Diagnostic agents and uses thereof

Abstract

The present disclosure relates to 2-deoxy-D-glucose (2DG) compounds comprising one or more isotopically substituted hydrogen atoms, uses and methods thereof.

Description

[0001] DIAGNOSTIC AGENTS AND USES THEREOF

[0002] TECHNOLOGICAL FIELD

[0003] The present disclosure relates to diagnostic agents and methods fortheir use.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] [1] HM De Feyter, et al. , Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo Science Advances, 4, 2018.

[0007] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0008] BACKGROUND

[0009] Deuterium Metabolic Imaging (DMI) is used to map the distribution of a deuterium-labelled metabolite and its metabolic fates in a biological sample or subject [1]. Deuterium-labelled glucose ([6,6-D2]D-glucose) has been used together with DMI to follow metabolic fates of glucose such as lactate and glutamine / glutamate [1].

[0010] GENERAL DESCRIPTION

[0011] The present disclosure provides in accordance with some aspects, a 2-deoxy-D- glucose (2DG) compound comprising one or more isotopically substituted hydrogen atoms for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image.

[0012] The present disclosure provides in accordance with some other aspects, a 2DG compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, X8is2H (D).

[0013] The present disclosure provides in accordance with some other aspects, a 2DG compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is represented by Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of X1, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0014] The present disclosure provides in accordance with some further aspects, a 2DG compound for use in a method of diagnosing a subject, wherein the 2DG compound comprising one or more isotopically substituted hydrogen atoms.

[0015] The present disclosure provides in accordance with yet some aspects, a 2DG compound for use in a method of diagnosing a disease in a subject, wherein the 2DG compound comprising one or more isotopically substituted hydrogen atoms.

[0016] The present disclosure provides in accordance with yet some other aspects, a 2DG compound for use in detecting a metabolite of said compound.

[0017] The present disclosure provides in accordance with yet some further aspects, a 2DG compound for use in (i) a method of monitoring a disease state in said subject and / or (ii) a method of determining a site of a disease in said subject, wherein the 2DG compound comprising one or more isotopically substituted hydrogen atoms.

[0018] The present disclosure provides in accordance with yet some further aspects, a 2DG compound for use in a method of distinguishing between healthy and abnormal tissues or organs and / or distinguishing or differentiating between malignant and benign tumors, wherein the 2DG compound comprising one or more isotopically substituted hydrogen atoms.

[0019] The present disclosure provides in accordance with yet some aspects, a diagnostic formulation comprising at least one 2DG compound comprising one or more isotopically substituted hydrogen atoms.

[0020] The present disclosure provides in accordance with yet some aspects, a kit comprising a formulation as described herein, and instructions for use thereof. The present disclosure provides in accordance with yet some aspects, a method of imaging a subject, the method comprising monitoring a signal from a subject using an MR imaging method, the subject having been administered at least one 2DG compound to thereby acquire at least one MR image, wherein said 2DG compound is deuterium- labeled 2DG comprising one or more isotopically substituted hydrogen atoms.

[0021] The present disclosure provides in accordance with yet some aspects, a method for diagnosis of a disease or condition in a subject, said method comprising (i) administering to the subject a diagnostically effective amount of at least one 2DG compound and (ii) imaging and / or acquiring a spectrum of said subject or a body region of the subject to thereby identify body regions in which said compound, or any metabolite thereof has been localized, wherein said 2DG compound is deuterium-labeled 2DG, comprising one or more isotopically substituted hydrogen atoms.

[0022] The present disclosure provides in accordance with yet some aspects, a method for monitoring a disease state in a subject, the method comprising (i) provided a compound is administered to the subject; (ii) obtaining an image from the subject's body or any one or more regions thereof, whereby obtaining at least one imaging parameter indicative of the disease or disorder state; and (iii) comparing said at least one imaging parameter to at least one parameter obtained from said subject at an earlier timepoint; wherein the comparison enables determining the progression of the disease or disorder state; and wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H?]2- deoxy-D-glucose, [2Hg]2-deoxy-D-glucose or a combination thereof, (c) |2Hx|2-dcoxy- D-glucose, (d) represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xe, X7, Xg is2H (D), (e) represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

[0023] The present disclosure provides in accordance with yet some aspects, a method for determining the severity of a disease or disorder in a subject, the method comprising administering to said subject a compound, imaging and / or acquiring a spectrum the subject’s body or region thereof to obtain at least one imaging parameter, and comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement, wherein the comparison permits determining the severity of the disease or disorder in the subject, wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D- glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, |2Hs|2- deoxy-D-glucose or a combination thereof, (c) [2Hs]2-deoxy-D-glucose, (d) represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula

[0024] (III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xe, X7, Xs is2H (D), (e) represented by Formula

[0025] (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

[0026] The present disclosure provides in accordance with yet some aspects, a method for determining the effectiveness of a therapeutic treatment of a disease or disorder in a subject, the method comprising administering to said subject a compound, imaging the subject’s body or region thereof to obtain at least one imaging parameter, and comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement, wherein the comparison permits determining the effectiveness of the therapeutic treatment of the disease or disorder in the subject, wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D- glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose or a combination thereof, (c) [2Hs]2- deoxy-D-glucose, (d) represented by Formula (I) or Formula (I’) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, Xs is2H (D), (e) represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

[0027] The present disclosure provides in accordance with yet some aspects, a method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one condition in a subject in need thereof, said method comprising the steps of: (a) diagnosis a disease or condition in a subject as described herein and (b) administering to the subject a treatment regimen based on said disease or condition thereby treating the subject.

[0028] The present disclosure provides in accordance with yet some aspects, use of at least one 2DG compound in the preparation of a formulation or a composition, wherein the compound is wherein said 2DG compound is deuterium-labeled 2DG.

[0029] EMBODIMENTS

[0030] Some embodiments of this disclosure will now be described in the following numbered paragraph. The following description intends to add on the above general description and not limit it in any manner.

[0031] 1. A 2-deoxy-D-glucose (2DG) compound comprising one or more isotopically substituted hydrogen atoms for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image.

[0032] 2. A 2DG compound comprising one or more isotopically substituted hydrogen atoms for use in a method of acquiring at least one MR spectrum and / or at least one MR image from a subject.

[0033] 3. A 2DG compound comprising one or more isotopically substituted hydrogen atoms for use in a method of diagnosing a subject.

[0034] 4. A 2DG compound comprising one or more isotopically substituted hydrogen atoms for use in a method of diagnosing a disease in the subject.

[0035] 5. A pharmaceutical composition comprising at least one 2DG compound, wherein the compound comprising one or more isotopically substituted hydrogen.

[0036] 6. A diagnostic formulation comprising at least one 2DG compound, wherein the compound comprising one or more isotopically substituted hydrogen. 7. A kit comprising at least one 2DG compound, wherein the compound comprising one or more isotopically substituted hydrogen.

[0037] 8. A method of acquiring at least one MR spectrum and / or at least one MR image from a subject, the method comprising monitoring a signal from a subject, the subject having been administered at least one 2DG compound to thereby acquire at least one MR image, wherein the 2DG compound comprising one or more isotopically substituted hydrogen.

[0038] 9. A method of imaging a subject, the method comprising monitoring a signal from a subject using an MR imaging method, the subject having been administered at least one 2DG compound to thereby acquire at least one MR image, wherein the 2DG compound comprising one or more isotopically substituted hydrogen.

[0039] 10. A method for diagnosis of a disease or condition in a subject, the method comprising (i) provided a diagnostically effective amount of at least one 2DG compound to the subject and (ii) obtaining an image and / or spectrum of the subject or of a body region of the subject; (iii) identifying body regions in which the compound, or any metabolite thereof has been localized, wherein the 2DG compound comprising one or more isotopically substituted hydrogen; thereby enabling the diagnosis of a disease or condition in a subject according to the localization of the 2DG compound or its metabolites.

[0040] 11. A method for monitoring a disease state in a subject, the method comprising (i) provided the subject has been administering a compound; (ii) imaging the subject's body or any one or more regions thereof, in order to obtain at least one imaging parameter indicative of the disease or disorder state; and (iii) comparing the at least one imaging parameter to at least one parameter obtained from the subject at an earlier timepoint; wherein the comparison enables determining the progression of the disease or disorder state, and thereby monitoring the disease state of the subject; and wherein the compound comprising one or more isotopically substituted hydrogen.

[0041] 12. A method for determining the severity of a disease or disorder in a subject, the method comprising (i) provided the subject has been administered a compound, (ii) imaging and / or acquiring a spectrum the subject’s body or region thereof to obtain at least one imaging parameter, and (iii) comparing the at least one imaging parameter to at least one parameter obtained from the subject at the onset of treatment or prior to treatment commencement, and thereby determining the severity of the disease or disorder in the subject, wherein the compound comprising one or more isotopically substituted hydrogen.

[0042] 13. A method for determining the effectiveness of a therapeutic treatment of a disease or disorder in a subject, the method comprising (i) provided the subject has been administered a compound, (ii) imaging the subject’s body or region thereof and thereby obtaining at least one imaging parameter, and (iii) comparing the at least one imaging parameter to at least one parameter obtained from the subject at the onset of treatment or prior to treatment commencement; and thereby determining the effectiveness of the therapeutic treatment of the disease or disorder in the subject, wherein the compound comprising one or more isotopically substituted hydrogen.

[0043] 14. A method of treating a subject in need thereof, the method comprising the steps of: (i) provided the subject has been administered a compound, (ii) imaging the subject’s body or region thereof and thereby obtaining at least one imaging parameter, (iii) diagnosis of a disease or condition in a subject according to the localization of the 2DG compound or its metabolites; (iv) administering a treatment to the subject compatible with the diagnosis obtained on step (iii) wherein the compound comprising one or more isotopically substituted hydrogen.

[0044] 15. A method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one condition in a subject in need thereof, said method comprising the steps of: (a) diagnosis a disease or condition in a subject and (b) administering to the subject a treatment regimen based on said disease or condition thereby treating the subject, wherein said diagnosis comprises(i) provided a diagnostically effective amount of at least one 2DG compound to the subject and (ii) obtaining an image and / or spectrum of the subject or of a body region of the subject; (iii) identifying body regions in which the compound, or any metabolite thereof has been localized, wherein the 2DG compound comprising one or more isotopically substituted hydrogen; thereby enabling the diagnosis of a disease or condition in a subject according to the localization of the 2DG compound or its metabolites. 16. Use of at least one DG labeled compound for the preparation of a formulation and / or composition, wherein the compound comprising one or more isotopically substituted hydrogen.

[0045] 17. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the 2DG compound is at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2- deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D- glucose, [2H7]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose or a combination thereof.

[0046] 18. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the 2DG compound is [2Hs]2-deoxy-D-glucose.

[0047] 19. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the 2DG compound is [2H2]2-deoxy-D-glucose.

[0048] 20. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (I), Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0049] 21. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein in the compound is represented by Formula (I), Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), one or more of (i) one of Xi, X2, X3, X4, X5, Xg, X7, and Xs is2H, (ii) two of Xi, X2, X3, X4, X5, Xe, X7, and Xs is2H, (iii) three of Xi, X2, X3, X4, X5, Xg, X7, and Xs is2H, (iv) four of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (v) five of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vi) six of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vii) seven of Xi, X2, X3, X4, X5, X6, X7, and Xsis2H, (viii) eight of Xi, X2, X3,X4,X5,X6,X7, and Xs is2H or a combination thereof. 22. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (IV), Formula (V), Formula (VI), Formula (VII) , Formula (VIII) , Formula (IX) , Formula (X), Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0050] 23. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (IV), or Formula (V) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0051] 24. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (VI), or Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0052] 25. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (VIII), or Formula (IX) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0053] 26. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound is represented by Formula (X), or Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0054] 27. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the compound has a Ti relaxation of a2H nucleus of between about 5 milliseconds to about 200 milliseconds. 28. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the method comprises acquiring at least one MR spectrum and / or at least one MR image from a subject.

[0055] 29. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for use in a method of diagnosing the subject.

[0056] 30. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for use in a method of diagnosing a disease in the subject.

[0057] 31. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for use in detecting a metabolite of the compound.

[0058] 32. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the metabolite is one of [D]2-deoxy-D-glucose-6-phosphate, [D2]2-deoxy-D-glucose-6- phosphate, [D3]2-deoxy-D-glucose-6-phosphate, [D4]2-deoxy-D-glucose-6-phosphate, [D5]2-deoxy-D-glucose-6-phosphate, [D6]2-deoxy-D-glucose-6-phosphate, [D?]2- deoxy-D-glucose-6-phosphate, [D8]2-deoxy-D-glucose-6-phosphate or a combination thereof.

[0059] 33. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the metabolite is a phosphorylation product of a compound represented by one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI) or any combination thereof.

[0060] 34. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the metabolite is represented by one or more of Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII) or any combination thereof. 35. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for use in (i) a method of monitoring a disease state in the subject and / or (ii) a method of determining a site of a disease in the subject.

[0061] 36. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the disease is associated with increased glucose metabolism.

[0062] 37. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the disease may be oncological, neurological, psychiatric, cardiovascular, infectious or inflammatory.

[0063] 38. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the disease is a proliferative disorder.

[0064] 39. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the disease is ischemia.

[0065] 40. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for distinguishing between healthy and abnormal tissues or organs and / or distinguishing or differentiating between malignant and benign tumors.

[0066] 41. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein at least one MR image is at least one2H image.

[0067] 42. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the at least one2H image is acquired at an acquisition time of at most about 5 min.

[0068] 43. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the at least one2H MR image from a subject with a spatial resolution of between about 2mm and about 20mm, at times between about 2mm and about 10mm, at times between about 2mm and about 5 mm (in plane resolution).

[0069] 44. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein at least one MR image is of at least one compound or a metabolite thereof.

[0070] 45. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for determining a site of a disease and / or for distinguishing between healthy and abnormal tissues or organs.

[0071] 46. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, for distinguishing or differentiating between malignant and benign tumors.

[0072] 47. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the method comprising prior to the administration step, acquiring at least one2H image from the subject’s body or one or more body regions.

[0073] 48. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the method comprising comparing at least one parameter obtained from the at least one2H MR image to at least one parameter obtained from the at least one2H MR image in the same subject at an earlier timepoint, wherein the comparison enables diagnosis of the disease.

[0074] 49. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the method comprising administering to a subject diagnosed with a disease, a treatment regimen based on said disease or condition thereby treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of the disease.

[0075] 50. The 2DG compound, the pharmaceutical composition, the diagnostic formulation, the kit, the methos, the use of any one of the preceding Embodiments, wherein the treatment regimen is designed for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying a disease is associated with increased glucose metabolism. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0077] Figure 1 are deuterium Nuclear Magnetic Resonance (NMR) spectra of brain slices perfused with artificial cerebrospinal fluid (aCSF) containing [6,6-D2]D-glucose with two ischemic periods, D-Glc, [6,6-D2]D-glucose; D-Lac, [3,3-D2]lactate.

[0078] Figures 2A-2C show individual time courses of [6,6-D2]D-glucose (D-Glc) and [3, 3 -D2] lactate (D-Lac) in brain slices on three experimental days, respectively, Y-axis shows concentration in the NMR tube in mM for the three species (HDO, D-Glc, and D- Lac), the breaks in D-NMR acquisitions in Figure 2C were taken to record31P spectra.

[0079] Figures 3A-3H are31P NMR spectra of the brain slices during the three ischemia experiments; Figure 3A is a31P NMR spectrum at day 1 before 1stischemia; Figure 3B is a31P NMR spectrum at day 1 after 2ndischemia; Figure 3C is a31P NMR spectrum at day 2 before 1stischemia; Figure 3D is a31P NMR spectrum at day 2 after 2ndischemia; Figure 3E is a31P NMR spectrum at day 3 before 1stischemia; Figure 3F is a31P NMR spectrum at day 3 after 2ndischemia; Figure 3G is a31P NMR spectrum at day 3 during 3rdischemia; Figure 3H is a31P NMR spectrum at day 3 after 3rdischemia.

[0080] Figure 4 are stacked deuterium NMR spectra of an experiment with three ischemic conditions, only the third ischemic duration is shown, D-Glc, [6,6-D2]D- glucose; D-Lac, [3,3-D2]lactate; D-Glx deuterium-labeled-glutamate and -glutamine

[0081] Figure 5 shows partial time course of the experiment with three ischemic conditions, for clarity, the D-Glx level was multiplied 5-fold compared to HDO, D-Glc, and D-Lac, the X-axis represents 2-minute intervals, and X=0 is at the start of the reperfusion after the first ischemic condition, where the D-Glx signal was first observed.

[0082] Figures 6A and 6B are 'H NMR spectra of commercial 2-deoxyglucose-6,6-H2 (Figure 6A) and 2-deoxyglucose-6,6-D2 (Figure 6B). DETAILED DESCRIPTION OF EMBODIMENTS

[0083] The diagnosis of disease, particularly early diagnosis, is critically important as it assist in identifying disease, tracking its progression, determining appropriate treatment regimens and planning follow-ups measures.

[0084] Imaging and spectroscopic techniques, such as positron emission tomography (PET), computed tomography (CT), magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), are commonly employed for diagnosis a wide range of disease and condition. Among others, PET and CT involve the use of ionizing radiation, whereas MRS and MRI are non-invasive, safe non-radioactive diagnostic methods.

[0085] Disease diagnosis using PET frequently relies on the contrast agent18F-fluoro-2- deoxy-D-glucose (FDG), a fluorinated analogue of 2-deoxy-D-glucose (2DG). 2DG is a non-metabolic derivative of D-glucose that enters cells via the glucose transporters and subsequently phosphorylated by hexokinases into a phosphorylated product. This product (may also considered as a metabolite) is largely non-metabolized and does not proceed through the glycolysis pathway, resulting in its accumulation within the cells. This accumulated compound (metabolite) can be visualized following administration, enabling the diagnosis of tissues exhibiting high glucose uptake and phosphorylation.

[0086] However, the use of ionising radiation associated with the FDG-PET poses significant limitations, including restrictions on the frequency of examinations, prolonged intervals between repeated scans and concerns regarding its use in vulnerable populations such as children and pregnant women.

[0087] The present disclosure relates to 2-deoxy-D-glucose (2DG) compounds, in which one or more carbon-bound hydrogen atoms are replaced with deuterium (2H or D), a stable, non-radioactive hydrogen isotope, that may be used as contrast agents in non- invasive MR methods.

[0088] Hence, in accordance with some aspects, the present disclosure provides a 2DG compound comprising one or more isotopically substituted hydrogen atoms for use in a method of acquiring at least one MR spectrum and / or at least one MR image.

[0089] In the following text, when referring to the 2DG compound or compound it is to be understood as also referring to pharmaceutical compositions, methods, kits and uses, disclosed herein. Thus, whenever providing a feature with reference to the 2DG compound or compound, it is to be understood as defining the same feature with respect to the pharmaceutical compositions, the methods, the kits and the uses, mutatis mutandis.

[0090] 2-Deoxyglucose is also known by the IUPAC name 2-Deoxy-D-ara ufio- hexopyranose, by the systematic IUPAC name (4 / ?.5.S'.6 / ?)-6-(hydroxymcthyl)oxanc- 2,4,5-triol as well as by other names: 2-Deoxy-d-mannose, 2-Deoxy-d-arabino-hexose or 2-DG. It has CAS Number of 154-17-6.

[0091] As appreciated, 2DG may exist in various forms, such as open-chain and cyclic (pyranose and furanose) structures, which can interconvert depending on the chemical environment and specific conditions.

[0092] The 2DG compound as used herein may refer to the linear form and to the cyclic (ring) form as is further shown herein below.

[0093] In accordance with the present disclosure, reference to 2DG compound encompasses any tautomer thereof or isomer thereof.

[0094] The 2DG compound as described herein comprises one or more isotopically substituted hydrogen atom is referred herein as a "labeled compound," “isotopically enriched 2DG compound” or “isotopologue 2DG compound”.

[0095] In some examples, isotopologue 2DG compound may be employed in the diagnosis and prognosis of pathological conditions.

[0096] In accordance with some other aspects, it is provided a 2DG compound comprising one or more isotopically substituted hydrogen atoms for use in a method of diagnosing a condition or disease in a subject.

[0097] The term "isotopically substituted hydrogen atom" or "isotopically labeled hydrogen atom" is meant to encompasses a hydrogen atom in the 2DG compound that has been replaced / substituted with a different isotope of hydrogen. The different isotope of hydrogen has an atomic mass which is different than the atomic mass of the prevalent naturally abundant isotope of the same atom. Due to different number of neutrons in the nuclei, the atomic mass of an isotopically labeled atoms is different. The total number of neutrons and protons in the nucleus represents its isotopic number. In the context of this disclosure, the term "isotope labeling" (or "isotopically substituted atom") explicitly excludes radioactive labeling. In other words, the present disclosure pertains solely to stable isotopes and excludes the use of radioactive isotopes in the described compounds.

[0098] Natural hydrogen has two stable (non-radioactive) isotopes, hydrogen-1 (H-l or H or hydrogen), which represents the majority of naturally occurring hydrogen, and hydrogen-2 (H-2 or2H or D or deuterium), which is less common. Each of H-l or D has 1 proton, hydrogen has no neutrons and deuterium has 1 neutron.

[0099] The isotopically labeled hydrogen or isotopically substituted hydrogen atom refers in some examples to2H (D, deuterium).

[0100] In some examples, the 2DG compound comprises one or more deuterium atoms.

[0101] When referring to a compound comprising at least one isotopically substituted atom (i.e. the isotopologue 2DG compound), it should be understood to include compounds in which the isotopically substituted atoms are present at levels above their natural abundance. In other words, the isotopologue 2DG compound is isotopically enriched with deuterium (2H).

[0102] In embodiments, the isotopic enrichment of the compound is between about 0.015% and about 99.9%. Thus, a compound as described herein may exhibit varying degrees of isotopic enrichment.

[0103] Unless otherwise stated, the terms compound, labeled compound or isotopically substituted compound, refers to a 2DG compound in which one or more hydrogen atom(s) was replaced (also denoted herein as substituted or labelled) with one or more (at least one) deuterium (2H) atom.

[0104] It should be noted that the present disclosure also encompasses such 2DG compounds, which are optionally, isotopically substituted with one or more additional atom, such as nitrogen or carbon atoms.

[0105] In some embodiments, the 2DG compound of the invention comprises at least one substituted hydrogen atom, at times at least two substituted hydrogen atoms, at times at least three substituted hydrogen atoms, at times at least four substituted hydrogen atoms, at times at least five substituted hydrogen atoms, at times at least six substituted hydrogen atoms, at times even at least seven substituted hydrogen atoms. As noted the hydrogen atom(s) is substituted by deuterium atom.

[0106] In some embodiments, the 2-deoxy-D-glucose compound comprises one2H atom. In some embodiments, the compound is [2H] 2-deoxy-D-glucose.

[0107] In some embodiments, the 2-deoxy-D-glucose compound comprises two2H atoms. In some embodiments, the compound is [2H2]2-deoxy-D-glucose.

[0108] In some embodiments, the 2-deoxy-D-glucose compound comprises three2H atoms. In some embodiments, the compound is [2H3]2-deoxy-D-glucose.

[0109] In some embodiments, the 2-deoxy-D-glucose compound comprises four2H atoms. In some embodiments, the compound is [2H4]2-deoxy-D-glucose.

[0110] In some embodiments, the 2-deoxy-D-glucose compound comprises five2H atoms. In some embodiments, the compound is [2H5]2-deoxy-D-glucose.

[0111] In some embodiments, the 2-deoxy-D-glucose compound comprises six2H atoms. In some embodiments, the compound is [2H6]2-deoxy-D-glucose.

[0112] In some embodiments, the 2-deoxy-D-glucose compound comprises seven2H atoms. In some embodiments, the compound is [2H?]2-deoxy-D-glucose

[0113] In some embodiments, the 2-deoxy-D-glucose compound comprises eight2H atoms. In some embodiments, the compound is [2H8]2-deoxy-D-glucose

[0114] In some embodiments, the compound is or comprises at least one of [2H]2-deoxy-D- glucose (one deuterium atom), [2H2]2-deoxy-D-glucose (two deuterium atoms), [2H3]2- deoxy-D-glucose (three deuterium atoms), [2H4]2-deoxy-D-glucose (four deuterium atoms), [2H5]2-deoxy-D-glucose (five deuterium atoms), [2H6]2-deoxy-D-glucose (six deuterium atoms), [2H7]2-deoxy-D-glucose (seven deuterium atoms), [2Hs]2-deoxy-D- glucose (eight deuterium atoms) or a combination thereof.

[0115] As is well understood, the isotopic substitution of specific atoms in a compound described herein can be achieved using techniques known to those skilled in the art, such as synthesizing the compound from isotopically enriched reactants or by directly enriching specific nuclei of the compound with isotopes. These atom substitutions render the 2DG compounds particularly useful for MR applications.

[0116] Magnetic resonance (MR) methods, unlike positron emission tomography (PET), are not associated with ionizing radiation and do not require the use of a radioactive contrast agent such as FDG. Consequently, the application of a non-radioactive, deuterium-labeled 2DG in MR methods presents a safer alternative to FDG-PET examinations.

[0117] Hence, in accordance with some aspects, the present disclosure provides a compound comprises at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, |2Hr>|2- deoxy-D-glucose, [2H7]2-deoxy-D-glucose, [2H8]2-deoxy-D-glucose or a combination thereof for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image.

[0118] As described herein, the isotopologue compound is proposed as a promising candidate for the diagnosis of various diseases and conditions.

[0119] In some embodiments which may be considered as aspects of the present disclosure, the compound comprising at least one of [2H]2-deoxy-D-glucose, [2H2]2- deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2Hs]2-deoxy-D- glucose, [2H6]2-deoxy-D-glucose, [2H?]2-deoxy-D-glucose, [2H8]2-deoxy-D-glucose or a combination thereof is for use in a method of diagnosing a condition or disease in a subject.

[0120] In some examples, the compound is or comprises [2H]2-deoxy-D-glucose.

[0121] In accordance with some aspects, the present disclosure provides [2H]2-deoxy-D- glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0122] In some examples, the compound is or comprises [2H2]2-deoxy-D-glucose.

[0123] Hence, in accordance with some aspects, the present disclosure provides [2H2]2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D2]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0124] In some examples, the compound is or comprises [2H3]2-deoxy-D-glucose.

[0125] Hence, in accordance with some aspects, the present disclosure provides [2H3]2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D3]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0126] In some examples, the compound is or comprises [2H4]2-deoxy-D-glucose.

[0127] Hence, in accordance with some aspects, the present disclosure provides [2H4]2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D4]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0128] In some examples, the compound is or comprises [2H5]2-deoxy-D-glucose.

[0129] Hence, in accordance with some aspects, the present disclosure provides |2Hs|2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D5]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0130] In some examples, the compound is or comprises [2H5]2-deoxy-D-glucose.

[0131] Hence, in accordance with some aspects, the present disclosure provides [2Hs]2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D6]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0132] In some examples, the compound is or comprises [2H7]2-deoxy-D-glucose.

[0133] Hence, in accordance with some aspects, the present disclosure provides [2H?]2- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [D7]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0134] In some examples, the compound is or comprises [2Hs]2-deoxy-D-glucose.

[0135] Hence, in accordance with some aspects, the present disclosure provides 12H« 12- deoxy-D-glucose for use in a method of acquiring at least one MR spectrum and / or at least one MR image. In some embodiments which may be considered as aspects of the present disclosure, the compound [Ds]2-deoxy-D-glucose is for use in a method of diagnosing a condition or disease in a subject.

[0136] The position at which the one or more hydrogen atoms is substituted is not limited to a specific position.

[0137] In accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0138] In accordance with some aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xe, X7, Xs is2H (D). As described herein, the compounds represented by a cyclic form as in the compound represented by Formula (I) encompass the cyclic form as well as the linear form represented below by Formula (F).

[0139] As appreciated, both forms may be in equilibrium under appropriate conditions. In addition, the compound represented by Formula (I) and / or Formula (F) encompasses any isomer thereof.

[0140] In accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (F): or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0141] In accordance with some aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (F) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0142] The compound represented by Formula (I) and / or (F) encompasses any isomer thereof.

[0143] As also described herein below, the term isomer thereof as used herein includes stereoisomers (e.g., D- and L-glucose) and / or anomers (e.g., a- and -forms).

[0144] In some examples, the compound represented by Formula (I) and / or (F) comprises L-glucose.

[0145] In some examples, the compound represented by Formula (I) and / or (F) comprises D-glucose. In accordance with some embodiments that may be considered as aspects of the present disclosure, the compound is represented by Formula (II). In accordance with some embodiments that may be considered as aspects of the present disclosure, the compound is represented by Formula (II’).

[0146] In accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of X1, X2, X3, x4, X5, X6, X7, X8is2H (D).

[0147] In accordance with some aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, X8is2H (D).

[0148] In accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (IF): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of X1, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0149] In accordance with some aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (II’) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X&, X7, X8is2H (D).

[0150] In accordance with some embodiments that may be considered as aspects of the present disclosure, the compound is represented by Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of X1, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0151] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (III) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D). In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (III) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, X8is2H (D).

[0152] As described, the present disclosure encompasses both the keto and enol forms of the compounds.

[0153] The compound described herein may refer in some examples to a mixture of tautomer’s represented for example Formula (III) and Formula (III’) as shown below: or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0154] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one MR spectrum and / or at least one MR image, wherein the compound is a represented by Formula (III’) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0155] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a disease in a subject, wherein said compound is represented by Formula (III’) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xe, X7jX8is2H (D).

[0156] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0157] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), two of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0158] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), three of X1, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0159] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), four of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0160] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), five of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0161] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), six of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0162] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), seven of X1, X2, X3, X4, X5, X6, X7, X8is2H (D).

[0163] In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), eight of X1, X2, X3, X4, X5, X6, X7, X8is2H (D). In accordance with some embodiments that may be considered as aspects of the present disclosure, in the compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), one or more of the following (i) one of Xi, X2, X3, X4, X5, Xe, X7, and X8is2H, (ii) two of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (iii) three of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (iv) four of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (v) five of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vi) six of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vii) seven of Xi, X2, X3, X4, X5, Xe, X7jand X8is2H, (viii) eight of Xi, X2jX3jX4jX5, Xg, X7jand X8is2H or a combination thereof.

[0164] For the sake of simplicity, the compounds below are represented by the closed ring / cyclic form. However, it should be noted that all the compounds provided herein below by the closed ring form also encompass the respective linear form as described herein and exemplified above for compound having Formula (I’) and / or (IF) and / or (III’).

[0165] In accordance with some embodiments that may be considered as aspects of the present disclosure, the compound is represented by Formula (IV): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0166] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof. In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0167] It should be noted that in accordance with the present disclosure, a compound represented by Formula (IV) encompasses any isomer thereof.

[0168] In some examples, the compound is represented by Formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0169] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (V) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0170] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (V) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0171] In accordance with some embodiments that may be considered as aspects of the present disclosure, the compound is a compound represented by Formula (VI):

[0172] or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0173] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (VI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0174] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (VI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0175] It should be noted that in accordance with the present disclosure, a compound represented by Formula (VI) encompasses any isomer thereof. The isomer includes tautomer of compounds represented by Formula (VII).

[0176] In some examples, the compound is represented by Formula (VII): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0177] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0178] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0179] In some examples, the compound is 2-deoxyglucose-6,6-D2.

[0180] In some examples, the compound is represented by Formula (VIF): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0181] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (VIF) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0182] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (VIF) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0183] In some examples, the compound is D-Arabino-2-deoxyhexose-dl. In some examples, the compound is characterized by a CAS No.: 188004-07-1.

[0184] In some examples, the compound is represented by Formula (VIII): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0185] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (VIII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0186] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (VIII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0187] In some examples, the compound is represented by Formula (IX): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0188] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (IX) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0189] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (IX) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0190] In some examples, the compound is 2-deutero-2-deoxy-D-glucose.

[0191] In some examples, the compound is represented by Formula (X): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0192] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (X) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0193] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (X) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0194] In some examples, the compound is represented by Formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0195] Hence, in accordance with some aspects, the present disclosure provides a compound for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image, wherein the compound is a represented by Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0196] In accordance with some other aspects, the present disclosure provides a compound for use in a method of diagnosing a subject, wherein said compound is represented by Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0197] In accordance with some examples, the compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2- deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D- glucose, [2H?]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose or a combination thereof, (c) [2Hs]2-deoxy-D-glucose, (d) represented by Formula (I) or Formula (I’) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (IIF), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, Xs is2H (D), (e) represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

[0198] The labeled compound described herein may comprise, an additional isotopically labeled atom, further to the labeled hydrogen atom. In some embodiments, the compound comprises at least one isotopically labeled nitrogen atom,15N and / or at least one isotopically labeled carbon atom,13C.

[0199] The isotopically substituted compound or compound of the present disclosure may be used in the form of a composition or a kit. Thus, the present disclosure further provides a composition comprising at least one compound detailed herein. It is noted that the composition may comprise at least one compound of the invention in a mixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0200] Compositions and compounds of the invention may be administrated by any known method in the art. These include, but are not limited to, injection (e.g., using a subcutaneous, intramuscular, intravenous, intraarterial, or intradermal injection), dermal, intranasal administration and oral administration. The amount of a compound according to the invention that may be used in a formulation of the invention, or generally administered to a subject, may be determined by the practitioner to provide an effective diagnosis, e.g., imaging.

[0201] Compositions administrable to a subject include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association a compound of the invention with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, anti-oxidants, and wetting agents.

[0202] Compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration.

[0203] The present disclosure further provides a composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for diagnosis as detailed herein. For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g. gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulizers or insufflators.

[0204] The present disclosure further provides a kit comprising at least one labeled compound of the invention and means for administering the at least one labeled compound and optionally instructions for use the kit in methods described herein.

[0205] As described above, 2DG compounds including the isotopically substituted 2DG compound described herein do not have a hydroxyl at C-2 as this hydroxyl is replaced by a hydrogen atom (in 2DG) or with a deuterium atom in one or more of the compounds described herein. The hydroxyl replacement (either to a hydrogen atom or a deuterium atom) does not interfere with the first step of glycolysis and hence 2DG compound or labeled compound undergo phosphorylation mediated by hexokinase at the C-6 hydroxyl to 2DG 6-phosphate and / or deuterated 2DG 6-phosphate (at times phosphorylated product). However, further metabolism of 2DG 6-phosphate and / or deuterated 2DG 6- phosphate to D-fructose 6-phosphate is not possible.

[0206] The phosphorylated product of any of the compounds described herein is denoted as a metabolite of the 2DG isotopically substituted / labeled compound.

[0207] In some examples, the metabolite is at least one of [2H]2-deoxy-D-glucose-6- phosphate, [2H2]2-deoxy-D-glucose-6-phosphate, [2H3]2-deoxy-D-glucose-6-phosphate, [2Hy|2-deoxy-D-glucose-6-phosphate, [2H5]2-deoxy-D-glucose-6-phosphate, 12Hr, |2- deoxy-D-glucose-6-phosphate, [2H7]2-deoxy-D-glucose-6-phosphate, |2Hx|2-dcoxy-D- glucose-6-phosphate or a combination thereof.

[0208] In some examples, the metabolite is [2H]2-deoxy-D-glucose-6-phosphate.

[0209] In some examples, the metabolite is [2H2]2-deoxy-D-glucose-6-phosphate.

[0210] In some examples, the metabolite is [2H3]2-deoxy-D-glucose-6-phosphate. In some examples, the metabolite is [2H4]2-deoxy-D-glucose-6-phosphate.

[0211] In some examples, the metabolite is [2H5]2-deoxy-D-glucose-6-phosphate.

[0212] In some examples, the metabolite is [2H6]2-deoxy-D-glucose-6-phosphate.

[0213] In some examples, the metabolite is [2H7]2-deoxy-D-glucose-6-phosphate.

[0214] In some examples, the metabolite is [2H8]2-deoxy-D-glucose-6-phosphate.

[0215] In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (I). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (II). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (III). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (IV). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (V). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (VI). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (VII). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (VIII). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (IX). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (X). In some examples, the metabolite is a phosphorylation product of a compound represented by Formula (XI).

[0216] In accordance with some examples, the metabolite is represented by Formula (XII): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0217] In accordance with some examples, the metabolite is represented by Formula

[0218] (XIII): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0219] In accordance with some examples, the metabolite is represented by Formula (XIV): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D).

[0220] In accordance with some examples, the metabolite is represented by Formula

[0221] (XV):

[0222] or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0223] In accordance with some examples, the metabolite is represented by Formula

[0224] (XVI): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0225] In some examples, the metabolite is or comprises [2H2]2-deoxy-D-glucose-6- phosphate.

[0226] In accordance with some examples, the metabolite is represented by Formula

[0227] (XVII):

[0228] or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0229] In accordance with some examples, the metabolite is represented by Formula (XVIII): or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0230] In some embodiments that may be considered as aspects of the invention, the compound of the present disclosure as well as a metabolite thereof is for use in a method of diagnosis a subject. In some embodiments that may be considered as aspects of the invention, the 2DG labeled compound and / or a metabolite thereof is for use in a method of diagnosis a condition or a disease in a subject.

[0231] In some embodiments that may be considered as aspects of the invention, the 2DG labeled compound and / or a metabolite thereof is for use in a method of monitoring a disease state in the subject.

[0232] In some embodiments that may be considered as aspects of the invention, the 2DG labeled compound and / or a metabolite thereof is for use in a method of determining a site of a disease in the subject. In some embodiments that may be considered as aspects of the invention, the 2DG labeled compound and / or a metabolite thereof is for use in a method of (i) diagnosis a condition or a disease in a subject, (ii) monitoring a disease state in the subject or (iii) determining a site of a disease in the subject, wherein the 2DG labeled compound is at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2- deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2He]2-deoxy-D-glucose, [2H?]2-deoxy-D- glucose, [2H8]2-deoxy-D-glucose or a combination thereof and wherein the metabolite is at least one of [2H]2-deoxy-D-glucose-6-phosphate, [2H2]2-deoxy-D-glucose-6-phosphate, [2H3]2-deoxy-D-glucose-6-phosphate, [2H4]2-deoxy-D-glucose-6-phosphate, |2Hs |2- deoxy-D-glucose-6-phosphate, [2H6]2-deoxy-D-glucose-6-phosphate, [2H?]2-deoxy-D- glucose-6-phosphate, [2H8]2-deoxy-D-glucose-6-phosphate or a combination thereof.

[0233] In some embodiments that can be considered as aspects of the present disclosure, the 2DG labeled compound and / or a metabolite thereof is for use in a method of (i) diagnosis a condition or a disease in a subject, (ii) monitoring a disease state in the subject or (iii) determining a site of a disease in the subject, wherein the 2DG labeled compound is |2Hx 12- deoxy-D-glucose and the metabolite is or comprises [2H8]2-deoxy-D-glucose-6-phosphate.

[0234] As described herein, the compounds of the disclosure are applicable to use in MR methods such as MRS and / or MRI.

[0235] In accordance with some aspects, it is provided a method of acquiring at least one MR spectrum and / or MR image from a subject, the method comprises monitoring a signal from a subject using an MR g method, the subject having been administered at least one compound, a composition or a kit comprising the at least one compound to thereby acquire at least one MR image, wherein the compound is an isotopically substituted compound.

[0236] MRS and MRI methods make use of magnetic fields, radio waves, and in case of MRI also field gradients to generate at least one spectrum or at least one image of the organs in the body. The methods of the invention are applicable by using a magnetic resonance scanner (an MRI scanner). Magnetic resonance signals obtained by the methods described herein may be converted by conventional manipulations into 2-, 3- or 4-dimensional data (spatial and temporal) including metabolic, kinetic, diffusion, relaxation, and physiological data. Magnetic resonance spectroscopy may be conducted by any suitable probe, for example using a2H Radio Frequency coil. Detecting such signal using MR can be done by using for example specialized probes for acquiring the signal. For example, diagnosis of breast cancer may be done by subjecting a subject to magnetic field and using specific MR sequences and equipment (e.g. probes) to acquire signal from the breast region of a subject.

[0237] In another example, diagnosis of an ischemic tissue in the brain or body may be done by subjecting a subject to magnetic field and using specific MR sequences and equipment (e.g. probes, i.e. radio-frequency circuits, i.e. radio-frequency coils) to acquire signal from the brain or the body region of a subject.

[0238] In accordance with some aspects, it is provided a method of imaging a subject, the method comprises monitoring a signal from a subject using an MR imaging method, the subject having been administered at least one compound, a composition or a kit comprising the at least one compound to thereby acquire at least one MR image, wherein the compound is deuterium substituted compound.

[0239] In accordance with some aspects, it is provided a method of imaging a subject, the method comprises monitoring a signal from a subject using an MR imaging method, the subject having been administered at least one compound, a composition or a kit comprising the at least one compound to thereby acquire at least one MR image of the at least one compound or a metabolite thereof, wherein the compound is deuterium labeled 2DG.

[0240] In some examples, in the methods described herein, the subject has been administered with at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D- glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose or a combination thereof. In some examples, the subject has been administered with [D8]2-deoxy-D-glucose.

[0241] In some examples, in the methods described herein, the subject has been administered with [2H]2-deoxy-D-glucose.

[0242] In some examples, in the methods described herein, the subject has been administered with [2H2]2-deoxy-D-glucose.

[0243] In some examples, in the methods described herein, the subject has been administered with [2H3]2-deoxy-D-glucose. In some examples, in the methods described herein, the subject has been administered with [2H4]2-deoxy-D-glucose.

[0244] In some examples, in the methods described herein, the subject has been administered with [2H5]2-deoxy-D-glucose.

[0245] In some examples, in the methods described herein, the subject has been administered with [2H6]2-deoxy-D-glucose.

[0246] In some examples, in the methods described herein, the subject has been administered with [2H7]2-deoxy-D-glucose.

[0247] In some examples, in the methods described herein, the subject has been administered with [2Hg]2-deoxy-D-glucose.

[0248] In some examples, in the methods described herein the subject has been administered with at least one compound represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xe, X7, Xx is2H (D), a composition or a kit comprising the at least one compound.

[0249] In some examples, in the methods described herein the subject has been administered with at least one compound represented by Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xx is2H (D), a composition or a kit comprising the at least one compound.

[0250] In some examples, in the methods described herein the subject been administered at least one compound represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), in which one, two, three, four, five, six, seven or eight of Xi, X2, X3, X4, X5, Xg, X7, and Xx is2H.

[0251] In some examples, in the methods described herein the subject been administered at least one compound represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof. In some examples, in the methods described herein the subject been administered at least one compound represented by Formula (IV), or Formula (V) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0252] In some examples, in the methods described herein the subject been administered at least one compound represented by Formula (VI), or Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0253] In some examples, the subject been administered at least one compound represented by Formula (VIII), or Formula (IX) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0254] In some examples, the subject been administered at least one compound represented by Formula (X), or Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0255] In another aspect, the invention provides a method for imaging at least one body region of a subject, the method comprising (i) administering to the subject an effective amount of a deuterium labeled 2DG, a composition or a kit comprising the at least one compound and (ii) imaging at least one body region. In some embodiments, the method comprises imaging full body. It should be noted that full body imaging (also termed as whole-body imaging) refers to display of the entire body in a single imaging examination.

[0256] In some embodiments, the imaging methods comprises monitoring a signal from a subj ect using an MR imaging method, wherein the compound is at least one of [2H] 2-deoxy- D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, [2Hs]2-deoxy- D-glucose or a combination thereof.

[0257] In some embodiments, the imaging method comprises monitoring a signal from a subject using an MR imaging method, wherein the subject has been administered with a compound being [D8]2-deoxy-D-glucose. In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (I) or Formula (I’) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), in which one, two, three, four, five, six, seven or eight of Xi, X2, X3, X4, X5, Xg, X7, and Xx is2H.

[0258] In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0259] In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (IV), or Formula (V) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0260] In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (VI), or Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0261] In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (VIII), or Formula (IX) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0262] In some embodiments, the imaging methods comprise monitoring a signal from a subject using an MR imaging method, wherein subject has been administered with at least one compound represented by Formula (X), or Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

[0263] As described herein, the methods may include a monitoring step. As described herein, monitoring and detection a signal from the compounds and / or a metabolite thereof for the invention may be performed by any non-invasive method, preferably, as detailed herein, by MRS, MRI and magnetic resonance spectroscopic imaging.

[0264] It should be noted that monitoring a signal encompasses collecting data possibly in a form of an MR image or a MR spectrum from a subject including any region of the subject body. The term "monitoring" as used herein is meant to encompass the quantitative and / or qualitative detection and observation of a signal originating from the compound of the invention being administered to the subject or a metabolite thereof as described herein. Monitoring of the signal originating from the compound of the invention encompasses monitoring / detecting the distribution of the compound in at least one body region and / or full body as further described herein.

[0265] It should be noted that as described herein, monitoring may encompass quantitative and / or qualitative detection and observation of a signal obtained prior to administration of a compound of the invention.

[0266] In some examples, the MR method comprises monitoring uptake of the deuterated labeled compound of the present disclosure. In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite of the present disclosure.

[0267] In some examples, the method comprises monitoring uptake of the deuterated labeled compound of the present disclosure by acquiring at least one2H MR image from a subject. In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite of the present disclosure by acquiring at least one2H MR image from a subject.

[0268] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the labeled metabolite is at least one of [2H]2-deoxy-D-glucose-6-phosphate, [2H2]2-deoxy-D-glucose-6-phosphate, [2H3]2-deoxy-D-glucose-6-phosphate, [2H4]2- deoxy-D-glucose-6-phosphate, [2H5]2-deoxy-D-glucose-6-phosphate, [2H6]2-deoxy-D- glucose-6-phosphate, [2H7]2-deoxy-D-glucose-6-phosphate, [2H8]2-deoxy-D-glucose-6- phosphate or a combination thereof. In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H]2-deoxy-D-glucose-6-phosphate.

[0269] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H2]2-deoxy-D-glucose-6-phosphate.

[0270] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H3]2-deoxy-D-glucose-6-phosphate.

[0271] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H4]2-deoxy-D-glucose-6-phosphate.

[0272] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H5]2-deoxy-D-glucose-6-phosphate.

[0273] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H6]2-deoxy-D-glucose-6-phosphate.

[0274] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is or comprises [2H7]2-deoxy-D-glucose-6-phosphate.

[0275] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the labeled metabolite is or comprises [2H8]2-deoxy-D-glucose-6-phosphate.

[0276] In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the metabolite is a phosphorylation product of a compound represented by one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI) or any combination thereof. In some examples, the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one2H MR image from a subject, wherein the labeled metabolite is represented by Formula (XII)- (XVIII).

[0277] As appreciated, MR imaging rely on averaging, i. e. , accumulating the same data multiple times for improving the image signal-to-noise ratio (SNR), that is often required to enable high spatiotemporal resolution.

[0278] The relaxation times of the sampled atom, e.g. deuterons or protons, respectively, specifically their T2*, T2, and Ti, limit and dictate the MRI acquisition parameters and the number of averages that can be acquired per unit time.

[0279] The term relaxation describes how signals change with time. In general signals deteriorate with time, becoming weaker and broader. The deterioration reflects the fact that the MR signal, which results from nuclear magnetization, arises from the over-population of an excited state. Relaxation is the conversion of this non-equilibrium population to a normal population. In other words, relaxation describes how quickly spins "forget" the direction in which they are oriented. The deterioration of an MR signal is analyzed in terms of two separate processes, each with their own time constants. One process, associated with Ti, is responsible for the loss of signal intensity. Thus, the effective lifetime of the compound is dictated by the compound's Ti relaxation.

[0280] The free induction decay (FID) of the deuterium signal of the species with the longest T2*, T2 or Ti will, in principle, limit the repetition time and the number of averages that can be recorded per unit time in a manner that will be dependent on the pulse sequence used for recording the image. The relaxations times will always, from first principles, follow the order Ti> T2> T2* , i. e. , Ti is always the longest relaxation time constant.

[0281] As shown in Table 1 in the examples that form a part of this application, Ti of deuterium nuclei attached to a ring carbon (including sugars) is significantly shorter (about 6- to 10-fold) than that of deuterium nuclei in water (HDO). Hence, it was suggested that it is possible to use compounds having2H directly bound to carbon atoms and hence to decrease (reduce) the compound's Ti. In this way it has been suggested by the inventors to dramatically reduce the MR repetition time, allowing acquisition of multiple MR scans, hence improving SMR and improving clinical conclusions. Based on these findings, it was suggested that the application of 2DG compounds labelled with one or more deuterium atoms as described herein, allow on one hand very fast deuterium imaging (for example in the range of seconds or minutes, e.g. about 30 seconds, about 1 minute, about 2 minutes) and on the other hand high SNR. It should be noted that application of [6,6-D2]D-glucose is often challenging due to the need of a long acquisition time, usually more than 15 min.

[0282] Without being bound by theory, it was suggested that the T1 relaxation time of the 2DG deuterated compound, for example [2H8]2-deoxy-D-glucose, allow reduction of the acquisition time of the images and increase the images spatiotemporal resolution. These advantages make the compounds described herein to be clinically practical.

[0283] In some embodiments, the compound is characterized by a Ti relaxation of a2H nucleus of between about 5 milliseconds to about 400 milliseconds, at times between about 5 milliseconds and about 300 milliseconds, at times between about 5 milliseconds and about 200 milliseconds, at times between about 5 milliseconds and about 100 milliseconds, at times between about 5 milliseconds and about 60 millisecond.

[0284] In some examples, the methods comprise acquiring at least one MR spectrum from a subject. In some examples, the method comprises acquiring at least one2H MR spectrum from a subject.

[0285] The methods described herein may be of value as they reduce the acquisition time of a deuterium image and increase the signal to noise ratio of a deuterium image. It was suggested that the methods described herein may reduce / attenuate / decrease the signal acquired from naturally abundant signals of deuterium in water (HDO).

[0286] In some examples, the method comprises acquiring at least one MR image from a subject. In some examples, the method comprises acquiring at least one2H MR image from a subject. In some examples, the method comprises acquiring at least one2H MR image from a subject with an acquisition time of at most about 5 min, at most about 4 min., at times at most about 2 min. In some examples, the method comprises acquiring at least one2H MR image from a subject with a spatial resolution of between about 2mm and about 20mm, at times between about 2mm and about 10mm, at times between about 2mm and about 5 mm (in plane resolution). As noted herein, compounds of the invention and / or metabolites thereof are suitable for imaging and subsequent diagnosis. Diagnosis is required for the identification of specific subjects (sub-population) suffering from a specific disorder or condition.

[0287] In the context of the present disclosure, when referring to diagnosis and specifically to MRS and / or MRI diagnosis it should be understood to encompass a medical imaging technique used in radiology to provide spectra or to form pictures (images) of the anatomy and the physiological processes of the body in both health and disease.

[0288] As described herein, the 2DG labeled compound and / or a metabolite thereof may be for use in diagnosis of a condition of a disease.

[0289] In some embodiments, the method of the invention is utilized for determining a site of a disease or condition and / or for distinguishing between healthy and abnormal tissues or organs. In some embodiments, the method is used for distinguishing or differentiating between malignant and benign tumors.

[0290] In a further aspect, the invention provides a method for diagnosis of a disease or condition in a subject, the method comprising administering to the subject a diagnostically effective amount of a compound according to the invention and monitoring the subject or a body region of the subject to thereby identify body regions susceptible of having a disease or a condition. In some examples, the body regions susceptible of having a disease or a condition are associated with accumulation of a metabolite as described herein.

[0291] In another aspect, the invention provides a method for diagnosis of a disease or condition in a subject, the method comprising administering to the subject a diagnostically effective amount of a compound according to the invention and monitoring the subject or a body region of the subject to thereby identify body regions in which the compound or a metabolite thereof are accumulated.

[0292] In another aspect the invention provides a method for diagnosing a disease or condition or disease in a subject, said method comprising: administrating to the subject a diagnostically effective amount of a labeled compound and monitoring the compound or a metabolite thereof, thereby diagnosing the condition or disease in the subject.

[0293] In another aspect the invention provides a method for diagnosis of a disease or condition in a subject, the method comprising (i) administering to the subject a diagnostically effective amount of at least one 2DG compound and (ii) imaging and / or acquiring a spectrum of the subject or a body region of the subject to thereby identify body regions in which the compound, or any metabolite thereof has been localized, wherein the 2DG compound is deuterium-labeled 2DG.

[0294] The term "diagnostically effective amount" refers to the quantity of a substance (e.g. 2DG compound as described herein) that is sufficient to produce a measurable effect or result for diagnostic purposes, without causing harm or toxicity. It is the dose needed to achieve the desired outcome, such as detecting a disease, condition, while ensuring patient safety.

[0295] The term "diagnosing a condition or disease" is meant to encompass any process of investigating, identifying, recognizing, assessing a condition, disease or disorder of the mammalian body, including all tissues and structures in the body (for example a tissue or blood vessels). A diagnosis according to the present disclosure using a compound described herein includes, but is not limited to objective quantitative diagnosis of a condition or disease, prognosis of a condition or disease, genetic predisposition of a subject to have a condition or disease, efficacy of treatment of a therapeutic agent administered to a subject (either continually or intermittently), quantification of neuronal function, diagnosis and evaluation from the fields of oncology, neurology, psychiatry, cardiology, vascular, infection and inflammation of a therapeutic agent activity, determination of drug efficacy, characterization of masses, tumors, cysts, blood vessel abnormalities, and internal organ function; quantification of brain, kidney, liver, and other organs’ metabolic function; examination of the action, response or progress of therapy (involving medicinal and non- medicinal treatment) aimed at alleviating or curing at least one of oncology, neurology, psychiatry, cardiology, vascular, infection and inflammation diseases and disorders.

[0296] In some embodiments, the methods of the invention comprise a step of detecting a signal prior to administration of the compound. This may be possible by exposing the subject to magnetic field using MR to obtain a detectable signal. In some embodiments, prior to administration of the compounds of the invention, at least one anatomical1H image may be acquired.

[0297] In some embodiments, prior to administration of the compounds of the invention, suspected regions of having a disease or condition may be recorded using similar conditions to the conditions at which the compound is acquired to obtain base-line information. In some embodiments, the method comprising prior to the administration step, acquiring at least one2H spectrum and / or at least one image from the subject's body or any one or more regions thereof. Monitoring the subject or any subject's region may be subjected to signal analysis of the MR spectrum or spectra and / or image processing of the acquired image(s). The results of the spectrum and / or image is indicative for the methods described herein.

[0298] In some embodiments, the method comprising comparing at least one parameter obtained from the at least one2H MR spectrum and / or at least one2H MR image to at least one parameter obtained from the at least one2H MR spectrum and / or at least one2H MR image in the same subject at an earlier point in time, wherein the comparison permits diagnosis of the disease.

[0299] In some embodiments, the method comprising comparing at least one parameter obtained spectrum and / or image analysis to at least one parameter obtained from spectrum and / or image analysis in the same subject obtained at an earlier point in time, wherein the comparison permits diagnosis of the disease. The earlier time point may be for example, prior to compound administration.

[0300] The compound, compositions or kits used according to the invention may be utilized for imaging a region or organ of a subject's body after or during treatment or otherwise state of a disease, it may be further utilized in determining severity of the disease, for, e.g., enabling determination of treatment effectiveness and continued treatment.

[0301] Therefore, in accordance with some aspects, it is provided a method for monitoring a disease state in a subject.

[0302] Monitoring a disease state as used herein refers to a process of tracking the progression of a disease or condition in a subject.

[0303] In such a method, the subject is administered with the compound of the present disclosure, the subject's body or any one or more regions thereof is imaged, to obtain at least one imaging parameter indicative of the disease or disorder state, and comparing said at least one imaging parameter to at least one parameter obtained from said subject at an earlier point in time or upon identification of, e.g., at least one symptom associated with said disease or disorder, wherein the comparison permits determining the progression of the disease or disorder state. Effective monitoring, made possible by utilization of a compound of the invention, involves obtaining multiple parameters indicative of a disease state and progression at various points in time, prior to, during or after commencement of treatment, and comparing the collected data to determine any one therapeutic parameter. The monitoring may be conducted over a period of time, for example every few days or weeks, once a week, once a month, at the onset of treatment and at any time thereafter, etc.

[0304] In a further aspect, the invention provides a method for determining the severity of a disease or disorder in a subject, the method comprising administering to said subject a compound according to the invention, imaging the subject’s body or region thereof to obtain at least one imaging parameter (e.g., indicative of the state of the disease or disorder), and comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement, wherein the comparison permits determining the severity of the disease or disorder in the subject.

[0305] In another aspect the invention provides a method for determining the effectiveness of a therapeutic treatment of a disease or disorder in a subject, the method comprising administering to said subject a compound according to the invention, imaging the subject’s body or region thereof to obtain at least one imaging parameter (e.g., indicative of the state of the disease or disorder), and comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement, wherein the comparison permits determining the effectiveness of the therapeutic treatment of the disease or disorder in the subject.

[0306] The determination of the effectiveness of treatment may be achieved at the end of treatment or at any point in time during the treatment period. Generally, and depending on the disease and disease state, the effectiveness is indicated by any one or more changes in the disease state or any symptom associated therewith, such as decreased proliferation.

[0307] In some embodiments, the methods of the invention are used for evaluating the effectiveness of drug treatment in cancer treatment, for example, in evaluating the ability of a drug to reduce the size of a tumor or to prevent the tumor from growing, wherein the method comprises imaging the tumor with a compound according to the invention, as disclosed herein, and measuring the size of the tumor; administering the drug to the subject to affect at least one of reduction in the size of the tumor and prevention of growth of the tumor; re-imaging the tumor with the same or different compound and measuring the size of the tumor, and comparing the size of tumor after administration of the drug to the size of the tumor prior to administration of the drug. As compounds of the invention are not intended nor suitable for therapeutic use, the "drug" used for treatment is a material different from any compound used for diagnosis and accordance with the invention.

[0308] In some examples, the disease or condition is selected from oncology, neurology, psychiatry, cardiology, vascular, infection and inflammation.

[0309] Given the observed increased glycolysis in certain pathologies, for example, proliferative disease, the labeled 2DG described herein may be applicable in the diagnosis of such pathologies.

[0310] In some embodiments, the disease or condition is associated with increased glucose metabolism. There are various diseases that are associated with increased glucose metabolism and hence can be monitored using the compounds of the present disclosure and / or metabolites thereof as described herein.

[0311] In some examples, the disease or condition associated with increased glucose metabolism is a proliferative disease.

[0312] A proliferative disorder, diagnosed by utilizing compounds of the invention, is a disorder displaying cell division and growth that is not part of normal cellular turnover, metabolism, growth, or propagation of the whole organism. Unwanted proliferation of cells is seen in tumors and other pathological proliferation of cells, does not serve normal function, and for the most part will continue unbridled at a growth rate exceeding that of cells of a normal tissue in the absence of outside intervention. A pathological state that ensues because of the unwanted proliferation of cells is referred herein as a "hyper- proliferative disease" or "hyper-proliferative disorder." It should be noted that the term “proliferative disorder”, “cancer”, “tumor” and “malignancy” all relate equivalently to a hyperplasia of a tissue or organ.

[0313] Non-limiting examples of cancers include blastoma, carcinoma, lymphoma, leukemia, sarcoma, mesothelioma, glioma, germinoma, choriocarcinoma, melanoma, glioblastoma, lymphoid malignancies, squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.

[0314] In some embodiments, the disease or condition is breast cancer. In some embodiments, the disease or condition is hepatocellular carcinoma. In some embodiments, the disease or condition is a metastatic tumour in the lungs.

[0315] In some embodiments, the compound and / or metabolite described herein are applicable for use in a method of distinguishing between healthy and abnormal tissues or organs and / or distinguishing or differentiating between malignant and benign tumors. As noted herein, without being bound by theory, it was suggested that high accumulation of the metabolite described herein indicate abnormal tissues or organs and / or malignant tumors (tissue).

[0316] In some examples, the disease or condition associated with increased glucose metabolism is an inflammatory disease.

[0317] An inflammatory disorder, diagnosed by utilizing compounds of the invention, is a disorder encompassing any immune response. The inflammatory disorder may be an infectious or a non-infectious disorder. Non-infectious inflammatory disorders are any disorder which the activation of macrophages or activated macrophages play a role such as auto-immune disorders and inflammatory disorders which are not infection related, i.e. non- pathogenic, caused by other than an infectious agent (e.g. auto-antigen, hypersensitivity, wound). Not limiting examples include inflammatory diseases of the gastrointestinal tract such as Crohn's disease, inflammatory bowel disease, gastritis, colitis, ulcerative colitis, colon irritable, gastric ulcer and duodenal ulcer, inflammatory diseases of the skin such as psoriasis, inflammatory diseases of the respiratory system such as asthma, allergic rhinitis or chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, sarcoidosis, inflammatory diseases of the musculoskeletal system such as rheumatoid arthritis, osteomyelitis, osteoporosis, or neuritis, systemic sclerosis, inflammatory diseases of the kidneys such as glomerulonephritis, renal ischemia, or renal inflammation; inflammatory diseases of the nervous system such as multiple sclerosis, Alzheimer's disease and H1V-1- associated dementia; autoimmune diseases such as diabetes, type 1 and 2 diabetes mellitus and graft versus host reaction; infectious disease such as nephritis, sepsis, septic shock, endotoxic shock, adult respiratory distress syndrome; inflammatory conditions of the cardiovascular system, such as myocardial infarction, myocarditis, atherosclerosis, hypertensive cardiomyopathy, atheroma, intimal lasia or restenosis or autoimmune disorders such as Multiple Sclerosis (MS), inflammatory arthritis, rheumatoid arthritis (RA).

[0318] In some examples, the disease or condition associated with increased glucose metabolism is a cardiovascular disease. In some examples, the cardiovascular disease or condition is coronary artery disease or stroke. In some examples, the cardiovascular disease is ischemic heart disease (coronary artery disease) or stroke. In some examples, the disease or condition associated with increased glucose metabolism is a vascular disease. In some examples, the vascular disease is ischemic cerebrovascular disease.

[0319] In some examples, the disease or condition associated with increased glucose metabolism is a neurological disease. In some examples, the neurological disease is a neurodegenerative disease. In some examples, the neurodegenerative disease is Alzheimer disease. In some examples, the neurological disease is epilepsy.

[0320] In some examples, the disease or condition associated with decreased glucose metabolism is a neurological disease. In some examples, the neurological disease is a neurodegenerative disease. In some examples, the neurodegenerative disease is stroke.

[0321] In some examples, the disease or condition associated with decreased glucose metabolism is a systemic disease. In some examples, the diseases or condition cause ischemia in bodily organs or the brain. In some examples, the systemic disease or condition is diabetes or metabolic syndrome. In some examples, the ischemic condition is in the legs.

[0322] The methods of the present discourse provide a method for treating a disease or condition in a subject. The method comprises:

[0323] First (a), diagnosis of a disease or condition in a subject according to the method of the invention described above. The second step (b) involves administrating to the subject a treatment regimen based on said disease or condition thereby treating the subject.

[0324] Hence, the present disclosure provides in accordance with some aspects, a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one condition in a subject in need thereof, the method comprises diagnosis a disease or condition in a subject according to the method of the invention described above and administration to the subject a treatment regimen based on said disease or condition thereby treating the subject.

[0325] As used herein, “disease”, “disorder”, “condition” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms.

[0326] It should be noted that for the method of treatment and prevention provided in the present invention, may use therapeutic effective amount, or dosage, dependent on severity and the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is affected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient.

[0327] The term subject as used herein refers to human and non-human subjects. Specifically, the subject in accordance with the present disclosure is suspected to or suffering from a pathological disorder or a related condition.

[0328] It is understood that the interchangeably used term "associated" or “related”, when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder condition or pathology causes the second disease, disorder, condition or pathology.

[0329] As noted herein, the present disclosure relates to pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, metabolite, or physiologically functional derivative thereof.

[0330] The term "pharmaceutically acceptable salt" refers to salts derived from organic and inorganic acids of the SMC described herein. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluene sulfonate, camphorsulfonate, napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The term “pharmaceutically acceptable salt” as used herein also refers to a salt of a compound described herein having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide 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 trialkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-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. The term “pharmaceutically acceptable salt” also includes hydrates of a salt of a compound described herein.

[0331] The term “solvate” refers to an aggregate of a compound with one or more solvent molecules, such as hydrate, alcoholate (aggregate or adduct with alcohol), and the like.

[0332] The term “hydrate” refers to a compound formed by the addition of water. The hydrates may be obtained by any known method in the art by dissolving the compounds in water and recrystallizing them to incorporate water into the crystalline structure.

[0333] The term “tautomer” refers to a compound that exists in equilibrium with another compound having the same molecular formula but differing in the arrangement of atoms and the position of hydrogen atoms and / or double bonds. Tautomers interconvert via a chemical process such as proton transfer or the shifting of bonds, typically in response to changes in environmental conditions such as pH or solvent polarity. Examples include the equilibrium between the linear and cyclic forms of a monosaccharide or between keto and enol forms of a compound

[0334] "The term “isomer” refers to a compound that shares the same molecular formula with another compound but differs in the arrangement of its atoms or the spatial orientation of its functional groups. Isomers can include structural isomers (differing in the connectivity of atoms) and stereoisomers (differing in the spatial arrangement of atoms, such as enantiomers or diastereomers). Examples include D-glucose and L- glucose (enantiomers) or a-D-glucose and P-D-glucose (anomers)."

[0335] The term "metabolite" or “pharmaceutically acceptable metabolite" as used herein refers to a compound that is formed under physiological conditions to of degrading and eliminating the compounds. Oxidative metabolite may an example. Specifically, as described herein, the metabolite may be a phosphorylated compound.

[0336] The term "physiologically functional derivative" used herein relates to any physiologically acceptable derivative of a compound as described herein. The physiologically functional derivatives also include prodrugs of the compounds of the invention.

[0337] The term "about" as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. As used herein the term "about" refers to ± 10 %.

[0338] It should be noted that various embodiments of this invention may be presented in a range format. The description of a range should be considered to have specifically disclosed all the possible sub ranges as well as individual numerical values within that range inclusive the end points values. For example, description of a range such as from 1 to 6 or between 1 and 6 should be considered to have specifically disclosed sub ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6.

[0339] It should be noted that the term “at least one” refers to one or more of the following and encompasses any one of 1, 2, 3, or more of the specified information.

[0340] It is to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof. Throughout this specification and the Examples and claims which follow, unless the context requires otherwise, the word “comprise” , and variations such as “comprises” and “comprising” , will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0341] It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0342] The following examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.

[0343] It should be noted that the various embodiments and examples detailed herein in connection with various aspects of the invention may be applicable to one or more aspects disclosed herein. It should be further noted that any embodiment described herein may be applied separately or in various combinations. Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples. The phrases “in another embodiment” or any refence made to embodiment as used herein do not necessarily refer to different embodiment, although it may. Thus, various embodiments of the invention can be combined (from the same or from different aspects) without departing from the scope of the invention.

[0344] SOME NON-LIMITING EXAMPLES

[0345] Material and methods

[0346] Synthesis of deutero-2-deoxy-D-glucose

[0347] Isotopically substituted 2DG compounds can be synthesized by any method known in the art. For example, per-O-acetylated D-glucal may be used as the starting material and being deacetylated and benzylated. Further, D20 may be added in the presence of DBr in tetrahydrofuran.

[0348] Example 1: Determinations of deuterons Ti in sugar molecules

[0349] Table 1 describes the difference in Ti of deuterons in water (HDO, natural abundance) and in sites labelled with deuterons in various molecules that were determined using an Inversion Recovery technique. As can be seen from Table 1, deuterons that are directly bound to carbons in a ring (glucose or tyrosine) or aliphatic deuterons near the ring, show very short Tis of 40 - 60 ms, while methylene positions (choline) show longer Ti that is of the order of HDO’s Ti (ca. 400 ms). It is also demonstrated that binding to13C or12C nuclei does not affect the deuteron’ s T i in that position, which further suggests that motion restriction is the dominant mechanism for Ti shortening of the sugar deuterons.

[0350] Table 1: Ti relaxation times of deuterons directly bound to carbons in an aqueous saline solution3 aAll measurements were carried out at 5.8T in medical grade saline solution, at 16-17 °C, except the measurement marked ‘b’ which was performed at 20°C. Example 2: Recording of [6,6-D2]D-glucose uptake and metabolism in brain slices during stress

[0351] Materials and Methods

[0352] Chemicals

[0353] [6,6-D2]D-glucose was obtained from Cambridge Isotope Laboratories (Tewksbury, MA, USA). NaCl, KC1, D-glucose, NaHCCL, MgSCL, NaLLPCL, N-methyl- D-glucamine (NMDG), HEPES, pyruvic acid, ascorbic acid, thiourea, and CaCU were purchased from Sigma- Aldrich, (Rehovot, Israel). Isoflurane was obtained from the Institutional Authority for Biological and Biomedical Models of the Hebrew University (Jerusalem, Israel).

[0354] Animals

[0355] Male Sprague-Dawley rats (n = 4, 70-100 g) were obtained from the Hebrew University Authority of Biological and Biomedical Models. The joint ethics committee (IACUC) of the Hebrew University and Hadassah Medical Center approved the study protocol for animal welfare. The Hebrew University is an AAALAC International accredited institute. Care was taken to minimize the animals' pain and discomfort. Animals were housed in the animal facilities 3-5 days after delivery for acclimatization and fed ad libitum. On the experimental day, animals were transferred to the laboratory and anesthetized within one hour of arrival.

[0356] Solutions

[0357] To improve the health of acute brain slices obtained from mature adult rats, we modified a slice preparation technique optimized for in vitro electrophysiology in mature adult rat brain slices. In brief, slice health is improved by a so-called “protective recovery” method. NMDG is an extracellular replacer of sodium ions that prevents sodium ions and water influx into cells, the primary insult causing cell death following brain slicing. Ting et al. showed that the presence of NMDG during a 12-minute recovery phase after slicing dramatically improved the health of acute slices from mature adult rats in electrophysiological recordings. Furthermore, incubation in HEPES-buffered artificial cerebrospinal fluid (aCSF) improved slice health. The following solutions were prepared in the current study, and their use is described in the sections below. Solution 1 - NMDG-aCSF

[0358] NMDG-aCSF was used for transcardial perfusion, tissue slicing, and slice recovery. This medium contained 93 mM NMDG, 2.5 mM KC1, 1.2 mM NaH2PO4, 26 mM NaHCCh, 20 mM HEPES, 25 mM D-glucose, 10 mM MgSO4, 0.5 mM CaCh, 5 mM ascorbic acid, 2 mM thiourea, and 3 mM pyruvic acid in double distilled water.

[0359] Solution 2 - HEPES-holding aCSF

[0360] HEPES-holding aCSF was used to incubate slices following the surgical procedure. This medium contained 84 mM NaCl, 2.5 mM KC1, 1.2 mM NaEEPCh, 30 mM NaHCCh. 20 mM HEPES, 25 mM Glc (D-glucose, non-labeled), 2 mM MgSO4, 2 mM CaCh, 5 mM ascorbic acid, 2 mM thiourea, and 3 mM pyruvic acid in double distilled water.

[0361] Solution 3- Perfusion aCSF

[0362] Perfusion aCSF was used for perfusion in the NMR spectrometer. This medium contained 115 mM NaCl, 2.5 mM KC1, 1.2 mM NaH2PO4, 24 mM NaHCCh, 5 mM HEPES, 10 mM Glc (to be replaced with 10 mM D-Glc), 2 mM MgSO4, and 2 mM CaCh in double distilled water.

[0363] All three solutions (1-3) were bubbled with 95% / 5% O2 / CO2 for at least one hour before use and titrated to a pH of 7.35-7.45 using HC1 or NaOH. All concentrations were optimized for a calculated osmolarity of 310 ± 15 mOsm.

[0364] Surgery and Brain slices

[0365] Brain slices were extracted and maintained using the above solutions as previously described. Briefly, the rats were anesthetized using a gas anesthesia system (Somnosuite, Kent Scientific, Torrington, CT, USA). Induction was performed in a chamber with 3.5% isoflurane in room air with a flow rate of 440 mL / min. Following 4-7 min of induction, anesthesia was maintained with 3.1-3.2% isoflurane at the same flow rate. Upon obtaining a negative pedal pain reflex, surgery was initiated. First, the diaphragm was exposed and cut, and the rat was transcardially perfused with 30 mL of ice-cold NMDG-aCSF (Solution 1). The animals were then sacrificed by decapitation, and the brain was rapidly removed and placed in ice-cold NMDG-aCSF (Solution 1). The cerebrum was then cut into four parts (first, a sagittal cut along the hemispheric cleft and then a sagittal cut in the middle of each hemisphere). From each part, 350 pm slices were prepared using a McIlwain tissue chopper (The Mickle Laboratory Engineering Company Ltd., Surrey, UK). The process of brain extraction, from decapitation till the brain was in ice-cold NMDG-aCSF, took under 2 min, and the slicing procedure was done in less than 10 min. After cutting, the slices were transferred to warm, 32-34 °C, NMDG-aCSF (Solution 1) for 12 min for protective recovery. Then, the slices were transferred to HEPES-holding aCSF (Solution 2) at ~32 °C for 15-40 min incubation before transfer to the NMR spectrometer, where the slices were perfused with the aCSF of Solution 3.

[0366] Calculation of deuterated compounds ’ concentrations from deuterium NMR spectra

[0367] The natural abundance of HDO in water was used as an internal reference to calculate the concentration of the deuterated metabolites in the sample in each spectrum. To reduce the variability of the data that may result from variations in this internal standard's signal, the HDO signal was first averaged over ten spectra. Then, each HDO signal in all the spectra was converted to concentration units in the following way.

[0368] [HDO] = SHDO* 17.16 / SAV_HDO, where Snoo is the individual HDO signal in each spectrum, [HDO] is the concentration equivalent of each SHDO, and SAV HDO is the averaged HDO signal from 10 spectra at the beginning of the experiment (during perfusion with D-Glc). As the natural abundance of deuterium is 0.0156% and the concentration of protons in water is 110 M, the theoretical concentration of HDO is 17. 16 mM (0.0156%* 110 M).

[0369] For D-Glc and D-Lac, there are two deuterium nuclei per molecule. Therefore, their concentrations ([D-Glc] and [D-Lac], respectively) were calculated as follows.

[0370] [D-Glc] = SD-GIC*(17.16 / SAV_HDO) / 2, where SD-GIC is the individual signal of D- Glc. and

[0371] [D-Lac] = So-Lac*( 17. 16 / SAV_HDO) / 2, where So-Lac is the individual signal of D- Lac.

[0372] Note that the total concentration of lactate (deuterium-labeled and non-labeled) produced from D-Glc is twice that of D-Lac. Perfusion of brain slices in the NMR spectrometer and experimental workflow

[0373] The perfusion system was operated as described previously at 4 ml / min. D-Glc was introduced to the slices by addition to the external aCSF reservoir. To allow the utilization of a minimal amount of the labeled compound, 70 mL of aCSF was used for the perfusion of the slices with D-Glc.

[0374] Spectral Analysis

[0375] Spectral processing and intensity integrals were calculated using MNova (Mestrelab Research, Santiago de Compostela, Spain).

[0376] Statistical Analysis

[0377] Statistical analysis was performed in Excel (Microsoft Office, Ranana, Israel).

[0378] Results

[0379] Brain slices can be prepared by any method known in the art. Further details about this system can be found at Grieb et al.

[0380] A time course of glucose metabolism in perfused and ischemic brain is shown in Figure 1.

[0381] Individual and averaged D-Glc and D-Lac levels in each experiment and within the various experimental sections are provided in Table 2 and Figure 2.

[0382] Table 2. A summary of individual data used for statistical analysis is in the results section.

[0383] na, not applicable a, average, and standard deviation are for the three values for the three animals. b, the error is the standard deviation of the ten points used to determine this value. c, the error was taken as 15% of the single value of the single point in the time course.

[0384] The HDO, D-Glc, and D-Lac signals are consistently observed and allow the calculation of the concentration changes during the ischemic conditions. The time scale is in hh:mm (h, hour; m, min). The time of addition of D-Glc to the external perfusion medium was taken as the starting time (00:00). The durations of continuous perfusion and flow arrest (1stand 2ndischemic conditions) are marked. HDO, the natural abundance of deuterium in water.

[0385] Upon administration of D-Glc to the external reservoir of the perfusion medium, its signal (in the NMR tube) reached a plateau within 6 min (8.6 ± 0.7 mM). The D-Lac signal was observed within 8 min of the D-Glc administration, increased, and reached a plateau of 0.9 ± 0.4 mM (n=3) within 12-14 min.

[0386] The perfusion was arrested for 10 min (1stischemic condition) at 49 - 76 min (n = 3) from the administration of D-Glc. During this period, the signal of D-Lac increased gradually to a maximal level of 5. 1 ± 1.3 mM (n = 3), and the signal of D-Glc decreased gradually to a minimal level of 4.6 ± 1.5 mM (n = 3, two-tailed, paired t-test, before and at the end of the 1stischemic condition, P = 0.035). After the 1stischemic condition, the perfusion was resumed. Upon reperfusion, within about 8 min, the signal of D-Glc returned to the baseline level of 8.7 ± 0.7 mM (n = 3), and the signal of D-Lac returned to baseline at a level of 1. 1 ± 0.3 mM (two-tailed, paired t-test before and after ischemia, P = 0. 17, no difference). Continuous perfusion followed the 1stischemic condition for 53 - 70 min, and then the perfusion was again arrested for 10 min (2ndischemic condition).

[0387] During the 2ndischemic condition, the D-Lac concentration gradually increased to a similar maximal level of 5.91 ± 0.12 mM (n = 3, two-tailed, paired t-test, 1stand 2ndischemic conditions, P=0.50, no difference). The signal of D-Glc decreased to 4.1 ± 0.5 mM, as in the 1stischemic condition (n = 3, two-tailed, paired t-test, 1stand 2ndischemic conditions, P = 0.56, no difference, and two-tailed, paired t-test, before and at the 2ndischemic condition, P = 0.001). Further to the 2ndischemic condition, the perfusion was resumed, and again, within about 8 min, the D-Glc signal returned to the baseline level of 9.3 ± 1.1 mM (two-tailed, paired t-tests before the 1stischemic condition and after the 2ndischemic condition, P = 0.2). The D-Lac signal further to reperfusion after the 2ndischemic condition was similar to its level before the 1stischemic condition and between the two ischemic conditions, indicating that D-Lac did not accumulate within the cells due to the ischemic conditions (P= 0.4, ANOVA with replication). On both ischemic conditions, the increase in D-Lac concentration was the same as the maximal decrease in the D-Glc concentration (5.5 ± 1.1 mM and 4.3 ± 0.9 mM, respectively, n = 6, P=0.2, no difference, two-factor ANOVA with replication). This suggested that the D-Glc available to the brain slices during the ischemic conditions was fully converted to D-Lac (and, by inference, also to the same amount of non-labeled lactate).

[0388] 31P NMR spectra of the slices recorded before the 1stischemic condition and after the 2ndischemic condition confirmed the viability of the slices and the consistent presence of ATP and PCr in the slices. The individual spectra are shown in Figure 3. Information about the timing of acquiring the individual spectra of Figure 3 is provided in Table 3.

[0389] Table 3: Information about the timing of acquiring the individual spectra of Figure 3

[0390] *A11 spectra were acquired for 30 minutes except spectrum G, which was acquired for 15 minutes.

[0391] Analysis of ATP content in the slices, comparing the state before the 1stischemic condition and after the 2ndischemic condition, showed that during this time (about five h), it was decreased by 28 ± 5 % (n = 3, average ± standard deviation). This analysis was based on the y-ATP signal, as described previously.

[0392] In one of these experiments, an additional 3rdischemic condition was tested, which was applied at 87 min after the 2ndischemic condition for 64 min. In this 3rdischemic condition, the D-Lac concentration increased to 10.2 mM, and the D-Glc concentration decreased to 1.2 mM. A31P spectrum acquired towards the end of this ischemic condition showed almost no high-energy phosphate signals. However, 30 min further to reperfusion, some recovery was observed. Interestingly, in this experiment, D- Glx was sporadically observed during the 1stischemic condition and afterward. The level D-Glx increased towards the end of the long 3rdischemic condition (Figure 4 and Figure 5).

[0393] As can be seen in Figure 4, in addition to the HDO, D-Glc, and D-Lac signals, which are consistently observed, the signal of D-Glx can also be observed. The data are shown at 2-minute intervals starting at the beginning of the third ischemic condition and before reperfusion. The top spectrum, marked spectrum 21, was acquired at the end of the third ischemic condition, 22 min after the spectrum marked 20, and after 62 min of ischemia

[0394] In a control experiment without perfusion arrests (no ischemic conditions), the level of D-Lac was constant throughout, at a level similar to the three ischemia experiments under continuous flow. In a spectrum acquired without brain slices from the medium used for perfusion of these slices (without perfusion arrest) for five h in the presence of D-Glc (acquired at the same perfusion flow), the D-Lac signal was found to be 2.2% of the level of D-Lac in the NMR tube containing the brain slices.

[0395] Figure 5 shows the partial time course of the experiments, Breaks in D-NMR acquisitions are taken to record3'P spectra.

[0396] Example 3: Synthesis of [6,6-D2]2-deoxy-D-glucose

[0397] Figure 6A is a 'H NMR spectra of commercial 2-deoxyglucose-6,6-H2 and Figure 6B is an1H NMR spectra of 2-deoxyglucose-6,6-D2. The disappearance of the 1H signals (integration 2 protons) in the 3.8 ppm region indicates the successful replacement of two protons by two deuterium in position 6,6.

[0398] A normal mammalian brain as a model system will be used to estimate the rate of [D8]2-deoxy-D-glucose uptake by active tissues. The system of rat brain slices perfused with artificial cerebrospinal fluid (aCSF) provides a suitable model system for this investigation. In addition, this system will be used for initial evaluation of | Dx|2-dcoxy- D-glucose uptake in breast cancer, utilising breast cancer xenografts from triple -negative tumours. Example 4: Initial assessment of effective dose

[0399] The effective dose for [D8]2-deoxy-D-glucose is evaluated in vivo with suitable hardware and methodologies (RF coils / insert and pulse sequences).

[0400] As an initial dose, the amount of [Ds]2-deoxy-D-glucose that is injected intravenously can be calculated to be about 4.3 g per patient (ca. 60 mg / kg).

[0401] For injection in an isosmotic condition, a formulation of about 75 mb solution with a [D8]2-deoxy-D-glucose concentration of 330 mM is injected.

[0402] Example 5: Detecting and characterizing breast lesions

[0403] Detecting and characterizing breast lesions in women with high risk for developing breast cancer is done using [D8]2-deoxy-D-glucose.

[0404] A woman with high-risk for developing breast cancer is scanned by MRI with contrast enhancement using the standard-of-care MRI protocol, as part of her annual examination.

[0405] Prior to gadolinium-based contrast agent injection for contrast-enhanced MRI, the women will be intravenously injected with [D8]2-deoxy-D-glucose at a dose of about 60 mg / kg.

[0406] Imaging of deuterium distribution by deuterium-MRI according to the method of the invention will depict the distribution of [D8]2-deoxy-D-glucose in the breast. This will indicate the anatomical location of metabolically active regions in the breast. Taken together with contrast-enhanced imaging results, anatomical MRI images, and the finding of other breast imaging modalities (ultrasound and mammography), this information will enable the breast radiologist to reach a highly sensitive and highly specific diagnosis of the lesion(s) that may be found in the breast.

[0407] Example 6: Detecting and characterizing stroke and ischemia in the brain

[0408] Detecting and characterizing stroke and ischemia in the brain is done using [D 8] 2- deoxy-D-glucose.

[0409] A person is scanned by MRI using the standard-of-care MRI protocol, as part of the standard-of-care established in a particular medical center. Prior to the MRI, the patient will be intravenously injected with [D8]2-deoxy-D- glucose at a dose of about 60 mg / kg.

[0410] Imaging of deuterium distribution by deuterium-MRI in the brain according to the method of the invention will depict the distribution of [D8]2-deoxy-D-glucose in the brain. This will indicate the anatomical location of metabolically inactive regions in the brain. Taken together with anatomical MRI images, diffusion-weighted MRI and other MRI characteristics, this information will enable the radiologist and neuroradiologist to reach a highly sensitive and highly specific characterization of the condition and stratify treatment.

[0411] Example 7: Detecting and characterizing ischemic legs and feet

[0412] Detecting and characterizing ischemia in the legs of diabetes patients is done using [D8]2-deoxy-D-glucose.

[0413] A patient is scanned by MRI with contrast enhancement using the standard-of- care MRI protocol, as part of the standard-of-care established in a particular medical center.

[0414] Prior to the MRI, the patient will be intravenously injected with [D8]2-deoxy-D- glucose at a dose of about 60 mg / kg.

[0415] Imaging of deuterium distribution by deuterium-MRI in the legs and feet according to the method of the invention will depict the distribution of [D8]2-deoxy-D- glucose in the legs and feet. This will indicate the anatomical location of metabolically inactive regions in the legs and feet. Taken together with anatomical MRI images, diffusion-weighted MRI and other MRI characteristics, this information will enable the radiologist and the diabetes or metabolic specialist to reach a highly sensitive and highly specific characterization of the condition and stratify treatment.

Claims

CLAIMS:

1. A 2-deoxy-D-glucose (2DG) compound comprising one or more isotopically substituted hydrogen atoms for use in a method of acquiring at least one magnetic resonance (MR) spectrum and / or at least one MR image.

2. The 2DG compound of claim 1, wherein the 2DG compound is at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2- deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2Hfi] 2-deoxy-D-glucose, [2H7]2-deoxy-D- glucose, [2H8]2-deoxy-D-glucose or a combination thereof.

3. The 2DG compound of claim 2, wherein the 2DG compound is 12H8|2-dcoxy-D- glucose.

4. The 2DG compound of claim 2, wherein the 2DG compound is [2H2]2-deoxy-D- glucose.

5. The 2DG compound of claim 1, represented by Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, any tautomer thereof, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, X8is2H (D).

6. The 2DG compound of claim 5, wherein (i) one of Xi, X2, X3, X4, X5, Xe, X7, and X8is2H, (ii) two of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (iii) three of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (iv) four of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (v) five of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vi) six of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (vii) seven of Xi, X2, X3, X4, X5, X6, X7, and X8is2H, (viii) eight of Xi, X2, X3, X4, X5, X6, X7, and X8is2H or a combination thereof.

7. The 2DG compound of claim 5 or 6, wherein said compound is represented by Formula (IV):or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.

8. The 2DG compound of claim 5 or 6, wherein said compound is represented by Formula (VI):or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

9. The 2DG compound of claim 5 or 6, wherein said compound is represented by Formula (VIII):or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

10. The 2DG compound of claim 5 or 6, wherein said compound is represented by Formula (X):or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any tautomer thereof, any metabolite thereof or physiologically functional derivative thereof.

11. The 2DG compound of any one of claims 1 to 10, having a Ti relaxation of a2H nucleus of between about 5 milliseconds to about 200 milliseconds.

12. The 2DG compound of any one of claims 1 to 11, wherein said method comprises acquiring at least one MR spectrum and / or at least one MR image from a subject.

13. The 2DG compound of claim 12, for use in a method of diagnosing said subject.

14. The 2DG compound of claim 12, for use in a method of diagnosing a disease in said subject.

15. The 2DG compound of any one of claims 1 to 14, for use in detecting a metabolite of said compound.

16. The 2DG compound of claim 15, wherein said metabolite is one of [D]2-deoxy-D- glucose-6-phosphate, [D2]2-deoxy-D-glucose-6-phosphate, [D3]2-deoxy-D-glucose-6-phosphate, [D4]2-deoxy-D-glucose-6-phosphate, [Ds]2-deoxy-D-glucose-6-phosphate, [D6]2-deoxy-D-glucose-6-phosphate, [D7]2-deoxy-D-glucose-6-phosphate, | Dx|2- deoxy-D-glucose-6-phosphate or a combination thereof.

17. The 2DG compound of any one of claims 1 to 16, for use in (i) a method of monitoring a disease state in said subject and / or (ii) a method of determining a site of a disease in said subject.

18. The 2DG compound of claim 17, wherein the disease is associated with increased glucose metabolism.

19. The 2DG compound of claim 17, wherein the disease may be oncological, neurological, psychiatric, cardiovascular, infectious or inflammatory.

20. The 2DG compound of claim 1, wherein the disease is a proliferative disorder.

21. The 2DG compound of any one of claims 1 to 20, for use in a method of distinguishing between healthy and abnormal tissues or organs and / or distinguishing or differentiating between malignant and benign tumors.

22. A diagnostic formulation comprising at least one compound of any one of claims I to 21.

23. A kit comprising a formulation of claim 22 and instructions for use thereof.

24. A method of imaging a subject, the method comprising monitoring a signal from a subject using an MR imaging method, the subject having been administered at least one 2DG compound to thereby acquire at least one MR image, wherein said 2DG compound is deuterium -labeled 2DG.

25. A method for diagnosis of a disease or condition in a subject, said method comprising (i) provided a diagnostically effective amount of at least one 2DG compound is administered to the subject and (ii) obtaining an image and / or spectrum of said subject or of a body region of the subject; (iii) identifying body regions in which said compound, or any metabolite thereof has been localized, wherein said 2DG compound is a deuterium-labeled 2DG; thereby enabling the diagnosis of a disease or condition in a subject according to the localization of the 2DG compound or its metabolites.

26. The method of claim 24 or 25, wherein said 2DG compound is at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2Ha]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H?]2-deoxy-D- glucose, [2Hg]2-deoxy-D-glucose or a combination thereof.

27. The method of claim 26, wherein said 2DG compound is |2Hx|2-dcoxy-D- glucose.

28. The method of claim 27, wherein said 2DG compound is [2H2]2-deoxy-D- glucose.

29. The method of any one of claims 24 to 28, wherein said 2DG compound is represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, or Xx is2H (D).

30. The method of any one of claims 24 to 29, wherein at least one MR image is at least one2H image.

31. The method of claim 30, wherein said at least one2H image is acquired at an acquisition time of at most about 5 min.

32. The method of claim 30, wherein said at least one2H MR image from a subject with a spatial resolution of between about 2mm and about 20mm, at times between about 2mm and about 10mm, at times between about 2mm and about 5 mm (in plane resolution).

33. The method of claim 30, wherein at least one MR image is of the at least one compound or a metabolite thereof.

34. The method of any one of claims 24 to 33, for determining a site of a disease and / or for distinguishing between healthy and abnormal tissues or organs.

35. The method of any one of claims 24 to 33, for distinguishing or differentiating between malignant and benign tumors.

36. The method of any one of claims 24 to 35, comprising prior to said administration step, acquiring at least one2H image from said subject’s body or one or more body regions.

37. The method of claim 36, comprising comparing at least one parameter obtained from the at least one2H MR image to at least one parameter obtained from the at leastone2H MR image in the same subject at an earlier timepoint, wherein the comparison enables diagnosis of the disease.

38. The method of any one of claims 24 to 37, wherein the disease is associated with increased glucose metabolism.

39. The method of any one of claims 24 to 38, wherein the disease may be oncological, neurological, psychiatric, cardiovascular, infectious or inflammatory.

40. The method of claim 38 wherein the disease is a proliferative disorder.

41. The method of claim 38 wherein the disease is ischemia.

42. The method of any one of claims 24 to 41, comprising administering to said subject diagnosed with a disease or condition a treatment regimen based on said disease or condition thereby treating the subject.

43. A method for monitoring a disease state in a subject, the method comprising (i) provided the subject has been administering a compound; (ii) imaging the subject's body or any one or more regions thereof, in order to obtain at least one imaging parameter indicative of the disease or disorder state; and (iii) comparing said at least one imaging parameter to at least one parameter obtained from said subject at an earlier timepoint; wherein the comparison enables determining the progression of the disease or disorder state, and thereby monitoring the disease state of the subject; and wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2- deoxy-D-glucose, [2He]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, [2Hs]2-deoxy-D- glucose or a combination thereof, (c) [2Hs]2-deoxy-D-glucose, (d) represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (II’), and / or Formula(III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xs is2H (D), (e) represented by Formula(IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

44. A method for determining the severity of a disease or disorder in a subject, the method comprising (i) provided the subject has been administered a compound, (ii)imaging and / or acquiring a spectrum the subject’s body or region thereof to obtain at least one imaging parameter, and (iii) comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement, and thereby determining the severity of the disease or disorder in the subject, wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, [2H5]2-deoxy-D-glucose, [2Hs]2-deoxy-D-glucose, [2H?]2- deoxy-D-glucose, [2Hs]2-deoxy-D-glucose or a combination thereof, (c) [2Hs]2-deoxy- D-glucose, (d) represented by Formula (I) or Formula (F) and / or Formula (II), and / or Formula (IF), and / or Formula (III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, X6, X7, Xx is2H (D), (e) represented by Formula (IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

45. A method for determining the effectiveness of a therapeutic treatment of a disease or disorder in a subject, the method comprising (i) provided the subject has been administered a compound, (ii) imaging the subject’s body or region thereof and thereby obtaining at least one imaging parameter, and (iii) comparing said at least one imaging parameter to at least one parameter obtained from said subject at the onset of treatment or prior to treatment commencement; and thereby determining the effectiveness of the therapeutic treatment of the disease or disorder in the subject, wherein said compound is any one of (a) a deuterium labeled 2DG, (b) at least one of [2H]2-deoxy-D-glucose, [2H2]2-deoxy-D-glucose, [2H3]2-deoxy-D-glucose, [2H4]2-deoxy-D-glucose, |2Hs |2- deoxy-D-glucose, [2H6]2-deoxy-D-glucose, [2H7]2-deoxy-D-glucose, |2Hx|2-dcoxy-D- glucose or a combination thereof, (c) [2Hg]2-deoxy-D-glucose, (d) represented by Formula (I) or Formula (I’) and / or Formula (II), and / or Formula (II’), and / or Formula(III), and / or Formula (III’), or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof, wherein at least one of Xi, X2, X3, X4, X5, Xg, X7, Xg is2H (D), (e) represented by Formula(IV)-Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, any isomerthereof, any metabolite thereof or physiologically functional derivative thereof, or (f) a combination thereof.

46. A method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one condition in a subject in need thereof, said method comprising the steps of: (a) diagnosis a disease or condition in a subject and (b) administering to the subject a treatment regimen based on said disease or condition thereby treating the subject.

47. The method of claim 46, wherein said diagnosis is according to any one of claims 25 to 41.

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