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WO2025134122A1 - Agents de diagnostic et leurs utilisations - Google Patents

Agents de diagnostic et leurs utilisations Download PDF

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Publication number
WO2025134122A1
WO2025134122A1 PCT/IL2024/051204 IL2024051204W WO2025134122A1 WO 2025134122 A1 WO2025134122 A1 WO 2025134122A1 IL 2024051204 W IL2024051204 W IL 2024051204W WO 2025134122 A1 WO2025134122 A1 WO 2025134122A1
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Prior art keywords
compound
glucose
deoxy
subject
formula
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English (en)
Inventor
Rachel Katz-Brull
Jacob Sosna
Moshe John Gomori
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Hadasit Medical Research Services and Development Co
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Hadasit Medical Research Services and Development Co
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Publication of WO2025134122A1 publication Critical patent/WO2025134122A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids

Definitions

  • 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.
  • MR magnetic resonance
  • 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, X 8 is 2 H (D).
  • 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, X 8 is 2 H (D).
  • 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, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 is 2 H (D).
  • 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, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 is 2 H (D).
  • 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.
  • 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.
  • the present disclosure provides in accordance with yet some other aspects, a 2DG compound for use in detecting a metabolite of said compound.
  • 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.
  • 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.
  • a diagnostic formulation comprising at least one 2DG compound comprising one or more isotopically substituted hydrogen atoms.
  • 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.
  • 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.
  • a method for monitoring a disease state in a subject 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 [ 2 H]2-deoxy-D-glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D-glucose, [ 2 H4]2-deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 H6]2-deoxy-D-glucose, [ 2
  • a method for determining the severity of a disease or disorder in a subject 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 [ 2 H]2-deoxy-D- glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D-glucose, [ 2 H4]2-deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 H6]2-deoxy-D-glucose, [ 2 H7]2-deoxy-D-glucose,
  • a method for determining the effectiveness of a therapeutic treatment of a disease or disorder in a subject 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 [ 2 H]2-deoxy-D-glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D- glucose, [ 2 H4]2-deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 H6]2-deoxy-D-glucose, [ 2 H7]2-deoxy-D-glucose
  • 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.
  • NMR Nuclear Magnetic Resonance
  • the compound is a compound represented by Formula (VI):
  • 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.
  • a compound represented by Formula (VI) encompasses any isomer thereof.
  • the isomer includes tautomer of compounds represented by Formula (VII).
  • 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.
  • 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.
  • MR magnetic resonance
  • VII a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.
  • 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.
  • Formula (VII) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.
  • 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.
  • 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.
  • MR magnetic resonance
  • VIF pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.
  • 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.
  • VIF Formula (VIF) or a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.
  • the compound is D-Arabino-2-deoxyhexose-dl. In some examples, the compound is characterized by a CAS No.: 188004-07-1.
  • 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.
  • 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.
  • MR magnetic resonance
  • VIII a pharmaceutically acceptable salt, solvate, hydrate, any isomer thereof, any metabolite thereof or physiologically functional derivative thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • MR magnetic resonance
  • 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.
  • the compound is 2-deutero-2-deoxy-D-glucose.
  • 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.
  • 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.
  • 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.
  • injection e.g., using a subcutaneous, intramuscular, intravenous, intraarterial, or intradermal injection
  • dermal e.g., using a subcutaneous, intramuscular, intravenous, intraarterial, or intradermal injection
  • intranasal administration e.g., 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.
  • 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.
  • 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.
  • 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).
  • further metabolism of 2DG 6-phosphate and/or deuterated 2DG 6- phosphate to D-fructose 6-phosphate is not possible.
  • the phosphorylated product of any of the compounds described herein is denoted as a metabolite of the 2DG isotopically substituted/labeled compound.
  • the metabolite is at least one of [ 2 H]2-deoxy-D-glucose-6- phosphate, [ 2 H2]2-deoxy-D-glucose-6-phosphate, [ 2 H3]2-deoxy-D-glucose-6-phosphate, [ 2 Hy
  • the metabolite is [ 2 H]2-deoxy-D-glucose-6-phosphate.
  • the metabolite is [ 2 H2]2-deoxy-D-glucose-6-phosphate.
  • the metabolite is [ 2 H3]2-deoxy-D-glucose-6-phosphate. In some examples, the metabolite is [ 2 H4]2-deoxy-D-glucose-6-phosphate.
  • the metabolite is [ 2 H5]2-deoxy-D-glucose-6-phosphate.
  • the metabolite is [ 2 H6]2-deoxy-D-glucose-6-phosphate.
  • the metabolite is [ 2 H8]2-deoxy-D-glucose-6-phosphate.
  • 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).
  • 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).
  • 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 is 2 H (D).
  • the metabolite is represented by Formula
  • 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 is 2 H (D).
  • the metabolite is represented by Formula
  • the metabolite is represented by Formula
  • the metabolite is or comprises [ 2 H2]2-deoxy-D-glucose-6- phosphate.
  • the metabolite is represented by Formula
  • 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.
  • the compound of the present disclosure as well as a metabolite thereof is for use in a method of diagnosis a subject.
  • 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.
  • the 2DG labeled compound and/or a metabolite thereof is for use in a method of monitoring a disease state in the subject.
  • 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 [ 2 H]2-deoxy-D-glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D-glucose, [ 2 H4]2- deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 He]2-deoxy-D-glucose, [ 2 H?]2-deoxy-
  • 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
  • the compounds of the disclosure are applicable to use in MR methods such as MRS and/or MRI.
  • a method of acquiring at least one MR spectrum and/or MR image from a subject 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.
  • 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 a 2 H Radio Frequency coil. Detecting such signal using MR can be done by using for example specialized probes for acquiring the signal.
  • 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.
  • 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.
  • specific MR sequences and equipment e.g. probes, i.e. radio-frequency circuits, i.e. radio-frequency coils
  • a method of imaging a subject 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.
  • the subject has been administered with at least one of [ 2 H]2-deoxy-D-glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D- glucose, [ 2 H4]2-deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 H6]2-deoxy-D-glucose, [ 2 H7]2-deoxy-D-glucose, [ 2 Hs]2-deoxy-D-glucose or a combination thereof.
  • the subject has been administered with [D8]2-deoxy-D-glucose.
  • the subject has been administered with [ 2 H3]2-deoxy-D-glucose. In some examples, in the methods described herein, the subject has been administered with [ 2 H4]2-deoxy-D-glucose.
  • the subject has been administered with [ 2 H5]2-deoxy-D-glucose.
  • the subject has been administered with [ 2 H6]2-deoxy-D-glucose.
  • the subject has been administered with [ 2 H7]2-deoxy-D-glucose.
  • the subject has been administered with [ 2 Hg]2-deoxy-D-glucose.
  • 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 is 2 H (D), a composition or a kit comprising the at least one compound.
  • 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 is 2 H (D), a composition or a kit comprising the at least one compound.
  • 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 is 2 H (D), a composition or a kit comprising the at least one compound.
  • 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 is 2 H (D), a composition or a kit comprising the at least one compound.
  • the subject in the methods described herein 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 is 2 H.
  • the subject in the methods described herein 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.
  • the subject in the methods described herein 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the imaging methods comprises monitoring a signal from a subj ect using an MR imaging method, wherein the compound is at least one of [ 2 H] 2-deoxy- D-glucose, [ 2 H2]2-deoxy-D-glucose, [ 2 H3]2-deoxy-D-glucose, [ 2 H4]2-deoxy-D-glucose, [ 2 H5]2-deoxy-D-glucose, [ 2 H6]2-deoxy-D-glucose, [ 2 H7]2-deoxy-D-glucose, [ 2 Hs]2-deoxy- D-glucose or a combination thereof.
  • 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.
  • 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 is 2 H.
  • the method comprises monitoring uptake of the deuterated labeled compound of the present disclosure by acquiring at least one 2 H MR image from a subject.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite of the present disclosure by acquiring at least one 2 H MR image from a subject.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the labeled metabolite is at least one of [ 2 H]2-deoxy-D-glucose-6-phosphate, [ 2 H2]2-deoxy-D-glucose-6-phosphate, [ 2 H3]2-deoxy-D-glucose-6-phosphate, [ 2 H4]2- deoxy-D-glucose-6-phosphate, [ 2 H5]2-deoxy-D-glucose-6-phosphate, [ 2 H6]2-deoxy-D- glucose-6-phosphate, [ 2 H7]2-deoxy-D-glucose-6-phosphate, [ 2 H8]2-deoxy-D-glucose-6- phosphate or a combination thereof.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H2]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H3]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H4]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H6]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the metabolite is or comprises [ 2 H7]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the labeled metabolite is or comprises [ 2 H8]2-deoxy-D-glucose-6-phosphate.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H 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.
  • the MR method comprises monitoring accumulation of the deuterated labeled metabolite by acquiring at least one 2 H MR image from a subject, wherein the labeled metabolite is represented by Formula (XII)- (XVIII).
  • 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.
  • SNR image signal-to-noise ratio
  • 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.
  • 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.
  • 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.
  • the method comprises acquiring at least one MR image from a subject. In some examples, the method comprises acquiring at least one 2 H MR image from a subject. In some examples, the method comprises acquiring at least one 2 H 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 one 2 H 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.
  • 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.
  • the 2DG labeled compound and/or a metabolite thereof may be for use in diagnosis of a condition of a disease.
  • 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.
  • 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.
  • the body regions susceptible of having a disease or a condition are associated with accumulation of a metabolite as described herein.
  • 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.
  • 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.
  • 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.
  • diagnosis 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
  • 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.
  • a signal prior to administration of the compounds of the invention at least one anatomical 1 H image may be acquired.
  • 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.
  • the method comprising prior to the administration step, acquiring at least one 2 H 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.
  • the method comprising comparing at least one parameter obtained from the at least one 2 H MR spectrum and/or at least one 2 H MR image to at least one parameter obtained from the at least one 2 H MR spectrum and/or at least one 2 H MR image in the same subject at an earlier point in time, wherein the comparison permits diagnosis of the disease.
  • 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.
  • the labeled 2DG described herein may be applicable in the diagnosis of such pathologies.
  • Example 7 Detecting and characterizing ischemic legs and feet
  • 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.
  • the patient Prior to the MRI, the patient will be intravenously injected with [D8]2-deoxy-D- glucose at a dose of about 60 mg/kg.
  • 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.

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Abstract

La présente invention concerne des composés de 2-désoxy-D-glucose (2DG) contenant un ou plusieurs atomes d'hydrogène isotopiquement substitués, leurs utilisations et des méthodes associées.
PCT/IL2024/051204 2023-12-21 2024-12-19 Agents de diagnostic et leurs utilisations Pending WO2025134122A1 (fr)

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Citations (1)

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