775WO1 aldehydes (LysAld). Allysine aldehydes are central for collagen cross-linking and stabilization, and formation of allysine is the only enzymatic step in the collagen cross- linking cascade. Once allysine residues are formed, the aldehyde spontaneously react with other collagen LysAld or with amino groups on collagen lysine residues. This LOX-mediated oxidation also occurs in other ECM proteins like elastin. Oxidation of elastin’s lysine residues also initiated the cross-linking of elastin. This cross-linking is what provides is structure and stability to the extracellular matrix. The accumulation of allysine is a hallmark of active tissue remodelling and fibrosis (fibrogenesis), as well as active collagen deposition / active collagen cross- linking. There are currently no methods that can assess, quantify or visualize fibrogenesis in tissue and with cellular resolution. SUMMARY Some embodiments provide a compound of Formula (I): F-L-N(R’)H (I) or a pharmaceutically acceptable salt thereof, wherein: F is a fluorescent reporter moiety; L is a linker moiety; and R’ is absent, hydrogen, or a substituted acyl group. Some embodiments provide a method of imaging a tissue comprising (a) contacting the tissue with a compound disclosed herein; (b) irradiating the tissue at a wavelength absorbed by the compound; (c) and detecting a signal from the compound, thereby imaging the tissue. Some embodiments provide a method of assessing tissue remodeling, comprising (a) administering to a subject suspected of having tissue damage an imaging effective amount of a compound disclosed herein; (b) irradiating a tissue of the subject at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates the presence of tissue remodeling (e.g., due to tissue damage). Some embodiments provide a method of treating myocardial infarction, comprising (a) administering to a subject suspected of having tissue damage an imaging effective amount of a compound disclosed herein; (b) irradiating a tissue at a wavelength absorbed by the compound; (c) determining the presence or absence of a Attorney Docket No.29539-0775WO1 signal from the compound; and (d) if a signal is detected, administering to the subject a therapeutically effective amount of one more anti-platelet agents, one or more angiotensin-converting enzyme inhibitors, on or more beta-blocker agents, one or more angiotensin receptor blocker agents, one or more statin agents, or a combination thereof. Some embodiments provide a method of assessing protein oxidation and / or cross-linking of collagen in a subject in need thereof, comprising (a) contacting a sample from the subject with an imaging effective amount of a compound disclosed herein; (b) irradiating the sample at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates protein oxidation and / or cross-linking. In some embodiments, the sample is a histology section. In some embodiments, the sample is a biopsy sample. Some embodiments provide a kit comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein; and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG.1 shows the reactivity of a library of aldehyde-binding fluorescent probes. (a) Chemical structure of the synthesized TAMRA-based probes. (b) Aldehyde-ligation reaction types and corresponding reaction rate constants relative to the commercially available TMR-HZD. The rate constant of the oxyamine probe (TMR-O) is 27-fold higher than TMR-HZD. (c-h) Reaction rates of the probes with butyraldehyde were followed by HPLC with fluorescence detection. HPLC traces for the forward (c, e, g) Attorney Docket No.29539-0775WO1 and reverse (d, f, h) reactions for TMR-HZD, TMR-HZN and TMR-O with butyraldehyde showing the ligation product (orange) and the free, unbound probe (blue). Of note, the HPLC traces for the commercially available TMR-HZD (c, d) also contain a small unidentified impurity (black). (i) Plots of the observed rate constant for the formation of the aldehyde-ligation products, (j) the corresponding percent conversion as a function of time and, (k) the percent product generated at 100 minutes. The non-binding control probe (TMR-NB), in which a cyclic piperazine group replaces the reactive hydrazine, shows no reactivity, confirming the specificity of the oxyamine (TMR-O), hydrazine (TMR-HZN) and pyrrole (TMR-Pyr) based TAMRA probes for aldehydes. TMR-O, however, has the fastest reactivity and highest percent conversion to ligation product. Values are plotted as the average of three experiments ± standard deviation. FIG.2 shows the chemical structures of butyraldehyde and Allysine aldehyde. a) the structural similarity of the two moieties allows Butyraldehyde to be used as a model aldehyde to characterize the kinetics of aldehyde-binding probes in vitro. The binding of these aldehydes to TMR-O is shown in b and c. FIG. 3 shows HPLC traces of TMR-Rho reactions. a) HPLC traces of the reaction of TMR-Rho with butyraldehyde detected by fluorescence (excitation 545 nm, emission 566 nm) showing multiple reaction products. b) HPLC traces of the reaction of TMR-Rho with ethanolamine detected by fluorescence (excitation 545 nm, emission 566 nm) showing a single reaction product. Reaction conditions(0.4 mL pH 7.40 PBS, 10 μM and 110 μM butyraldehyde or ethanolamine. c) HPLC traces of TMR- O / butyraldehyde adduct after 24 hours. HPLC trace of TMR-O-butyraldehyde oxime after 24 hours showing little to no hydrolysis observed. Fluorescence detection with excitation at 545 nm, and emission 566 nm. FIG. 4 shows the superior selective binding of TMR-O to protein and tissue aldehydes. (a) Binding of the probes to aldehyde-rich protein (BSA-Ald) was determined by incubating the probes (10 mM) with BSA-Ald (25 mM protein, 100 mM aldehyde) with and without aldehyde-blocking with methoxylamine. After incubation at 37 °C for 3 h, free and protein-bound probe were separated by passing solutions through a 10 kD molecular weight cut-off (MWCO) filter. (b) UV-Vis spectra of a solution of TMR-O incubated with BSA-Ald before (blue) and after (red) MWCO filtration show a significant decrease in the TMR-O signal due to binding to BSA-Ald. (c) Blocking of the aldehyde-reactive sites on BSA-Ald obstructs TMR-O binding, Attorney Docket No.29539-0775WO1 resulting in little change in the UV-Vis absorption of TMR-O after filtration. (d, e) Quantification of the percent binding of aldehyde-reactive TAMRA-based probes to BSA-Ald without (d) and with (e) methoxamine pre-blocking demonstrates their specificity for aldehydes. (f) Lysine aldehydes (LysAld) are abundant in healthy mammalian aorta and zebrafish bulbus due to elastin turn-over and cross-linking (top). These tissues, therefore, provide a robust control to characterize the accuracy of TAMRA-based aldehyde-reactive probes for lysine aldehydes such as allysine and hydroxy-allysine. (g, h) White light and fluorescence reflectance images of whole mouse (g) and zebrafish (h) hearts excised after systemic injection of TMR-O or TMR- NB. TMR-O binds specifically to the aorta and bulbus, while the non-binding control probe TMR-NB produces no signal. Imaging was performed in 3 mice / fish per group with consistent results. (i) Quantification of fluorescence signal intensity in the zebrafish bulbus 4 h after IP injection of an allysine-binding probe (2 nmol / g) shows >2-fold higher signal for TMR-O compared to other probes and no uptake of TMR-NB. Signal is normalized to the fluorescence signal of a phantom made from the injected dose of each probe. Data are means ± SD of three independent experiments. FIG. 5 shows the collagen oxidation and cross-linking in the injured zebrafish heart. a) In the early stages of healing, a similar process occurs in injured zebrafish and murine hearts: Lysyl-oxidase- (LOX)-mediated oxidation of collagen in the wound converts lysine / hydroxylysine residues to highly reactive aldehydes (allysine / hydroxyallysine, LysAld), which form cross-links. TMR-O binds to LysAld, providing a readout of the initial steps in collagen cross-linking. (b) Natural history of collagen oxidation and cross-linking in a zebrafish cryoinjury model. Adult zebrafish, with cardiomyocyte-specific expression of GFP, were injected with TMR-O (2 nmol / g, IP) and the hearts were excised and imaged 4 hours after injection. The absence of GFP delineates the area of injury, which shows a steady increase in TMR-O signal from 10- 21 days post injury (dpi). (c) AFOG-stained histology sections show the collagen / elastin rich bulbus and collagen-rich healing injury at 10-35 dpi. (d) Fluorescence microscopy of adjacent sections shows that the TMR-O signal is localized to the collagen-rich areas of the injured heart. (e) The total area of injured myocardium, quantified by histology, decreased steadily between 10-35 dpi, consistent with the regenerative capacity of the zebrafish heart. (f) However, within the area of injury, TMR-O fluorescence intensity peaked between 21-35 dpi. (g) Likewise, collagen content within the area of injury peaked 21-35 dpi. (h) The hearts of injured zebrafish Attorney Docket No.29539-0775WO1 injected with the non-binding probe TMR-NB (2 nmol / g, IP) at 15 dpi showed no fluorescence signal in the heart or bulbus. Data are means ± SD of five-six measurements, where each data point represents one zebrafish. P values are shown where significant, one-way ANOVA with post hoc comparisons, two tailed. Scale bar = 300 mm. FIG.6 shows collagen oxidation and cross-linking in the infarcted mouse heart. (a) The hearts of adult mice injected with TMR-O (2 nmol / g, IV) at 5-35 days after myocardial infarction (MI) are shown in their long axis. TMR-O fluorescence in the infarct is, qualitatively, already high at day 10. (b) Sectioning of the heart into 1mm thick short axis slices confirms that the TMR-O signal is arising from 334 the infarcted myocardium and is patchy but substantial by day 10. (c) Time course of TMR-O fluorescence in murine infarcts. The oxidation and cross linking of collagen is already significant by day 10, peaks at day 21 and subsequently decreases. Data are means ± SD of 5-6 measurements where each data point represents one mouse. P values are shown where significant, one-way ANOVA with post hoc comparisons, two tailed. (d, e) AFOG stained histology sections at the mid-ventricular level show that the collagen- rich injury area (blue) colocalizes well with the TMR-O signal on fluorescence microscopy. Healthy myocardium is stained with a green, fluorescent nuclear stain (NucSpot). Scale bars = 1 mm. FIG.7 shows the dynamic deposition and oxidation of new collagen in chronic infarcts. (a, b) Whole-heart and short axis section of a mouse heart 45 dpi. Some areas of the remodeled scar are structurally static with little TMR-O uptake (arrows). However, other areas of the scar show substantial amounts of TMR-O uptake, consistent with the oxidation of newly deposited collagen. (c, d) Similarly, at day 62 some areas of the scar show high amounts of probe uptake, consistent with dynamic collagen deposition. (e-g) K376 means clustering (4 clusters) of the infarct zone in the whole-heart TMR-O images. (e) TMR-O clusters in a day 62 infarct zone, demarcated by the dashed lines in panel C. The cluster of highest TMR-O signal (4thcluster, brown) occupies a substantial portion of the infarct. (f, g) The centroid value and area of the 4thcluster did not change significantly over time, consistent with active / new collagen deposition in the infarcts at all stages of healing. (h, i) AFOG staining, and fluorescence microscopy confirmed the heterogeneity of TMR-O uptake in the day 45 and 62 murine infarcts. (j, k) In injured zebrafish hearts (n=5) most of the myocardium had been regenerated by 45 dpi and the size of the residual injury was small. However, within Attorney Docket No.29539-0775WO1 these small residual areas of injury substantial levels of TMR-O uptake were still seen. (l, m) Within 2 months of injury no evidence of myocardial injury or TMR-O uptake was seen in the zebrafish hearts (n=5), consistent with complete resorption of the scars and successful regeneration of the myocardium. Scale bars in g-j are 300 μm. FIG. 8 shows lysine aldehyde cross-links maturing into degradation-resistant final products in infarcted mouse hearts but not in zebrafish hearts. (a) Enzymatic oxidation of telopeptide [hydroxy]lysine residues of collagen by Lysyl oxidase (LOX) to form [hydroxy]allysine aldehydes is a prerequisite of collagen cross linking and fibril formation. (b) Subsequent self-assembly of collagen molecules is spontaneous and is stabilized by intramolecular reactions of [hydroxy]allysine groups with one another or with helical [hydroxy]lysine residues. (c) Initial allysine cross-links further rearrange and react with additional [hydroxy]allysine or [hydroxy]lysine groups to form stable pyridinium-containing cross-links. (d) Chemical structures of pyridinoline (Pyd) and deoxypyridinoline (DPD), the mature degradation-resistant products of collagen cross- linking. (e) HPLC traces of a solution of DPD (100 nM, top, black) and Pyd (100 nM, bottom, red) juxtaposed with traces of solutions of hydrolyzed mouse or zebrafish hearts excised 21 days after injury. All zebrafish and mouse heart hydrosylates were prepared to contain similar amounts of hydroxyproline (30-80 μg / mL). (f) Quantification of Pyd in infarcted mouse and zebrafish hearts 21 days post injury (dpi) shows no detectable Pyd levels in zebrafish hearts despite substantial hydroxyproline content in the analyzed tissue. Similarly, DPD could not be detected in the HPLC traces of the zebrafish hearts. (g) In infarcted mouse hearts, Pyd levels increase with infarct age consistent with scar maturation. 36 (h) Levels of DPD in infarcted mouse hearts peak earlier after infarction and are lower than Pyd (note the scale difference between panels g and h). Data are means ± SD of 3-5 independent measurements where each data point represents one animal. FIG. 9 shows that the hydroxylation of lysine in newly deposited collagen differs markedly in infarcted murine and zebrafish hearts. HPLC traces of the amino acids in infarcted zebrafish (a, b) and mouse (c, d) hearts at 1 and 3 weeks after injury. The expanded regions in the insets are for the hydroxyproline (Hyp) and hydroxylysine (OHK) peaks, at 9.3 min and 26.7 min respectively, and the Aspartic acid (Asp) peak at 11.3 min to which the chromatogram is normalized. Aspartic acid (Asp) was quantified and used to normalize Hyp and OHK values to account for total tissue content in each sample. The Asp peak is denoted with a red asterisks (*) in the full HPLC Attorney Docket No.29539-0775WO1 chromatograms. Quantification of Hyp:Asp and OHK:ASP in mouse (e, n = 5 for W1, n = 4 for W3) and zebrafish (f, n = 4) hearts at 1 and 3 weeks after injury. Hyp:Asp increases significantly in both zebrafish and mice, while OHK:Asp increases significantly in mice but not zebrafish. g Comparison of the percent change of Hyp and OHK from week 1 to week 3 after injury in mice and zebrafish hearts. Despite a marked increased in Hyp from weeks 1–3, indicative of new collagen deposition, little change in OHK is seen in the zebrafish hearts. Statistical comparison by unpaired t-test, n = 4– 5 per sample values are plotted as the average ± the standard deviation. FIG. 10 shows that TMR-O fluorescence can sensitively quantify cardiac remodeling in a mouse model of heart failure with preserved ejection fraction. FIG. 11 shows that TMR-O fluorescence can sensitively quantify kidney remodeling in a mouse model of renal injury with ischemia-reperfusion. FIG. 12 shows the differential accumulation of a library of TAMRA-based probes in the zebrafish bulbus. Images of zebrafish hearts injected with 2 nmol / g of the indicated probes are shown (n=3 each). Probe accumulation in the bulbus recapitulates the level of probe reactivity with model aldehydes in vitro. FIG. 13 shows the Preparation of zebrafish and mouse tissue hydrosylates for collagen crosslink (CCL) analysis via HPLC. Created in part with Biorender.com. The large difference in size between the zebrafish and murine hearts required the hydrosylates to be reconstituted to contain similar amounts of collagen (hydroxyproline) for CCL analysis: The zebrafish hearts were dissected to separate the ventricle from the atrium and the bulbus. In the infarcted mouse heart, a 1mm-thick short axis slice through the apical portion of the infarct was removed. The zebrafish ventricle and the apical infarct slice in the mice were separately hydrolyzed in 200 μL of 6M HCl. These hydrosylates were then assessed for hydroxyproline (Hyp) content. Depending on the Hyp concentration, a portion of the digest containing approximately 2 nanomoles of Hyp was removed and evaporated to dryness. Each dried sample was then reconstituted in PBS to achieve a hydroxyproline concentration of approximately 40 micromolar. The samples, now containing similar amounts of collagen, were then assessed for collagen crosslink (CCL) concentration by HPLC. FIG. 14 shows Labeling of amine groups of amino acids with 9- Fluorenylmethyl Chloroformate (FMOC-Cl). FMOC labeling results in a fluorescent tag on each free alpha amine as well as on any side-chain amines. This results in a double-label on hydroxylysine and a single label on hydroxyproline. Attorney Docket No.29539-0775WO1 FIG. 15 shows the concentration of the amino acid Aspartic acid (Asp, D) across tissue samples. This concentration did not differ significantly across all tissue samples, providing a suitable internal control of tissue content in each sample. Values are in micromole amino acid per milligram of tissue. Statistical analysis: ANOVA with Tukey’s post hoc analysis n=3-5 per column. Fig. 16 shows additional fluorescent reporter moieties contemplated in this disclosure. DETAILED DESCRIPTION A high-precision molecular imaging probe was developed to characterize the oxidation and cross-linking of collagen. Compounds of Formula (I) In some embodiments, the present disclosure provides a compound of Formula (I): F-L-N(R’)H (I) or a pharmaceutically acceptable salt thereof, wherein: F is a fluorescent reporter moiety; L is a linker moiety; and R’ is absent, hydrogen, or a substituted acyl group. In some embodiments, R’ is absent. In some embodiments, R’ is hydrogen. In some embodiments, R’ is a substituted acyl group. In some embodiments, L is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, a bond, -O-, -N(RA)-, -N(RA)RB-, -N(RA)RBO-, - N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, -N(RA)RBC(=O)RC-, - RB- , C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl. Attorney Docket No.29539-0775WO1 In some embodiments, each RCis hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6- 10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is not -NH-. In some embodiments, L is selected from C1-10 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -O-, -N(RA)-, -N(RA)RB-, -N(RA)RBO-, - N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, -N(RA)RBC(=O)RC-, - N(RA)RBC(=O)O-, -ORAC(=O)-, -ORAC(=O)O-, and -OC(=O)N(RA)RB-; and each RAand RBis independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is 3-10 membered heterocyclyl. In some embodiments, L is 5 or 6 membered heterocyclyl. In some . In some -N(RA)-,A B A B N(R )R -, -N(R )R O-, - N(RA)RBN(RC)-, and -N(RA)RBNC(=O)RC-; each RAand RBis independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis is selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10alkyl, C2-10alkenyl, C2-10 Attorney Docket No.29539-0775WO1 alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6- 10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is -N(RA)RB-; and RA, and RBare independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl. In some embodiments, L is -N(RA)RB-; and RAand RBare joined to form a 3- 10 membered heterocyclyl. In some embodiments, R’ is absent and LN(R’)H is In some embodiments, L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10alkyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some L is . In some (RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is -N(RA)RBN(RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, L is . In some RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 Attorney Docket No.29539-0775WO1 membered heteroaryl; and RCis selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1- 3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis selected from C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1- 3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis C1-10 alkyl optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some . In some 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6- 10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, L is -N(RA)-; and RAis C1-10alkyl, C1-10heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, L is -N(RA)-; and RAis C1-10 alkyl. In some embodiments, L is -N(RA)-; and RAis C2alkyl. Attorney Docket No.29539-0775WO1 In some embodiments, R’ is −C(=O)RXand RXis selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 C2-10 alkenyl, C2-10 alkynyl, 6-10 membered aryl, and 5-10 membered heteroaryl are with 1-3 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, RXis selected from C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, RXis C1-10 alkyl optionally substituted with 1 or 2 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. In some embodiments, RXis C1-10 alkyl substituted with 5 or 6 membered heteroaryl. In some embodiments, RXis C1-10 alkyl substituted with 5 membered heteroaryl. In some embodiments, RXis C1-10 alkyl substituted with 6 membered heteroaryl. In some . In some . In some In some Attorney Docket No.29539-0775WO1 In some embodiments, F is selected from the fluorescent reporter moiety in Figure 16. In some embodiments, the compound is selected from: o Attorney Docket No.29539-0775WO1 In some embodiments, R’ is absent. In some embodiments, the compound is: . R’ is a substituted acyl group. In some embodiments, the compound is: . In some embodiments, the compound is selected from: Attorney Docket No.29539-0775WO1 HO O OH group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, Attorney Docket No.29539-0775WO1 fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)- alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. Compositions and Methods of Use The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure (e.g., Formula (I)) disclosed herein and a pharmaceutically acceptable carrier. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the Attorney Docket No.29539-0775WO1 formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. In some embodiments, the composition comprises a mixture of compounds of Formula (I), or a pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure provides a method of imaging a tissue comprising contacting the tissue with a compound of Formula (I); irradiating the tissue at a wavelength absorbed by the compound; and detecting a signal from the compound, thereby imaging the tissue. In some embodiments, the tissue comprises collagen. In some embodiments, the collagen is cross-linked. In some embodiments, the contacting comprises the compound forming a covalent bond with the collagen. In some embodiments, the compound is administered to an organism comprising the tissue. In some embodiments, the organism is human. In some embodiments, the compound of Formula (I)has a peak absorbance at about 450 nm to 650 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 475 nm to 625 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. In some embodiments, the tissue is imaged ex vivo. In some embodiments, the tissue is imaged in vivo. In some embodiments, the disclosure provides a method of assessing tissue remodeling, comprising (a) administering to a subject suspected of having myocardial infarction an imaging effective amount of a compound of Formula (I); (b) irradiating a tissue at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates a diagnosis of tissue damage. In some embodiments, the disclosure provides a method of assessing tissue remodeling in the heart of a subject suspected of having a myocardial infarction, the method comprising (a) administering to a subject suspected of having a myocardial infarction an imaging effective amount of a compound of Formula (I); (b) irradiating a tissue (e.g., heart tissue) at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates a diagnosis of myocardial infarction. Attorney Docket No.29539-0775WO1 Some embodiments provide a method of determining the location of tissue damage in a subject in need thereof, the method comprising (a) administering to a subject suspected of having tissue damage an imaging effective amount of a compound of Formula (I); (b) irradiating the subject at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates tissue damage. In some embodiments, the subject has a heart condition. In some embodiments, the tissue comprises collagen. In some embodiments, the tissue damage is caused by heart disease. In some embodiments, the heart disease is a heart condition or myocardial infarction. Some embodiments provide a method of determining levels of protein oxidation in a sample from a subject, the method comprising (a) contacting the sample with an imaging effective amount of a compound disclosed herein; (b) irradiating the sample at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates the level of protein oxidation in the sample. Some embodiments provide a method of determining levels of collagen cross- linking in a sample from a subject, the method comprising (a) contacting the sample with an imaging effective amount of a compound disclosed herein; (b) irradiating the sample at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates the level of protein oxidation in the sample. In some embodiments, the tissue damage is caused a gastrointestinal (GI) disease. in some embodiments, the gastrointestinal (GI) diseases are selected from eosinophilic esophagitis, interstitial bowel diseases such as Chron’s disease and ulcerative Colitis, as well as diseases of the upper GI such as eosinophilic esophagitis. In some embodiments, the compounds of Formula (I) can be used to differentiate neoplastic and fibrotic polyps in GI polyposis syndromes, and guide resection of tissue. In some embodiments, the tissue damage is caused by cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the compounds of Formula (I) can be used to delineate tumor margins. Attorney Docket No.29539-0775WO1 In some embodiments, the tissue is the skin. In some embodiments, the compounds of Formula (I) can be used to enable facile assessment of deposition of newly synthesized collagen and elastin in the skin. In some embodiments, the tissue is the cornea. In some embodiments, the compounds of Formula (I) can be used to enable facile assessment of deposition of newly synthesized collagen and elastin in the skin. In some embodiments, the tissue is the heart. In some embodiments, the tissue is the gastrointestinal tract. In some embodiments, the tissue is the skin. In some embodiments, the tissue is the cornea.In some embodiments, the collagen is cross-linked. In some embodiments, the contacting comprises the compound forming a covalent bond with the collagen. In some embodiments, the compound of Formula (I) has a peak absorbance at about 450 nm to 650 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 475 nm to 625 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. In some embodiments, the disclosure provides a method of treating myocardial infarction, comprising: (a) administering to a subject suspected of having myocardial infarction an imaging effective amount of a compound of Formula (I); (b) irradiating a tissue at a wavelength absorbed by the compound; (c) determining the presence or absence of a signal from the compound; and (d) if a signal is detected, administering to the subject a therapeutically effective amount of one more anti- platelet agents, one or more angiotensin-converting enzyme inhibitors, on or more beta-blocker agents, one or more angiotensin receptor blocker agents, one or more statin agents, or a combination thereof. In some embodiments, the subject is human. In some embodiments, the tissue comprises collagen. In some embodiments, the collagen is cross-linked. In some embodiments, the contacting comprises the compound forming a covalent bond with the collagen. In some embodiments, the compound of Formula (I) has a peak absorbance at about 450 nm to 650 nm. In some embodiments, the compound of Formula (I) has a Attorney Docket No.29539-0775WO1 peak absorbance at about 475 nm to 625 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. In some embodiments, the signal may be in the form of absorption, such as occurs during photoacoustic imaging. In some embodiments, the imaging agents can have a signal-to-background ratio (SBR) suitable to permit fluorescence detection. SBR is a measure of the intensity of the fluorescent signal obtained from a target (peak signal) over the measure of the intensity of the fluorescent signal obtained nearby the target (background signal), the target being the tissues, cells, space targeted by the imaging agent. SBR measurements can be readily obtained through routine measurement procedures. For fluorescent imaging systems, and other optical- type systems, digital images recording optical signals of the target facilitate SBR measurement. Higher SBR values are more desirable, resulting in greater resolution of the imaged tissues. In some embodiments, the imaging agents achieve an SBR of at least about 1.1 (i.e., peak signal is at least 10% over background). In further embodiments, the imaging agents achieve an SBR of at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0. In yet further embodiments, the imaging agents achieve an SBR of about 1.1 to about 50, about 1.5 to about 30, about 2.0 to about 20, about 2.0 to about 5.0, or about 5.0 to about 10. In some embodiments, the disclosure provides a method of tissue imaging comprising (a) administering to a subject suspected of having a fibrotic organ or a fibrotic disease an imaging effective amount of a compound of Formula (I); (b) irradiating a tissue at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates a diagnosis of the fibrotic organ or the fibrotic disease. In some embodiments, the subject is human. In some embodiments, the subject is an animal. In some embodiments, the tissue is imaged ex vivo. In some embodiments, the tissue is imaged in vivo. In some embodiments, the compound of Formula (I) has a peak absorbance at about 600 nm to 850 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 660 nm to 850 nm. In some embodiments, the compound of Formula (I) has a peak absorbance at about 760 nm to 800 nm. Attorney Docket No.29539-0775WO1 Definitions As used herein, the term “about” means “approximately” (e.g., plus or minus 10% of the indicated value). The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine. The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, and tert-butyl. The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon- carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent. The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon group. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl). The term “heterocyclyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more constituent heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. The heteroatom or ring carbon can be the point of attachment of the heterocyclyl substituent to another moiety. Any atom can be optionally substituted, e.g., by one or more substituents. Heterocyclyl groups can include groups such as tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. By way of example, a phrase such as “heterocyclic ring containing from 5-6 ring atoms”, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C1-C6alkyl), NC(O)(C1-C6alkyl), O, Attorney Docket No.29539-0775WO1 and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected Rawould include (but not be limited to) tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (> 3 fused rings) hydrocarbon ring system. One or more ring atoms can be optionally substituted by one or more substituents for example. Aryl moieties include groups such as phenyl and naphthyl. The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (> 3 fused rings) hydrocarbon groups having one or more heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. One or more ring atoms can be optionally substituted, e.g., by one or more substituents. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, coumarinyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1, −C(=O)−O−C(=O)RX1, −C(=O)SRX1, −C(=O)N(RX1)2, −C(=S)RX1, C1-10 alkyl; C2-10alkenyl; C2-10alkynyl; 6-10 membered aryl, 5 to 10 membered heteroaryl, C1-10 alkyloxy, C1-10 heteroalkyloxy, 6-10 membered aryloxy, 5-10 membered heteroaryloxy, C1-10alkylthioxy, C1-10heteroalkylthioxy, 6-10 membered arylthioxy, and 5-10 membered heteroarylthioxy. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety Attorney Docket No.29539-0775WO1 (e.g., alkyl, alkenyl, alkynyl, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like). The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated or synthesized as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound of Formula (I) has the (R)-configuration. In some embodiments, the compound of Formula (I) has the (S)-configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. Attorney Docket No.29539-0775WO1 As used herein, the term “subject” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “imaging effective amount” refers to the necessary amount of active compound or pharmaceutical agent that allows for imaging of a tissue in an animal, individual, or human to be detected by the detection method chosen. For example, a detectable quantity can be an administered amount sufficient to enable detection of binding of the labeled compound to a target of interest including, but not limited to cartilage. As used herein, the term “conjugate” refers to the non-covalent association of a compound of Formula I with a tissue such as cartilage and thereby produces a signal that can be captured as a means for imaging the tissue. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring. Attorney Docket No.29539-0775WO1 NUMBERED EMBODIMENTS Embodiment 1. A compound of Formula I: F-L-N(R’)H I or a pharmaceutically acceptable salt thereof, wherein: F is a fluorescent reporter moiety; L is a linker moiety; and R’ is absent, hydrogen, or a substituted acyl group. Embodiment 2. The compound of embodiment 1, wherein L is selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, a bond, -O-, -N(RA)-, - N(RA)RB-, -N(RA)RBO-, -N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, - N(RA)RBC(=O)RC-, -N(RA)RBC(=O)O-, -ORAC(=O)-, -ORAC(=O)O-, - OC(=O)N(RA)RB-, -S(O)2N(RA)RB-, and -N(RA)RBS(O)2-; and each RAand RBis independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and wherein L is not -NH-. Embodiment 3. The compound of embodiment 1 or 2, wherein L is selected from C1-10 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -O-, -N(RA)- , -N(RA)RB-, -N(RA)RBO-, -N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, - N(RA)RBC(=O)RC-, -N(RA)RBC(=O)O-, -ORAC(=O)-, -ORAC(=O)O-, and - OC(=O)N(RA)RB-; and each RAand RBis independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; each RCis hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered Attorney Docket No.29539-0775WO1 heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein L is not -NH-. Embodiment 4. The compound of any one of embodiments 1-3, wherein L is 3-10 membered heterocyclyl. Embodiment 5. The compound of any one of embodiments 1-4, wherein L is 5 or 6 membered heterocyclyl. Embodiment 6. The compound of any one of embodiments 1-5, wherein L is 7. The compound of any one of embodiments 1-3, wherein L is selected from -N(RA)-, N(RA)RB-, -N(RA)RBO-, -N(RA)RBN(RC)-, and - N(RA)RBNC(=O)RC-; each RAand RBis independently selected from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis is selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein L is not -NH-. Embodiment 8. The compound of any one of embodiments 1-3 or 7, wherein L is -N(RA)RB-; and RA, and RBare independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl. Embodiment 9. The compound of any one of embodiments 1-3, 7 or 8, wherein L is -N(RA)RB-; and RAand RBare joined to form a 3-10 membered heterocyclyl. Attorney Docket No.29539-0775WO1 Embodiment 10. The compound of any one of embodiments 1-3 or 7-9, wherein R’ is absent Embodiment any one of embodiments 1-3, wherein L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 12. The compound of any one of embodiments 1-3 or 11, wherein L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 13. The compound of any one of embodiments 1-3, 12, or 13, wherein L . The compound of any one of embodiments 1-3, wherein L is -N(RA)RBN(RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 15. The compound of any one of embodiments 1-3 or 14, wherein L is -N(RA)RBN(RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 16. The compound of any one of embodiments 1-3, 14, or 15, wherein L is . The compound of any one of embodiments 1-3, wherein L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered Attorney Docket No.29539-0775WO1 aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl. Embodiment 18. The compound of any one of embodiments 1-3 or 17, wherein L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis selected from C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein L is not -NH-. Embodiment 19. The compound of any one of embodiments 1-3, 17, or 18, wherein L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis C1-10alkyl optionally with 1-3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 20. The compound of any one of embodiments 1-3 or 17-19, wherein . of any one of embodiments 1-3, wherein L is -N(RA)-; and RAis C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. Embodiment 22. The compound of any one of embodiments 1-3 or 21, wherein L is -N(RA)-; and RAis C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. Embodiment 23. The compound of any one of embodiments 1-3, 21, or 22, wherein L is -N(RA)-; and RAis C1-10 alkyl. Attorney Docket No.29539-0775WO1 Embodiment 24. The compound of any one of embodiments 1-3, or 21-23, wherein L is -N(RA)-; and RAis C2alkyl. Embodiment 25. The compound of any one of embodiments 1-3 or 21-24, wherein R’ is −C(=O)RXand RXis selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen, C1- C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 26. The compound of any one of embodiments 1-3 or 21-25, wherein RXis selected from C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 27. The compound of any one of embodiments 1-3, or 21-26, wherein RXis C1-10 alkyl optionally substituted with 1 or 2 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl. Embodiment 28. The compound of any one of embodiments 1-3 or 21-27, wherein RXis C1-10alkyl substituted with 5 or 6 membered heteroaryl. Embodiment 29. The compound of any one of embodiments 1-3 or 21-28, wherein RXis C1-10alkyl substituted with 5 or 6 membered heteroaryl. Embodiment 30. The compound of embodiment 1-3 or 21-29, wherein R’31. The compound of any one of embodiments 1-3, or 21-30, wherein . of any one of embodiments 1-31, wherein F is of or Attorney Docket No.29539-0775WO1 Embodiment 33. The compound of embodiment 1, wherein the compound is Attorney Docket No.29539-0775WO1 o Embodiment 34. A pharmaceutical composition comprising a compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Embodiment 35. A method of imaging a tissue comprising: (a) contacting the tissue with a compound of any one of embodiments 1-33; (b) irradiating the tissue at a wavelength absorbed by the compound; (c) and detecting a signal from the compound, thereby imaging the tissue. Embodiment 36. The method of embodiment 35, wherein the tissue comprises collagen. Embodiment 37. The method of embodiment 36, wherein the collagen is cross-linked. Embodiment 38. The method of any one of embodiments 35-37, wherein the contacting comprises the compound forming a covalent bond with the collagen. Embodiment 39. The method of any one of embodiments 35-38, wherein the compound is administered to an organism comprising the tissue. Embodiment 40 The method of embodiment 39, wherein the organism is human. Embodiment 41. The method of any one of embodiments 35-40, wherein the compound of Formula (I) has a peak absorbance at about 450 nm to 650 nm. Embodiment 42. The method of any one of embodiments 35-41, wherein the compound of Formula (I) has a peak absorbance at about 475 nm to 625 nm. Embodiment 43. The method of any one of embodiments 35-42, wherein the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. Embodiment 44. The method of any one of embodiments 35-43, wherein the tissue is imaged ex vivo. Embodiment 45. The method of any one of embodiments 35-43, wherein the tissue is imaged in vivo. Attorney Docket No.29539-0775WO1 Embodiment 46. A method of assessing tissue remodeling, comprising (a) administering to a subject suspected of having tissue damage an imaging effective amount of a compound of any one of embodiments 1-33; (b) irradiating a tissue at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates a diagnosis of tissue damage. Embodiment 47. The method of embodiment 46, wherein the tissue is selected from the heart, the gastrointestinal tract, the cornea, the skin. Embodiment 48. The method of embodiment 46, wherein the tissue damage is caused by a heart disease, a gastrointestinal disease, or cancer. Embodiment 49. The method of any one of embodiments 46-48, wherein the tissue comprises collagen. Embodiment 50. The method of embodiment 49, wherein the collagen is cross-linked. Embodiment 51. The method of any one of embodiments 46-50, wherein the contacting comprises the compound forming a covalent bond with the collagen. Embodiment 52. The method of any one of embodiments 46-51, wherein the compound of Formula (I) has a peak absorbance at about 450 nm to 650 nm. Embodiment 53. The method of any one of embodiments 46-52, wherein the compound of Formula (I) has a peak absorbance at about 475 nm to 625 nm. Embodiment 54. The method of any one of embodiments 46-53, wherein the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. Embodiment 55. A method of assessing protein oxidation and / or cross- linking of collagen, comprising: (a) administering to a subject suspected of having myocardial infarction an imaging effective amount of a compound of any one of embodiments 1-33; (b) irradiating a tissue at a wavelength absorbed by the compound; (c) determining the presence or absence of a signal from the compound wherein the presence of a signal indicates a diagnosis of disease activity. Embodiment 56. The method of embodiment 55, wherein the subject is human. Embodiment 57. The method of embodiment 55 or 56, wherein the tissue comprises collagen. Embodiment 58. The method of embodiment 57, wherein the collagen is cross-linked. Attorney Docket No.29539-0775WO1 Embodiment 59. The method of embodiment 57, wherein the contacting comprises the compound forming a covalent bond with the collagen. Embodiment 60. The method of any one of embodiments 55-59, wherein the compound of Formula (I) has a peak absorbance at about 450 nm to 650 nm. Embodiment 61. The method of any one of embodiments 55-60, wherein the compound of Formula (I) has a peak absorbance at about 475 nm to 625 nm. Embodiment 62. The method of any one of embodiments 55-61, wherein the compound of Formula (I) has a peak absorbance at about 525 nm to 600 nm. Embodiment 63. A method of assessing protein oxidation and / or cross- linking of collagen, comprising (a) administering to a histology section an imaging effective amount of the compound of any of embodiments 1-33, or a pharmaceutically acceptable salt thereof; (b) irradiating a tissue at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates a diagnosis of disease activity. Embodiment 64. A kit comprising the compound of any of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34; and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject. Embodiment 65. Any and all compositions, articles of manufacture, methods, and uses disclosed and / or described in the above specification. Embodiment 66. The compounds designated in the accompanying documents filed herewith as TMR-O, TMR-HZN, TMR-Pyr, TMR-Rho, and TMR- LHZ. Embodiment 67. Use of any one of the compounds of embodiment 63 to assess collagen cross-linking formation in a mammalian subject. Embodiment 68. The use of embodiment 67 in which the mammalian subject has had a myocardial infarction. Embodiment 69. The use of embodiment 68 in which the mammalian subject is a human. Embodiment 70. Use of any one of the compounds of embodiment 65 in imaging zebrafish heart. EXAMPLES Materials and Instruments Attorney Docket No.29539-0775WO1 NMR spectra were recorded on a JEOL ECZ 500R 11.7 T NMR system equipped with a 5 mm broadband probe (1H: 499.81 MHz, 13C: 125.68 MHz). 1H NMR spectral shifts are reported as singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). High resolution mass spectra were acquired on a high-resolution time- of-fight mass spectrometer (AccuTOFDART, JEOL). UV-Vis spectra were recorded on a SpectraMax M2 spectrophotometer using cuvettes with a 1 cm path length. MilliQ purified water was used for all reactions and experiments where water is the solvent.6- carboxytetramethyl rhodamine was purchased from Fisher and used without purification. TAMRA hydrazide, 6 isomer was purchased from Lumiprobe and used without further purifications. Tert-Butyl 3-aminopropoxycarbamate was purchased from AmBeed and used without further purification. All other chemical supplies and reagents were purchased from common commercial suppliers and used without purifications unless otherwise noted. HPLC-MS: LC-MS analysis was carried out on an Agilent 1260 system (UV detection at 220, 254 and 550 nm) coupled to an Agilent Technologies 6130 Quadrupole MS system. Mobile Phases: A: 0.1% formic acid in H2O (v / v) B: 0.1% formic acid in CH3CN (v / v) C: 10 mm NH4OAc in H2O, D: 90% CH3CN + 10% solvent C. UV detection at 220, 254 and 280 and 550 nm. Preparative reversed-phase HPLC with UV detection at 220, 254 and 280 nm was performed using Agilent 1260 system. Mobile Phases: A: 0.1% formic acid in H2O (v / v) B: 0.1% formic acid in CH3CN (v / v) C: 0.1% trifluoroacetic acid in H2O (v / v) D: 0.1% trifluoroacetic acid in CH3CN (v / v). UV detection at 220, 254 and 280 nm Example 1 Compound 1. To a solution of 6-carboxy tetramethylrhodamine (6-TAMRA, 22 mg, 51 mmol) and HATU 102 (19 mg, 51 mmol) in DMF (1 mL) was added tert-Butyl 3-aminopropoxycarbamate (9.7 mg, 51 mmol) in DMF (0.1 mL). The mixture was stirred for 45 min, then purified by Prep-HPLC. Compound 1 was isolated as a red solid after freeze-drying. Mass= 25 mg, 81%. LC-MS: tR= 3.10 min. m / z =603.2 [M+]; Attorney Docket No.29539-0775WO1 calculated for [C33H39N4O7]+ 603.28. Purity: >99% (LC-MS, 106550 nm).1H NMR (500 MHz, Methanol-d4) δ 8.39 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 8.3, 1.8 Hz, 1H), 7.88 = 2.5 J = HCl 2.55 (LC- , 8.20 , 7.04 (t, J = 7.0 Hz, 3H), 3.30 (s, 12H), 1.98 (t, J = 7.0 Hz, 2H). 13C NMR (126 MHz, Methanol- D4) δ 167.63, 166.82, 159.21, 157.77, 157.67, 140.40, 138.91, 137.83, 134.30, 133.63, 131.55, 130.69, 129.11, 128.64, 127.38, 127.34, 126.00, 114.24, 113.53, 96.15, 72.70, 39.61, 36.32, 27.68. Example 2 Compound 2-1. To a solution of 6-carboxy tetramethylrhodamine (6-TAMRA, 22 mg, 51 mmol) and HATU (19 mg, 51 mmol) in DMF (1 mL) was added Tert-Butyl piperazin-1-ylcarbamate (11.3 mg, 51 mmol) in DMF (0.1 mL). The mixture was stirred for 45 min, then purified by Prep-HPLC, Method 6 using A and B as eluents. Compound 2-1 was isolated as a red solid after freeze-drying. Mass= 20 mg, 81%. LC- MS (Method 1): tR= 2.99 min, m / z =614.30 [M+]; Calculated for [C34H40N5O6]+ 614.30. Purity: >99% (LC-MS, 550 nm).1H NMR (500 MHz, D2O : CD3CN 10:1 ) δ 8.05 (dq, J = 4.1, 1.7 Hz, 2H), 7.84 (dd, J = 8.5, 1.9 Hz, 1H), 7.09 (dd, J = 9.4, 2.1 Hz, 2H), 6.71 (dd, J = 9.5, 2.5 Hz, 2H), 6.45 (d, J = 2.6 Hz, 2H), 3.00 (d, J = 2.2 Hz, 12H), Attorney Docket No.29539-0775WO1 2.74 (t, J = 5.0 Hz, 4H), 2.62 (s, 4H), 1.33 (s, 9H).13C NMR (126 MHz, D2O : CD3CN 10:1) δ 172.76, 172.38, 164.80, 162.72, 158.38, 155.91, 155.88, 155.56, 141.09, 137.14, 136.75, 129.80, 117.66, 114.52, 112.84, 112.03, 95.30, 43.06, 39.15, 26.83, 26.66. TMR-HZN. Compound 2-1 ( 27 mg, 44 mmol) was suspended in aqueous 1M J = 9.4, . 13C Compound 3-1. To a solution of 2-{(tert-butoxy)carbonyl]amino}-3-(1H- pyrrol-1-yl)propanoic acid (100 mg, 0.39 mmol), and N-Fmoc-ethylenediamine hydrochloride (126 mg, 0.39 mmol) in anhydrous DMF (1 mL) was added HATU (151 mg, 0.39 mmol) and diisopropyl ethylamine (DIPEA, 180 mL, 1.0 mmol). The mixture was stirred for one hour, with monitoring by LC-MS. After 3 hours, product was precipitates by addition of water, and then purified by combiflash using Method 5. Product was isolated as white solid after freeze-drying. Mass = 80 mg, 40% yield. LC- MS (Method 1): tR= 4.13 min, m / z = 519.2 [M+H]+ ; Calculated for [C29H35N4O5]+ Attorney Docket No.29539-0775WO1 519.26.1H NMR (500 MHz, Chloroform-d) δ 7.79 (dd, J = 7.6, 3.6 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.38 – 7.28 (m, 2H), 6.60 (t, J = 2.1 Hz, 2H), 6.04 – 5.97 (m, 2H), 5.75 (s, 1H), 5.16 – 5.07 (m, 1H), 4.85 (t, J = 6.2 Hz, 1H), 4.46 (ddd, J = 48.0, 10.6, 6.3 Hz, 2H), 4.37 – 4.15 (m, 3H), 4.00 – 3.91 (m, 1H), 3.37 – 3.11 (m, 2H), 3.11 – 2.90 (m, 2H), 1.44 (s, 9H). 13C NMR (126 MHz, Chloroform-D) δ 170.02, 170.02, 156.76, 155.19, 151.73, 143.94, 127.83, 127.20, 125.19, 121.25, 120.07, 109.20, 66.31, 51.76, 51.51, 51.01, 47.50, 44.77, 40.97, 39.99, 28.38. DMF room : tR= by , 6.05 – δ (16 58 mmol) in DMF (0.1 mL). The mixture was stirred for 2 hrs, then purified by Prep- HPLC, Method 6 using A and B as eluents. Compound 3-3 was isolated as a red solid after freeze-drying. Mass= 23 mg, 83%. LC-MS (Method 1): tR= 4.3 min, m / z =709.3 [M+]; Calculated for [C39H45N6O7]+ 709.33. >95.5% purity (LC-MS, 550 nm). 1H NMR (500 MHz, Acetonitrile-D3) δ 8.28 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.86 (s, 2H), 7.29 (s, 1H), 7.04 (dd, J = 9.5, 3.5 Hz, 2H), 6.81 (ddd, J = 9.5, 3.5, 2.1 Hz, 2H), 6.78 – 6.68 (m, 2H), 6.40 (s, 2H), 5.92 (t, J = 2.1 Hz, 2H), 5.82 (d, J = 8.0 Hz, 1H), 4.11 – 4.00 (m, 2H), 3.78 (dd, J = 15.0, 9.7 Hz, 1H), 3.48 (s, 1H), 3.18 (s, 14H), 2.97 (td, J = 6.6, 3.8 Hz, 2H), 1.72 – 1.67 (m, 2H), 1.22 (s, 9H).13C NMR (126 MHz, Methanol-D4) δ 171.61, 168.65, 166.51, 199166.01, 159.30, 157.65, 140.31, 137.89, 134.25, 133.39, 131.53, 130.66, 128.80, 128.13, 120.72, 114.24, 113.50, 107.89, 96.12, 79.68, 56.22, 48.19, 48.02, 47.85, 47.68, 47.51, 47.34, 47.16, 39.61, 38.48, 27.20, 26.13, 24.01. TMR-Pyr. Compound 3-3 was suspended in aqueous 1M HCl and stirred overnight protected from light. The solvent was then freeze-dried, resulting in Attorney Docket No.29539-0775WO1 compound 21 as a red solid. Mass= 20 mg, quantitative. LC-MS (Method 1): tR= 2.58 min, m / z =609.2 [M+]; Calculated for [C34H37N6O5]+ 709.33609.28. >99.5% purity (LC-MS, 550 nm). 1H NMR (500 MHz, Acetonitrile-D3) δ 8.28 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.86 (s, 2H), 7.29 (s, 1H), 7.04 (dd, J = 9.5, 3.5 Hz, 2H), 6.81 (ddd, J = 9.5, 3.5, 2.1 Hz, 2H), 6.78 – 6.68 (m, 2H), 6.40 (s, 2H), 5.92 (t, J = 2.1 Hz, 2H), 5.82 (d, J = 8.0 Hz, 1H), 4.09 – 4.00 (m, 2H), 3.78 (dd, J = 15.0, 9.7 Hz, 1H), 3.46 (d, J = 22.2 Hz, 2H), 3.21 (s, 2H), 3.16 (d, J = 18.9 Hz, 13H), 2.97 (td, J = 6.6, 3.8 Hz, 2H), 2.06 – 2.03 (m, 1H), 1.72 – 1.67 (m, 2H).13C NMR (126 MHz, Acetonitrile-D3) δ 186.88, 171.37, 167.19, 166.68, 166.20, 160.54, 158.15, 138.99, 134.10, 132.28, 131.83, 131.76, 129.83, 121.90, 118.26, 115.00, 114.16, 108.77, 97.13, 50.21, 46.89, 41.20, 28.32, 26.95, 1.74, 1.58, 1.41, 1.25, 1.08, 0.92, 0.75. Example 4 Compound 4-1. To a soluti39ypertensdanine-3-carboxylic acid (1g, 5.2 mmol) in dichloromethane (20 mL) was added DCC (1.6 g, 7.8 mmol), and N-hydroxy succinimide (800 mg, 7 mmol) and stirred for 5 minutes, resulting 39ypertrgange solution. To this orange solution was added mono-Fmoc ethylene diamine hydrochloride (1.9 g, 6.2 mmole) in DMF (10 mL), and the combined solution was stirred for an additional 10 hours. The resulting dark orange solution was purified by Combiflash using Method 5. The product was isolated as an orange oil, mass= 0.8 g, 47% yield.1H NMR (500 MHz, Acetonitrile-d3) δ 6.94 (s, 1H), 5.45 (s, 1H), 4.51 (s, 2H), 4.13 (s, 2H), 3.21 (q, J = 6.0 Hz, 2H), 3.09 (t, J = 6.1 Hz, 2H), 1.40 (s, 9H). 13C NMR (126 MHz, Acetonitrile-d3) δ 203.39, 174.11, 165.56, 156.43, 117.47, 78.65, 46.33, 39.83, 39.57, 36.04, 27.71 Attorney Docket No.29539-0775WO1 Compound 4-2. Compound 4-1 (0.8 g, 2.4 mmol) was placed in 1M HCl in dioxane and stirred overnight. Solvent was removed by freeze-drying, yielding compound 4-2 as an orange powder which was used without further purification. Mass product 0.56 g, quantitative yield. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (t, J = 5.7 Hz, 1H), 8.05 (s, 2H), 4.51 (s, 2H), 4.34 (s, 2H), 3.31 (q, J = 6.3 Hz, 2H), 2.83 (h, J = 6.1 Hz, 2H).13C NMR (126 MHz, DMSO-D6) δ 203.68, 174.52, 165.87, 46.55, 38.74, 37.04, 36.71. mg, DMF 5 (500 (d, J J = (dd, J 185.39, 179.93, 168.63, 167.26, 167.19, 159.15, 158.94, 155.91, 152.76, 151.72, 135.12, 132.38, 130.07, 130.07, 115.46, 115.02, 97.41, 78.00, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 40.92, 40.39, 40.39. Example 5 Compound 5-1. To a solution of N-(4-Bromobutoxy)phthalimide (5 g, 18.7 mmol) in dichloromethane (50 mL) was added a solution of t-butylcarbazate (4.9 g, 37.3 mmol) in 10 mL dichloromethane containing DIPEA (3.9 mL, 22.4 mmol). The Attorney Docket No.29539-0775WO1 resulting clear solution was stirred overnight then purified by Combiflash using silica column and Method 4. The resulting product was isolated as a clear oil that solidified on standing. Mass product = 4 g, 67% yield.1H NMR (500 MHz, Chloroform-d) δ 7.80 (dtd, J = 7.9, 4.8, 2.3 Hz, 2H), 7.68 (pd, J = 6.6, 5.7, 3.3 Hz, 2H), 6.24 (s, 1H), 3.75 (q, J = 6.7 Hz, 2H), 2.87 (q, J = 6.7 Hz, 2H), 1.81 (dp, J = 6.5 Hz, 2H), 1.41 (s, Hz, 9H). 13C NMR (126 MHz, Chloroform-d) δ 168.53, 156.92, 133.99, 132.22, 123.29, 80.55, 49.20, 35.87, 28.41, 26.82. Compound 5-2. To a solution of compound 5-1 (1.9 g, 0.62 mmol) in acetonitrile (50 mL) was added hydrazine hydrate (1 mL, 2 mmol) and the solution was brought to reflux and heated overnight. The resulting mixture was filtered through celite plug, and the clear solution was evaporated to dryness via rotary evaporation. The resulting clear oil was dried under high vacuum overnight and used without further purification. Mass, 1.1 g, quantitative yield.1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.28 (s, 1H), 7.68 (s, 2H), 2.83 (s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 1.57 (p, J = 9.2, 8.2 Hz, 2H), 1.36 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 156.91, 80.47, 56.21, 50.06, 39.96, 31.30, 28.41. added 1 hr 5- 3 (d, J = J = 9.5 3.47 (t, J .13C 134.22, 133.64, 131.50, 130.73, 128.99, 128.78, 114.23, 113.54, 96.14, 81.39, 39.61, 37.50, 27.14, 25.28. TMR-LHZ. Compound 5-3 (13 mg, 22 mmol) was suspended in aqueous 1M HCl and stirred overnight protected from light. The solvent was then freeze-dried, resulting in TMR-LHZ as a red solid. Mass= 21 mg, quantitative yield. LC-MS (Method 1): tR= 3.3 min, m / z =502.2 [M+]; calcd: 502.24. Purity = >99.9% (LCMS, 550 nm). 1H NMR (500 MHz, Methanol-D4) δ 8.48 – 8.32 (m, 1H), 8.29 – 8.14 (m, 1H), 7.84 Attorney Docket No.29539-0775WO1 (dd, J = 5.2, 2.7 Hz, 1H), 7.19 – 7.09 (m, 2H), 7.05 (tt, J = 7.0, 2.9 Hz, 2H), 6.97 (dt, J = 5.1, 2.6 Hz, 2H), 3.49 (t, J = 7.3 Hz, 2H), 3.29 (d, J = 3.2 Hz, 12H), 3.08 (q, J = 6.4 Hz, 2H), 1.94 (q, J = 7.1 Hz, 2H). 13C NMR (126 MHz, Methanol-D4) δ 167.06, 165.94, 159.20, 157.77, 157.66, 137.68, 134.29, 133.65, 131.56, 130.72, 129.02, 128.76, 114.27, 113.55, 96.15, 39.63, 36.78, 25.38. Example 6 TMR-NB. To a solution of TAMRA (10 mg, 23 mmol) and HATU (9.3 mg, 23 mmol) in DMF (0.5 mL) was added piperazine (2.2 mg, 25 mmol) in DMF (0.1 mL). The mixture was stirred for 2 hrs, then purified by Prep-HPLC, Method 14 using A and B as eluents. Compound 23 was isolated as a red solid after freeze drying. Mass= 11 mg, quantitative yield. LC-MS (Method 1): tR= 2.48 min, m / z =499.2 [M+]; calcd: 499.23. >% Purity (LC-MS. 550 nm). 1H NMR (500 MHz, Methanol-D4) δ 8.45 (dd, J= 8.2, 0.7 Hz, 1H), 8.18 (dd, J= 8.2, 1H) 0.7 Hz (m, 1H), 7.94 (dd, J = 2.0, 0.7 Hz, 1H), 7.16 – 7.1 (m, 2H), 7.03 (dd, J = 9.5, 2.9 Hz, 2H), 6.94 (d, J = 2.6 Hz, 2H), 3.32 (t, J = 7.2 Hz, 4H), 3.28 (s, 12H), 2.70 (t, J = 7.1 Hz, 4H). 13C NMR (126 MHz, Methanol-D4) δ 166.1, 165.9, 159.5, 157.8, 157.7, 134.68, 134.39, 134.05, 131.25, 130.83, 130.0, 129.76, 114.32, 113.65, 96.15, 39.53, 52.82, 47.42. Example 7 - Reactivity of fluorescent lysine-aldehyde binding probes A number of aldehyde-binding groups with varying structures (Fig. 1a) and binding mechanisms (Fig. 1b) were synthesized. The TMR-O probe bears an alkyl oxyamine, while TMR-LHZ and TMR-HZN feature hydrazines. TMR-HZN features a secondary piperazinyl alkyl hydrazine group that has superior reactivity to the hydrazide binding group11. TMR-HZD is insoluble in purely aqueous buffer, while TMR-HZN is readily soluble in aqueous solutions. TMR-NB is the non-binding (non- reactive) analog of TMR-HZN, featuring TAMRA and the cyclic piperazine group but lacking the reactive hydrazine. TMR-Pyr and TMR-Rho react with aldehydes via non- reversible iso-Pictet Spengler and Knoevenagel linkages respectively. While the iso- Attorney Docket No.29539-0775WO1 Pictet Spengler involves a reversible condensation step, the condensation reaction is followed by a cyclization step, allowing TMR-Pyr to irreversibly react with aldehydes. moiety is tested in vitro to the in vivo in which the was HPLC with fluorescence detection (Fig. 1c–h) and the observed rate constants (k obs) were measured for each reaction. The table in Fig. 1b provides a summary of the measured rate constants for the probe reactions with butyraldehyde at physiological pH and ambient temperature. The non-binding control probe TMR-NB showed no reactivity with butyraldehyde. Of the series of reactive probes, the oxyamine probe TMR-O had the fastest on-rate for the reaction, while the commercially available TAMRA hydrazide (TMR-HZD) was the slowest. The reaction rate of TMR-O was 27-fold higher than TMR-HZD. The remarkable difference in reactivity between probes is also evident from the HPLC traces for the reaction of TMR-O, TMR-HZN and TMR-HZD (Fig. 1c, e, and g) where at 56 min after the start of the reaction almost complete conversion is observed for TMR-O, less than 50% conversion for TMR-HZN, and minimal conversion for TMR-HZD. Additionally, for TMR-HZD, a small but significant impurity (Fig.1c, d, peak shown in black) could not identify by HPLC-MS. Notably, for the rhodanine-containing TMR-Rho, multiple reaction products with butyraldehyde, most of which could not be identifued by HPLC-MS (Fig. 3a). Additionally, TMR-Rho is non-selective, and reacts avidly with amines as well as aldehydes (Fig.3b). The oxime product of TMR-O is remarkably stable to hydrolysis, and no reaction reversibility was observed in the first hour of the reaction (Fig. 1h), and even after 24 h (Fig. 3c). For the hydrazones, the TMR-HZD adduct is much more stable to hydrolysis than the TMR-HZN adduct (Fig. 1d, and f), which is likely due a stabilization effect from the acyl group of TMR-HZD. Cyclic, secondary hydrazine in TMR-HZN may provide steric hindrance that slows the rate of hydrazone formation relative to a linear alkyl moiety such as that in TMR-O. A linear hydrazine analog, TMR-LHZ which features an almost identical Attorney Docket No.29539-0775WO1 structure to TMR-O, but with a hydrazine reactive group was synthesized (Fig.1a). The reaction rates for TMR-O and TMR-LHZ are near identical, confirming the faster reactivity of the linear alkyl vs. cyclic hydrazine (i.e., TMR-LHZ vs TMR-HZN Fig. 1i). While the on-rates for reaction of TMR-O and TMR-LHZ were similar, marked differences were observed in the extent of product formation. At 80 min after the start of the reaction, TMR-LHZ resulted in less than 50% product formation, while more than 80% of TMR-O was converted to the condensation product (Fig.1j, k). Example 8 - TMR-O shows superior binding to protein aldehydes in vitro and to tissue aldehydes in vivo The kinetics of fluorescent probes can be altered in biological milieus with large amounts of charged and hydrophobic / hydrophilic moieties. The binding of the fluorescent library of probes to LysAld side chains to bovine serum albumin that had been chemically oxidized to convert lysines to allysines (BSA-Ald) was tested (Fig. 4a). Solutions of BSA-Ald (25 µM protein, 100 µM aldehyde) were incubated with 10 µM of TAMRA-based probes for 3 h at 37 °C. UV-Vis absorption spectra were then collected, and the protein-bound probe was separated from unbound probe by ultrafiltration using a 10 kD molecular weight cut-off filter (MWCO). UV-Vis spectra were then collected for the filtrate and compared to the spectrum measured before separation, either with or without blocking (Fig.4b and Fig.4c). The extent of binding to protein-aldehydes was highest for TMR-O, followed by TMR-Pyr, and lowest for the non-binding probe TMR-NB. Despite differences in the reaction rates, the extent of BSA-Ald binding for TMR-HZN, TMR-Rho and TMR-HZD were very similar, about 20% (Fig.4d). Blocking of the aldehyde sites on BSA-Ald with methoxylamine almost completely eliminated binding of the compounds to BSA-Ald, confirming the specificity of our probes to aldehydes (Fig.4c–e). To evaluate the in vivo performance of the probes, their binding to healthy aldehyde-rich tissues in vivo was examined. Mammalian aorta and zebrafish bulbus are similar in composition and function. Both the aorta and bulbus are rich in elastin, which allows them to withstand dynamic increases in pressure during systole. The visco- elastic properties of elastin in these tissues are attributable to desmosine cross-links that are initiated by allysine aldehydes (Fig.4f). Since elastin in the aorta and bulbus is rich in LysAld, our probes may accumulate in both healthy aorta and bulbus. Attorney Docket No.29539-0775WO1 Intravenous injection of TMR-O (2 nmol / g) in healthy mice resulted in a strong accumulation of the probe in the aorta 90 min after injection (Fig.4g), while intravenous administration of an equivalent dose of the non-binding probe TMR-NB did not result in any observable fluorescence in the aorta (Fig.4g). In zebrafish, probes were injected intraperitonially at the same dose of 2 nmol / g, and the hearts were excised 4 h after injection. Similarly, TMR-O but not TMR-NB showed robust accumulation in healthy zebrafish bulbus (Fig.4h). To evaluate the performance of probes in vivo, the accumulation of each probe in the zebrafish bulbus was quantified (Fig.4i). TMR-O fluorescence was more that two-fold higher than all other compounds. Despite very similar rates for the forward reactions of TMR-O and TMR-LHZ, the accumulation of TMR-LHZ in zebrafish bulbus was 4-fold lower. Additionally, although TMR-HZD reacted 6-times slower than TMR-HZN and TMR-Pyr, all three compounds accumulated on the bulbus to the same extent (Fig.4i). As expected, the non-binding control probe TMR-NB did not bind to bulbus. Collectively, these results demonstrate the excellent specificity of our probes to protein and tissue aldehydes and indicate that the hydrolysis / dissociation kinetics of the aldehyde-bound adducts govern the accumulation of these probes on LysAld-rich proteins and tissue in vivo. Example 9 - Collagen oxidation and cross-linking in the zebrafish model of myocardial cryoinjury Based on its superior performance, the allysine-binding probe TMR-O was selected to investigate the natural history of collagen oxidation and cross-linking in a zebrafish model of myocardial necrosis. Injury was created using the well-established cryoinjury model, where a liquid-nitrogen cooled metal probe is used to injure ~25% of the zebrafish ventricle. This model simulates the acute injury that occurs in myocardial infarction. As collagen is deposited in the healing injury, it is stabilized by cross-linking, which is initiated by lysyl-oxidase-mediated oxidation of lysine residues. The resulting oxidized collagen is rich in LysAld, which can bind TMR-O (Fig.5a). Cryoinjuries were performed in transgenic animals expressing nuclear GFP under a cardiomyocyte-specific promoter which allowed us to distinguish the injured region based on the absence of GFP expression. To determine the dynamics of collagen oxidation and cross-linking in the injured zebrafish heart, the fish were injected with TMR-O (2 nmol / g, IP) at multiple time points after injury, euthanized 4 h after injection, following which the whole hearts Attorney Docket No.29539-0775WO1 were imaged ex vivo. Figure 5b shows the transmitted light, green fluorescence, and red fluorescence images of zebrafish hearts at 7, 10-, 15-, 21- and 35 days post injury (dpi). In all cases, the GFP images showed a lack of green fluorescence in the injury- zone and in the bulbus (Fig.5b). The red fluorescence images of TMR-O showed a consistent signal in the bulbus at all stages after injury (Fig.5b). In the injury, however, the TMR-O signal was weak at 7 dpi but then increased from days 10–35 post injury. Injection of injured zebrafish with the non-binding control probe Quantification of the fluorescence signal in the zone-of-injury, normalized to the uninjured area of the ventricle, showed a significant increase in fluorescence at 21 and 35 dpi vs. days 7 and 10 dpi (Fig.5c, p < 0.001, one-way ANOVA, comparison between 7 vs.21, 7 vs.35 dpi and 10 vs.21 and 10 vs.35 dpi). The TMR-O signal in the injured myocardium peaked at 21 dpi and remained high at 35 dpi consistent with ongoing fibrogenesis. Following whole-heart imaging, the hearts were sectioned and stained with the Acid Fuchsin-Orange G (AFOG) technique for detection of scar tissue. The slow hydrolysis of the TMR-O oxime (Fig.5h) allowed fluorescence microscopy of unstained sections to be compared with adjacent AFOG-stained histological sections in which collagen (blue), fibrin (red) and normal muscle (brown) are highlighted (Fig.3d). In all cases, a strong overlap was observed between collagen-positive areas by histology (blue) and areas of TMR-O fluorescence (Fig.5e). Infarct volume was quantified through the absence of GFP signal in the heart by fluorescence microscopy. A significant reduction was detected in the infarct volume at 21 and 35 dpi, compared to 7 and 10 dpi (Fig.5f, p < 0.006, one-way ANOVA), consistent with the initiation of the regenerative process. While the size of the injured zone decreased with time, the relative amount of collagen within this zone, assessed by AFOG staining, increased with time and collagen was apparent starting at 10 dpi (Fig.5g). TMR-NB did not result in any fluorescence in the bulbus or the area of injury, both on whole-heart imaging and by fluorescence microscopy (Fig.5h), confirming that the specificity of TMR-O for LysAldwas retained in vivo. Collectively these data show that, in the 35 days following acute injury in zebrafish, a portion of the injured myocardium does heal and regenerate, but high levels of collagen deposition and cross-linking persist, suggesting that in the residual injury the process of collagen deposition and resolution remains highly dynamic. Attorney Docket No.29539-0775WO1 Example 10 - Collagen cross-linking dynamics in a mouse model of myocardial infarction The oxidation and cross-linking of collagen in infarcted mammalian hearts, which lack the regenerative capacity of zebrafish, was evaluated. Permanent ligation of the left coronary artery was performed in adult mice, which were then imaged at 5, 10, 21 and 35 days after injury. The infarcted mice were injected with TMR-O (2 nmol / g) via a tail-vein catheter, and their hearts were excised for ex vivo imaging 90 min after injection. Figure 6 shows bright field and fluorescence reflectance images of hearts of infarcted mice. TMR-O uptake was robust in the aorta and did not vary over time (Fig.6a). Within the injured area, the uptake of TMR-O peaked in mice at 21 dpi, as it did in zebrafish. However, the peak target / background (infarct / remote) values of TMR- O uptake in the mice were substantially higher than in the zebrafish. In addition, the uptake of TMR-O in the mice began earlier and was close to its peak value already at day 10 dpi (Fig.6a–c, p < 0.005, one-way ANOVA with Tukey’s post hoc comparison). Short axis slices of the hearts (Fig.6b) showed that the uptake of TMR-O was uniform throughout the infarct. Histological analysis was performed on tissue sections at the mid-ventricular level. Staining with AFOG showed minimal collagen deposition at 5 dpi (Fig.6d), and a corresponding absence of TMR-O signal in confocal microscopy images at 5 dpi (Fig.6e). At 10–35 dpi, AFOG-stained sections showed that significant portions of the ventricle stain positive for collagen (Fig.6d), and that these areas correlated well with areas in adjacent sections that were positive for TMR-O (Fig.6e). Collectively, these data show that TMR-O retains its specificity for oxidized collagen in mice and, notwithstanding an earlier rise and higher peak in mice, that the oxidation and cross- linking of collagen during the first 35 days of injury is similar in mice and zebrafish. Example 11 - Collagen deposition and cross-linking persists in mature scar in the mouse model of MI The fibrotic scar in MI has been historically considered to mature within 3– 4 weeks of injury at which time an inert scar is formed and collagen deposition abates. However, at both 45 and 62 days after infarction large portions of the murine infarcts still showed high levels of TMR-O uptake (Fig.7a–d), indicating robust collagen oxidation. The periphery of the remodeling infarcts was most likely to show high levels of TMR-O uptake, and static portions of the infarct with little TMR-O uptake were most Attorney Docket No.29539-0775WO1 likely to be found at the center of the infarct. Nonetheless, significant levels of probe uptake were seen in the center of the infarct as well (Fig.7a–d). Pixel classification with k-means clustering showed that the size and mean value of the pixel cluster with the highest amount of probe uptake did not change as the scar matured over time (Fig.7e–g). The heterogeneous nature of TMR-O uptake in the day 45 and 62 infarcts was confirmed by histology and fluorescence microscopy (Fig.7h, i). Collectively, the data in the day 45–62 murine infarcts reveals that some areas of these mature infarcts are static, with little deposition and cross-linking of new collagen. However, large portions of the infarcts, particularly towards the periphery, remain highly dynamic with substantial deposition and cross-linking of new collagen. By day 45 In the zebrafish hearts only very small areas of injury could be detected (Fig.7j, k). However, these small injury zones remained dynamic and showed substantial uptake of TMR-O, consistent with ongoing collagen deposition and cross- linking, despite the greatly diminished area of injury (Fig.7j, k). At 62 dpi, the zebrafish ventricle was completely regenerated, and little evidence of infarction could be detected by TMR-O fluorescence or by histology (Fig.7l, m). These data demonstrate that the evolution of the fibrotic scars in zebrafish at days 45 and 62 after injury showed a very different pattern from that observed in the fibrotic scars in mouse hearts. Example 12 - Degradation-resistant cross-links develop in murine infarcts but not zebrafish infarcts The formation of lysine-aldehydes is the first step in the cross-linking of collagen. This process is initiated by lysyl oxidase-mediated oxidation of lysine residues of the collagen telopeptide, the non-helical ends of the collagen triple helix (Fig.8a). The lysine-aldehydes react with each other and other adjacent moieties to form the initial CCLs and stabilize the scar (Fig.8b). However, these immature CCLs are unstable and can be hydrolized. The maturation of collagen cross-links occurs by non-enzymatic processes and is considered to be spontaneous (Fig.8b, c), but can be influenced by the exact peptide-sequence and glycosylation state of collagen. The two most well-studied end-products of mature cross-linked collagen are pyridinoline (Pyd) and deoxypyridinoline (DPD) (Fig.8d). The quantification of Pyd and DPD levels in injured zebrafish and mouse hearts was performed using a previously validated HPLC method. As both aromatic cross- links are fluorescent, this method does not require a labeling step for detection of the cross-links, and can therefore be carried out on small amounts of tissue. Pyd and DPD Attorney Docket No.29539-0775WO1 were assessed in whole zebrafish ventricles and the apical portion of the mouse infarcts. The amount of hydroxyproline (Hyp), a major amino acid in collagen and a well- established surrogate marker of collagen levels, was quantified in the initial tissue digests, which were then reconstituted to contain similar amounts of hydroxyproline / collagen. At 21 dpi, a prominent peak was found for both DPD and Pyd in infarcted mouse hearts but not in injured zebrafish hearts despite similar hydroxyproline concentrations in the analyzed samples (Fig. 8e). Pyd levels at 21 dpi in injured zebrafish and murine hearts, normalized to total hydroxyproline content are shown in Fig. 8f. No Pyd or DPD was detected in zebrafish tissue at any point after injury. In contrast, in murine infarcts, Pyd was always detectable and increased linearly with infarct age (Fig. 8g). DPD levels in the murine infarcts were substantially lower than Pyd levels (Fig. 8h, note scale difference vs. Pyd in panel G) and showed a Gaussian-like distribution as a function of infarct age. Collectively, these data show that fundamental differences in the development of mature, degradation-resistant, collagen cross links exist in injured zebrafish and murine hearts. For quantitative analysis, the values of both Hyp and OHK were normalized to Asp levels in each sample. In the infarcted mouse hearts, significant increases in the amount of both Hyp and OHK were seen from 1–3 weeks after injury (Fig. 8e). In zebrafish, a significant increase in Hyp but not in OHK was seen between 1–3 weeks (Fig.8f). Between weeks 1 and 3, Hyp and OHK levels in mice increased by 530% and 300%, respectively (Fig. 8g). The percent increase in Hyp in the zebrafish hearts was also substantial (170%) but the percent increase in OHK was minimal (8%) (Fig. 7g). Collectively, these data suggest that the limited hydroxylation of lysine residues in newly deposited collagen in the injured zebrafish heart impedes the formation of irreversible collagen cross-links (Pyd and DPD) in zebrafish infarcts. Example 13 - Lysine hydroxylation in infarct collagen differs in murine and zebrafish hearts The formation of both Pyd and DPD requires the conversion of at least one collagen lysine residue to hydroxylysine. The lack of Pyd and DPD CCLs in the injured zebrafish hearts may be due to reduced hydroxylation of collagen lysine. The hydroxylation of collagen lysine residues occurs through the action of lysyl hydroxylases, and both hydroxylated and non-hydroxylated lysine residues in the telopeptide region of collagen undergo oxidation by lysyl oxidases to form Attorney Docket No.29539-0775WO1 (hydroxy)allysine [(OH)LysAld]. TMR-O and other aldehyde-reactive probes bind to both allysine (LysAld) and hydroxyallysine (OH-LysAld) and cannot provide a readout of lysine hydroxylation. To quantify hydroxylysine levels in injured zebrafish and mouse hearts, an HPLC method was used and involves a fast and quantitative derivatization reaction of amine groups with 9-Fluorenylmethyl Chloroformate (FMOC-Cl). Labeling of tissue hydrosylates with FMOC-Cl results in one fluorescent FMOC tag per amine group (Fig. 13), which includes the alpha amine groups in all amino acids as well as any additional amines on amino acid sidechains. Following the labeling, an HPLC method with a gradient of three solvent systems is used to resolve all amino acids from one another in one chromatogram. To account for differences in total tissue content between samples, aspartic acid (Asp), which showed a consistent concentration across all samples (Fig. 14), was used as an internal standard. The chromatograms shown in Fig. 9 are normalized to the Asp peak such that the Asp peak height is at 100%. In zebrafish, the hydroxyproline (Hyp) peak in the chromatograms increased from 1–3 weeks after injury, but the hydroxylysine (OHK) peak remained unchanged (Fig. 9a and Fig. 9b). In the mouse infarcts, however, the increase in the Hyp peak from 1–3 weeks was accompanied by a significant increase in the OHK peak (Fig.9c and Fig.9d). Example 14 - TMR-O can visualize diffuse cardiac fibrogenesis and response to therapy in an obesity / hypertension mouse model of cardiac fibrosis: An obesity and hypertension dual hit mouse model was used to assess the effectiveness of our fluorescent fibrogenesis probes in assessing cardiac remodeling in this model. Mice were treated with a high fat diet in which fat accounts for 60% of caloric load. To induce hypertention, we treated mice with the oxide (NO) synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME). This dual hit HFLN model results in obesity and hypertension, and promotes interstitial fibrosis in the myocardium. After 6 months of diet, mice were imaged with our lead fluorescent probe TMR-O. A subset of mice were returned to norma chow for an additional two months, then imaged with TMR-O and euthanized after imaging. We also had an additional cohort of age-matched naïve mice as controls. For this study, mice were injected with TMR-O (2nmol / g, IV), then euthanized one hour after injection and the hearts and aorta were excised for ex-vivo imaging. Attorney Docket No.29539-0775WO1 Analysis of fibrotic burden in the hearts using hydroxyproline (a marker for total collagen), showed that there are minimal but significant increase in fibrosis as measured by HYP in the HFLN mouse hearts compared to the age matched-naïve mouse hearts. (Figure 1E). Withdrawal from HFLN results in a decrease in HYP that is approaching statistical significance (Figure 1E). Our TMR-O probe on the other hand, could more sensitively detect differences between the three groups. While subtle differences in the fluorescence intensity can be visually distinguished between the HFLN and naïve whole-heart images, The differences become visually more distinct in the axial slices of the hearts (Fig. 10A). Quantification of the fluorescence intensity in the axial slices shows a >2-fold increase of fluorescence in the HFLN hearts compared to aged-matched naïve hearts (Fig. 10B). Withdrawal from HFLN diet for 2 months results in a return to baseline as detected by fluorescence (Fig. 10B). Additionally, quantification of allysine (the biochemical target of the probe) also showed statistically significant difference in allysine concentration between HFLN and naïve hearts (Fig. 10C). The TMR-O fluorescence intensity and the allysine concentration are statistically significantly correlated Figure 10D. Example 15 - TMR-O can visualize diffuse renal fibrogenesis in a Unilateral renal Ischemia Reperfusion Injury (IRI) mouse model of renal fibrosis: Renal fibrosis is a hallmark of all chronic kidney diseases (CKD). It is estimated that 500 million people worldwide are currently suffering from CKD and many of these patients will progress to end- stage renal disease (ESRD), a devastating disorder that requires dialysis or kidney transplantation. The incidence of ESRD has doubled over the last 25 years in the United States, and in fact, treatment of CKD and ESRD accounted for 27% ($60 billion) of Medicare expenses in 2005. Clinical studies have demonstrated a strong correlation between ESRD and the extent of renal fibrosis. Quantification of renal fibrosis should predict long-term outcome of renal function in CKD patients and could also be used to monitor response to new anti- fibrotic therapies. Currently, biopsy is the gold standard for diagnosing renal fibrosis. However, biopsy is not suitable for monitoring disease progression in CKD patients as it is invasive and subject to sampling error. Therefore, there is a major unmet medical need to develop strategies to detect and monitor progression of renal fibrosis. Renal function progressively declines in response to the excessive accumulation of extracellular matrix proteins. Myofibroblasts secrete collagens, as Attorney Docket No.29539-0775WO1 well as the enzyme lysyl oxidase (LOX) which crosslinks the collagen fibrils. Since LOX-mediated crosslinking of collagen is an aspect of active disease, our hypothesis is that molecular imaging of LOX-mediated collagen crosslinking accurately reflects renal fibrogenesis and thus can be used to detect renal fibrosis and monitor disease progression and response to therapy. There are at least two aspects that make our molecular imaging probes particularly suitable for imaging kidney fibrogenesis: 1) Molecular imaging of the kidney is particularly challenging because almost all probes are eliminated to some extent through the kidneys, resulting in a high background signal. To achieve specific molecular imaging of the kidneys with a targeted probe, the probe must have prolonged binding to the target that would allow waiting a sufficient amount of time to reduce the nonspecific background signal in the kidneys. Our TMR-O probe remains at the target even 24 hour after injection, and is there ideal for imaging the fibrotic kidney. 2) Although we have been able to quantify allysine (the target of our molecular imaging probes) in many organs, we have not been able to do so in the kidney or liver likely due to high enzymatic activity in these organs. Fluorescent imaging of allysine in the kidney would allow for a way to virtualize and quantify a surrogate of allysine. In this study, we used a unilateral renal ischemia-reperfusion injury (IRI) mouse model (where one kidney is clamped and then reperfused. This results in initial inflammation and cell death that then gives way to tissue fibrosis.37For this study, mice were injected with TMR-O or TMR non-0binding control probe (2nmol / g, IV), then euthanized 24 hours after injection and the kidneys were`` excised for ex-vivo imaging. The biochemical biomarker hydroxyproline was quantified (Fig. 11A) and showed obvious collagen deposition in the cortex and medulla of the IRI kidney, but not in the healthy kidney. For imaging with fluorescent probes, we found that the control probe TMR does not result in any fluorescence signal in either the injured IRI or control contralateral kidney (Fig.11B). On the other hand, TMR-O injection resulted in a robust diffuse signal in the injured IRI kidney, and minimal signal in the contralateral kidney (Fig.11C). OTHER EMBODIMENTS It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended Attorney Docket No.29539-0775WO1 to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.29539-0775WO1 WHAT IS CLAIMED IS:

1. A compound of Formula I: F-L-N(R’)H I or a pharmaceutically acceptable salt thereof, wherein: F is a fluorescent reporter moiety; L is a linker moiety; and R’ is absent, hydrogen, or a substituted acyl group.

2. The compound of claim 1, wherein L is selected from C1-10alkyl, C2-10alkenyl, C2-10 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, a bond, -O-, -N(RA)-, -N(RA)RB-, - N(RA)RBO-, -N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, - N(RA)RBC(=O)RC-, -N(RA)RBC(=O)O-, -ORAC(=O)-, -ORAC(=O)O-, - OC(=O)N(RA)RB-, -S(O)2N(RA)RB-, and -N(RA)RBS(O)2-; and each RAand RBis independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and wherein L is not -NH-.

3. The compound of claim 1 or 2, wherein L is selected from C1-10alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -O-, -N(RA)-, -N(RA)RB-, - N(RA)RBO-, -N(RA)RBN(RC)-, -NRAC(=O)-, -N(RA)RBNC(=O)RC-, - N(RA)RBC(=O)RC-, -N(RA)RBC(=O)O-, -ORAC(=O)-, -ORAC(=O)O-, and - OC(=O)N(RA)RB-; andAttorney Docket No.29539-0775WO1 each RAand RBis independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; each RCis hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein L is not -NH-.

4. The compound of any one of claims 1-3, wherein L is 3-10 membered heterocyclyl.

5. The compound of any one of claims 1-4, wherein L is 5 or 6 membered heterocyclyl.

6. The compound of any one of claims 1-5, wherein L .

7. The compound of any one of claims 1-3, wherein L is selected from -N(RA)-, N(RA)RB-, -N(RA)RBO-, -N(RA)RBN(RC)-, and -N(RA)RBNC(=O)RC-; each RAand RBis independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl; and each RCis is selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3Attorney Docket No.29539-0775WO1 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein L is not -NH-.

8. The compound of any one of claims 1-3 or 7, wherein L is -N(RA)RB-; and RA, and RBare independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, or RAand RBare joined to form a 3-10 membered heterocyclyl.

9. The compound of any one of claims 1-3, 7 or 8, wherein L is -N(RA)RB-; and RAand RBare joined to form a 3-10 membered heterocyclyl.

10. The compound of any one of claims 1-3 or 7-9, wherein R’ is absent and11. The compound of any one of claims 1-3, wherein L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

12. The compound of any one of claims 1-3 or 11, wherein L is -N(RA)RBO-; and RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

13. The compound of any one of claims 1-3, 12, or 13, wherein L is .of any one of claims 1-3, wherein L is -N(RA)RBN(RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl,Attorney Docket No.29539-0775WO1 C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

15. The compound of any one of claims 1-3 or 14, wherein L is -N(RA)RBN(RC)-; and RA, RB, and RCare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

16. The compound of any one of claims 1-3, 14, or 15, wherein L is .

17. The compound of any one of claims 1-3, wherein L is -N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally with 1-3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

18. The compound of any one of claims 1-3 or 17, wherein L is - N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10alkyl, C1-10heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis selected from C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C1-10 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally withAttorney Docket No.29539-0775WO1 1-3 substituents independently selected from halogen, C1-10alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein L is not -NH-.

19. The compound of any one of claims 1-3, 17, or 18, wherein L is - N(RA)RBNC(=O)RC-; RAand RBare independently selected from hydrogen, C1-10 alkyl, C1-10 heteroalkyl, 3- 10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and RCis C1-10alkyl optionally with 1-3 substituents independently selected from halogen, C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

20. The compound of any one of claims 1-3 or 17-19, wherein L is .

21. The compound of any one of claims 1-3, wherein L is -N(RA)-; and RAis C1-10 alkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

22. The compound of any one of claims 1-3 or 21, wherein L is -N(RA)-; and RAis C1-10alkyl, C1-10heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

23. The compound of any one of claims 1-3, 21, or 22, wherein L is -N(RA)-; and RAis C1-10 alkyl.

24. The compound of any one of claims 1-3, or 21-23, wherein L is -N(RA)-; and RAis C2alkyl.Attorney Docket No.29539-0775WO1 25. The compound of any one of claims 1-3 or 21-24, wherein R’ is −C(=O)RXand RXis selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 6- 10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

26. The compound of any one of claims 1-3 or 21-25, wherein RXis selected from C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the C1-10 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

27. The compound of any one of claims 1-3, or 21-26, wherein RXis C1-10 alkyl optionally substituted with 1 or 2 substituents independently selected from halogen, C1-C6 alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl.

28. The compound of any one of claims 1-3 or 21-27, wherein RXis C1-10 alkyl substituted with 5 or 6 membered heteroaryl.

29. The compound of any one of claims 1-3 or 21-28, wherein RXis C1-10alkyl substituted with 5 or 6 membered heteroaryl.

30. The compound of claim 1-3 or 21-29, .of any one of claims 1-3, or 21-30, wherein L-N(R’)H is .Attorney Docket No.29539-0775WO1 32. The compound of any one of claims 1-31, wherein F is of formula F1 or F2:

33. The compound of claim 1, wherein the compound isAttorney Docket No.29539-0775WO1or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound of any one of claims 1- 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A method of imaging a tissue comprising: (a) contacting the tissue with a compound of any one of claims 1-33; (b) irradiating the tissue at a wavelength absorbed by the compound; (c) and detecting a signal from the compound, thereby imaging the tissue.

36. A method of determining tissue remodeling, comprising (a) administering to a subject suspected of having tissue damage an imaging effective amount of a compound of any one of claims 1-33, or the pharmaceutical composition of claim 34; (b) irradiating a tissue at a wavelength absorbed by the compound; and (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates the presence of tissue remodeling.

37. A method of determining protein oxidation and / or cross-linking of collagen, comprising: (a) administering to a subject suspected of having myocardial infarction an imaging effective amount of a compound of any one of claims 1-33 or the pharmaceutical composition of claim 34; (b) irradiating a tissue at a wavelength absorbed by the compound;Attorney Docket No.29539-0775WO1 (c) determining the presence or absence of a signal from the compound, wherein the presence of a signal indicates the presence of protein oxidation and / or cross-linking of collagen.

38. A kit comprising the compound of any of claims 1-33, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34; and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject.

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