WO2009124250A1 - Compositions et procédés pour détecter un flux métabolique d'acide tricarboxylique (atc) - Google Patents

Compositions et procédés pour détecter un flux métabolique d'acide tricarboxylique (atc) Download PDF

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Publication number
WO2009124250A1
WO2009124250A1 PCT/US2009/039467 US2009039467W WO2009124250A1 WO 2009124250 A1 WO2009124250 A1 WO 2009124250A1 US 2009039467 W US2009039467 W US 2009039467W WO 2009124250 A1 WO2009124250 A1 WO 2009124250A1
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contrast agent
composition
subject
detecting
another embodiment
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PCT/US2009/039467
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English (en)
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Jerry D. Glickson
Steve Kadelcek
Rahim Rizi
Amos Smith
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The Trustees Of The University Of Pennsylvania
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Publication of WO2009124250A1 publication Critical patent/WO2009124250A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions

Definitions

  • the invention relates to compositions and methods for detecting a metabolite in the tricarboxylic acid (TCA) cycle. Specifically, the invention relates to a hydrogenated composition comprising a hyperpolarized [1- 13 C] propionic acid and methods for detecting a metabolite in the TCA cycle using the composition.
  • TCA tricarboxylic acid
  • the citric acid cycle also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle, is a series of enzyme-catalyzed chemical reactions of central importance in all living cells that use oxygen as part of cellular respiration.
  • TCA cycle tricarboxylic acid cycle
  • the citric acid cycle occurs in the matrix of the mitochondrion.
  • the components and reactions of the citric acid cycle were established by seminal work from both Albert Szent-Gyorgyi and Hans Krebs.
  • the citric acid cycle is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy.
  • Other relevant reactions in the pathway include those in glycolysis and pyruvate oxidation before the citric acid cycle, and oxidative phosphorylation after it.
  • it provides precursors for many compounds including some amino acids and is, therefore, functional even in cells performing fermentation.
  • NADH a product of all dehydrogenases in the TCA cycle with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase and ⁇ -ketoglutarate dehydrogenase, and also citrate synthase.
  • Acetyl-CoA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits succinyl-CoA synthase and citrate synthase.
  • ATP inhibits citrate synthase and ⁇ -ketoglutarate dehydrogenase; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise.
  • Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and ⁇ -ketoglutarate dehydrogenase. This increases the reaction rate of many of the steps in the cycle, and, therefore, increases flux throughout the pathway.
  • Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1,6-bisphosphate, a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme. Accordingly, a need exists for techniques for detecting a metabolite in the TCA cycle in order to diagnose, monitor, and treat diseases associated with TCA.
  • Magnetic Resonance Imaging is an important diagnostic technique. It is especially attractive since it is non-invasive and does not expose the patient to potentially harmful radiation such as X-rays or radiation from radioactive materials. Significant progress has recently been made in the quality of images as well as finding new applications of the technique. The progress relies on a rapid development of the digital image processing, the refined Nuclear Magnetic Resonance (NMR) techniques and the development of effective contrast agents (imaging agents).
  • NMR Nuclear Magnetic Resonance
  • imaging agents imaging agents
  • An emerging technique of particular interest involves Magnetic Resonance (MR) contrast agents based on the principle of pre-polarization of the nuclear spins, also called hyperpolarization. Accordingly, a need exists for hyperpolarized contrast agents for detecting a metabolite in the TCA cycle.
  • the invention relates to a hydrogenated composition for medical iimmaaggiinngg,, tthhee ⁇ composition comprising an effective amount of a hyperpolarized [1- 13 C] propionic acid or its analog.
  • a contrast agent comprising a hydrogenated composition that comprises an effective amount of a hyperpolarized [1- 13 C] propionic acid.
  • the invention relates to a method of producing a hydrogenated composition that detects a metabolite in the TCA cycle, in a subject, wherein the composition comprises a hyperpolarized [1- 13 C] propionic acid or its analog.
  • the invention relates to a method for diagnostic imaging, in a subject, the method comprising administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle.
  • the invention relates to a method for diagnosis of a disease mediated by the TCA cycle, in a subject, the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to diagnose said disease.
  • the invention relates to a method for detecting a metabolite in the TCA cycle, in a subject, the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- C] propionic acid; and detecting said contrast agent, thereby detecting said metabolite in the TCA cycle.
  • the invention relates to a method for monitoring the progression of a disease mediated by the TCA cycle, in a subject, the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to monitor the progression of said disease.
  • the invention relates to a method for providing a prognosis of a disease mediated by the TCA cycle, in a subject, the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to provide prognosis of said disease.
  • the invention relates to a method for treating a disease mediated by a metabolite in the TCA cycle, in a subject, the method comprising: administering to said subject a contrast agentthat comprises a hyperpolarized [1- 13 C] propionic acid; detecting said contrast agent, thereby detecting said metabolite in the TCA cycle; and treating said condition.
  • the invention relates to a composition comprising a hyperpolarized [1- C] propionic acid and methods for detecting a metabolite in the TCA cycle using the composition comprising a
  • a composition for detecting a metabolite in the TCA cycle, in a subject, by a medical imaging device comprising an effective amount of a hyperpolarized [1- 13 C] propionic acid or its analog.
  • a contrast agent for detecting a metabolite in the TCA cycle, in a subject, by a medical imaging device the contrast agent comprising an effective amount of a hyperpolarized [1- 13 C] propionic acid.
  • a method of producing a composition for detecting a metabolite in the TCA cycle, in a subject, by a medical imaging device the composition comprising an effective amount of a hyperpolarized [1- 13 C] propionic acid or its analog.
  • a method for detecting a metabolite in the TCA cycle, in a subject, by a medical imaging device the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting said metabolite in the TCA cycle.
  • a method of magnetic resonance imaging in a subject, comprising administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle.
  • a method for diagnosis of a disease mediated by the TCA cycle comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to diagnose said disease
  • a method for monitoring the progression of a disease mediated by the TCA cycle comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to monitor the progression of said disease.
  • the composition of the invention comprises a hyperpolarized [1- 13 C] propionic acid.
  • the composition of the invention comprises a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid.
  • the composition of the invention comprises a hydrogenated contrast agent that comprises a hyperpolarized [1- C] propionic acid.
  • the composition of the invention comprises a para-
  • composition of the invention comprises an ortho-hydrogenated contrast agent that comprises a hyperpolarized [1- C] propionic acid.
  • composition of the invention comprises a hyperpolarized hydroxyethyl propionate or its analogs.
  • composition of the invention comprises a contrast agent that comprises a hyperpolarized hydroxyethyl propionate or its analogs.
  • the hyperpolarized hydroxyethyl propionate is labeled on the carboxyl carbon, CHsCHiC ⁇ OOCI ⁇ CHiOH.
  • the hyperpolarized composition is produced by adding a hydrogen to a specific nuclear symmetric state to [1- 13 C] acrylic acid.
  • the specific nuclear symmetric state is a para state.
  • the specific nuclear symmetric state is an ortho state.
  • the hyperpolarized [ 1 - 13 C] propionic acid is produced by hydrogenation of hydroxyethylpropionate C labeled on the carboxyl carbon.
  • the hyperpolarized [ 1 - 13 C] propionic acid is produced by reacting hydroxyethylpropionate 13 C labeled on the carboxyl carbon with a hydrogen in a specific nuclear symmetric state.
  • the hyperpolarized [1- 13 C] propionic acid is produced by adding a hydrogen in a specific nuclear symmetric state to [1- 13 C] acrylic acid.
  • the hydrogenation is performed by reacting a hydroxyethylpropionate 13 C labeled on the carboxyl carbon with a para-hydrogen in presence of a catalyst. In some embodiments, the hydrogenation is performed by reacting a hydroxyethylpropionate C labeled on the carboxyl carbon with an ortho-hydrogen in presence of a catalyst.
  • Hydrogenation may be performed by methods known to one of skill in the art.
  • WO 00/71166 it is described how to catalytically hydrogenate unsaturated compounds comprising nonzero spin nuclei such as 13 C.
  • the spin correlation of the protons from the para-hydrogen can be preserved during and after hydrogenation, and the influence on the spins of the 13 C nuclei breaks the symmetry of the spin system.
  • a magnetic field cycling method is described for transforming the proton spin-order to carbon spin polarization.
  • the hydrogenation catalyst is known to one of skill in the art and described in WO99/24080, which is incorporated by reference in its entirety.
  • the catalyst includes, for example, a metal complex, in particular a rhodium complex.
  • a reaction chamber is filled with enriched hydrogen, optionally under pressure-preferably 5-20 bar, and the catalyst and substrate solution is introduced either as a thin jet, by spraying or by atomising, into this reactor.
  • the solution may be produced by mixing separate solutions of catalyst and of substrate.
  • a distributor or a plurality of spray nozzles may be used and the chamber contents may be mixed, e.g. by a mechanical stirrer or by appropriately shaping the chamber walls to cause turbulent mixing when there is a flow of reaction mixture in the chamber.
  • the process may be performed continuously with a flow reactor, e.g. a loop or tube reactor, or alternatively it may be a batch-wise process.
  • a flow reactor e.g. a loop or tube reactor
  • there can be a continuous or pulsed flow of enriched hydrogen and solution into the reactor a continuous or batch- wise removal of liquid solution from the base of the reactor, and a continuous or batch- wise venting of unreacted gas from the reactor.
  • the enriched hydrogen and solution passing into the reactor are preferably temperature-controlled to ensure that the gas/droplet phase in the reactor is at the desired temperature. This can be achieved by providing input lines with temperature sensors and heating and/or cooling jackets.
  • the resulting aqueous solution that comprises [1- 13 C] propionic acid may be frozen and stored or may preferably be used directly in an MR imaging or spectroscopy procedure, optionally after dilution or addition of further solution components, e.g. pH modifiers, complexing agents, etc.
  • further solution components e.g. pH modifiers, complexing agents, etc.
  • Such direct use may for example involve continuous infusion or alternatively injection or infusion of one or more dose units.
  • Bolus injection may also be used.
  • the whole process from beginning of hydrogenation to the delivery of the finished composition of the invention in. for example, a syringe may conveniently be effected in less than 100 seconds, and more preferably in less than 10 seconds, which is substantially less than IT 1 for the potentially interesting imaging nuclei.
  • a careful analysis and optimization routine considering the effects of field cycling on the nuclear spin states may advantageously be performed.
  • Hyper-polirisation methods are well known in the art. Any suitable hyper-polarization method may be used.
  • hyper-polarised we mean polarised to a level over that found at room temperature and IT, preferably polarised to a polarisation degree in excess of 0.1%, more preferably 1%, even more preferably 10%.
  • the solvent used with the present invention may be any convenient material which serves as a solvent for the substrate and the hydrogenation catalyst.
  • the solvent is preferably physiologically tolerable.
  • Water is a preferred choice of solvent, used in combination with a water-soluble catalyst. If other solvents that are not physiologically tolerable are used, the solvents has to be removed before use in a patient, for example by vacuum- spray. Other rapid solvent removal techniques, e.g. affinity techniques, may, however, be used.
  • the solvent is preferably used at or near the minimum quantities required to maintain substrate, catalyst and contrast agent in solution without experiencing viscosity problems during the hydrogenation reaction.
  • the hyperpolarized [ 1 - 13 C] propionic acid is produced by hydrolysis of hydroxyethylpropionate 13 C labeled on the carboxyl carbon or their analogs (e.g., esters of other alcohols that are more easily hydrolyzed or whose hydrolysis can be readily monitored using colorimetry).
  • the composition of the invention once polarised may remain so for a period sufficiently long to allow the imaging procedure to be carried out in a comfortable time span.
  • sufficient polarisation is retained by the composition of the invention in its administrable form (e.g., in injection solution) if it has a Ti value (at a field strength of 0.01-5T and a temperature in the range 20-40° C) of at least 5 s, more preferably at least 10 s, especially preferably 30 s or longer, more especially preferably 70 s or more, yet more especially preferably 100 s or more (for example at 37 ° C. in water at IT and a concentration of at least 1 mM).
  • the composition of the invention may be advantageously an agent with a long T 2 relaxation time.
  • the T 2 valve may be sensitive to the physiological parameters of interest.
  • a polarised solid composition of the invention is dissolved in administrable media (e.g. water or saline), administered to a subject and conventional administrable media (e.g. water or saline), administered to a subject and conventional administrable media (e.g. water or saline), administered to a subject and conventional administrable media (e.g. water or saline), administered to a subject and conventional administrable media (e.g. water or saline), administered to a subject and conventional
  • administrable media e.g. water or saline
  • compositions of the invention are preferably rapidly soluble
  • the composition of the invention dissolves in a physiologically tolerable carrier (e.g. water or Ringers solution) to a concentration of at least 1 mM at a rate of 1 mM/3T l5 or more, particularly preferably 1 mM/2Ti or more, especially preferably 1 mM/Ti or more.
  • a physiologically tolerable carrier e.g. water or Ringers solution
  • the administrable medium may be heated, preferably to an extent such that the temperature of the medium after mixing is close to 37 0 C.
  • the invention provides a method of producing a hyperpolarized hydroxyethylpropionate or its analogs, comprising the step of directly adding hydrogen in a specific nuclear symmetric state to [1- 13 C] acrylic acid.
  • provided herein is a method for preparing hyperpolarized propionate labeled on the carboxyl carbon by hydrolysis of products such as hydroxyethylpropionate or analogous compounds (e.g., esters of other alcohols that are more easily hydrolyzed or whose hydrolysis can be readily monitored using colorimetry) .
  • a method for preparing hyperpolarized propionate labeled on the carboxyl carbon by direct addition of para hydrogen to [1- 13 C] acrylic acid is provided herein.
  • the hyperpolarized hydroxyethylpropionate is labeled on the carboxyl carbon, CH3CH2C*OOCH2CH2OH.
  • the labeled hyperpolarized hydroxyethylpropionate is prepared by reacting hydroxyethylacrylate 13 C labeled on the carboxyl carbon with a hydrogen in a specific nuclear symmetric state.
  • the step of reacting hydroxyethylacrylate 13 C labeled on the carboxyl carbon with hydrogen in a specific nuclear symmetric state is performed in the presence of an appropriate catalyst.
  • the specific nuclear symmetric state is ortho or para.
  • the analog of a hyperpolarized hydroxyethylpropionate is an ester of an alcohol.
  • the invention provides a method for detecting a metabolite in the TCA cycle, in a subject, by a medical imaging device, the method comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid; and detecting said contrast agent, thereby detecting said metabolite in the TCA cycle.
  • the composition of the invention may be detected by any medical imaging device that detects nuclear magnetic resonance.
  • the composition of the invention may be detected by magnetic resonance imaging (MRI) device.
  • the composition of the invention may be detected by magnetic resonance spectroscopy (MRS) device.
  • metabolite is detected by using C NMR spectroscopy to monitor the labeling of aspartate, glutamate and methymalonate.
  • Other suitable devices that detect nuclear magnetic resonance may also be used.
  • the terms "medical imaging,” as used herein, refer to any technique used to detect a metabolite in the human or animal body, for the purposes of diagnosis, research or therapeutic treatment. Such techniques include principally X-ray imaging, MRI, and nuclear imaging, including PET. Agents useful in enhancing such techniques are those materials that enable visualization of a particular metabolite associated with a locus, organ or disease site within the body and/or that lead to some improvement in the quality of the images generated by the imaging techniques, providing improved or easier interpretation of those images. Such agents are referred to herein as contrast agents, the use of which facilitates the differentiation of different parts of the image, by increasing the "contrast" between those different regions of the image.
  • contrast agents thus encompasses agents that are used to enhance the quality of an image that may nonetheless be generated in the absence of such an agent (as is the case, for instance, in MRI), as well as agents that are prerequisites for the generation of an image (as is the case, for instance, in nuclear imaging).
  • the invention provides a method of magnetic resonance imaging (MRI), in a subject, comprising administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid: and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle.
  • MRI magnetic resonance imaging
  • the invention provides a method for diagnosis of a disease mediated by the TCA cycle, in a subject, comprising: administering to said subject a contrast agent that
  • 1 1 ⁇ comprises a hyperpolarized [1- C] propionic acid and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to diagnose said disease.
  • a method of diagnosing a disease associated with the TCA cycle or its intermediates (metabolites, byproducts) comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-administration period, a biological sample is collected from the subject and TCA metabolic flux is analyzed and compared to the TCA metabolic flux from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic flux level is different than the standard by more than a predetermined threshold, the subject has a disease.
  • a method of diagnosing a disease associated with the TCA cycle or its intermediates (metabolites, byproducts), comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-administration period, a biological sample is collected from the subject and TCA metabolic amount is analyzed and compared to the TCA metabolic amount from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic amount is different than the standard by more than a predetermined threshold, the subject has a disease.
  • a method of diagnosing a disease associated with the TCA cycle or its intermediates (metabolites, byproducts), comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-administration period, a biological sample is collected from the subject and TCA metabolic concentration is analyzed and compared to the TCA metabolic concentration from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic concentration is different than the standard by more than a predetermined threshold, the subject has a disease.
  • a method of monitoring a deficiency in TCA cycle in a subject comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-administration period, a biological sample is collected from the subject and a TCA metabolic amount is analyzed and compared to the TCA metabolic amount from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic amount is different than the standard by more than a predetermined threshold, the subject has a deficiency in TCA cycle.
  • the disease associated with a deficient TCA cycle is diabetes.
  • the disease associated with a deficient TCA cycle is a lung disorder.
  • the disease associated with a deficient TCA cycle is cancer.
  • the disease associated with a deficient TCA cycle is an ischemic disease such as but not limited to: atherosclerosis, heart disease, liver disease, kidney disease, circulatory disorders, stroke, or their combination.
  • kits are provided for the practice of this invention.
  • the kit comprises the composition of the present invention.
  • the kit is preferably designed so that the manipulations necessary to perform the desired reaction should be as simple as possible to enable the user to prepare from the kit the desired composition by using the facilities that are at his disposal. Therefore the invention also relates to a kit that comprises a composition of the invention.
  • the kit can optionally, additionally comprise a reducing agent and/or, if desired, a chelator, and/or instructions for use of the composition and/or a prescription for reacting the ingredients of the kit to form the desired product(s). If desired, the ingredients of the kit may be combined, provided they are compatible.
  • the kit components are preferably sterile and can, optionally be provided in a pharmacologically acceptable excipient.
  • the constituent(s) When the constituent(s) are provided in a dry state, the user should preferably use a sterile physiological saline solution as a solvent.
  • the constituent(s) can be stabilized in the conventional manner with suitable stabilizers, for example, ascorbic acid, gentisic acid or salts of these acids, or they may comprise other auxiliary agents, for example, fillers, such as glucose, lactose, mannitol, and the like.
  • kits additionally comprise instructional materials teaching the use of the compositions described herein in electron spin resonance applications for selectively imaging a metabolite in cells, tissue, organs, and the like.
  • provided herein is a method of monitoring TCA cycle metabolism in a subject, comprising the step of administering to a subject a hyperpolarized propionate produced by the methods as described herein.
  • a method of monitoring a deficiency in one or more Krebs' cycle intermediates comprising the step of administering to a subject a hyperpolarized propionate produced by the methods as described herein.
  • a method of monitoring a deficiency in one or more Krebs' cycle intermediates comprising the step of administering to a subject a hyperpolarized propionate produced by the methods as described herein.
  • a method of monitoring a deficiency in one or more Krebs' cycle intermediates comprising the step of administering to a subject a hyperpolarized propionate produced by the methods as described herein.
  • a method of monitoring a deficiency in one or more Krebs' cycle intermediates comprising the step of administering to a subject a hyperpolarized propionate produced by the methods as described herein.
  • provided herein is a method of monitoring a deficiency in malic acid. In another embodiment, provided herein is a method of monitoring a deficiency in fumaric acid. In another embodiment, provided herein is a method of monitoring a deficiency in both malic acid and fumaric acid, hi another embodiment, provided herein that a deficiency in both malic acid and fumaric acid is linked to chronic fatigue. In another embodiment, provided herein that a deficiency in both malic acid and fumaric acid is linked to psoriasis.
  • provided herein is a method of monitoring a deficiency in mitochondrial energy production. In another embodiment, provided herein is a method of monitoring disturbances in mitochondrial energy production. In another embodiment, disturbances in mitochondrial energy production contribute to a neurological disorder. In another embodiment, disturbances in mitochondrial energy production contribute to a physical disorder.
  • provided herein is a method of monitoring impaired oxidative and/or energy metabolism.
  • impaired oxidative and/or energy metabolism are indicators of Alzheimer' s disease.
  • disturbances of energy production create abnormal spilling of Krebs' cycle byproducts into the urine.
  • provided herein is a method of monitoring Krebs' cycle byproducts.
  • provided herein is a method of monitoring spilling of Krebs' cycle byproducts into the urine.
  • the terms byproducts and metabolites are used interchangeably.
  • provided herein is a method of monitoring mitochondrial insufficiency by monitoring Krebs' cycle byproducts. In another embodiment, provided herein is a method of monitoring a neurodegenerative disease by monitoring Krebs' cycle byproducts. In another embodiment, provided herein is a method of monitoring Alzheimer' s disease by monitoring Krebs' cycle byproducts.
  • CFS Chronic Fatigue Syndrome
  • ATP mitochondrial adenosine triphosphate
  • provided herein is a method of monitoring specific Krebs' cycle precursors and intermediates that stimulate energy production. In another embodiment, provided herein is a method of monitoring the effectiveness of supplying a range of Krebs' cycle factors and lactic acid-buffering agents. [0060] In another embodiment, the accumulation of large amounts of metabolic anaerobic byproducts can lower intracellular pH, inhibit muscle contraction, and may cause acidosis. In another embodiment, accumulation of metabolic byproducts, like hydrogen ions, interferes with muscle contractions and ATP energy release.
  • provided herein is a method of monitoring alpha-ketoglutaric acid, malic acid, fumaric acid, succinic acid, citric acid, pyruvic acid, pantothenic acid, or any combination thereof.
  • alpha-ketoglutaric acid, malic acid, fumaric acid, succinic acid, citric acid, pyruvic acid, and pantothenic acid are necessary to generate cellular energy for tissue fuel.
  • provided herein is a method of monitoring a completed Krebs' cycle.
  • provided herein is a method of monitoring the harmful byproducts that are generated from abnormal energy production in the mitochondria.
  • alpha-ketoglutaric acid plays a vital role in the Krebs' cycle production of energy
  • alpha-ketoglutaric acid is a precursor of the amino acid, glutamic acid.
  • AKG stabilizes blood glucose levels during exercise.
  • malic acid acts as a catalyst in the Krebs * cycle to increase energy production from the oxidation of pyruvic acid.
  • malic acid aids in exercise recovery by counteracting the buildup of lactic acid
  • fumaric acid is the trans-isomer of malic acid that enters the citric acid cycle.
  • fumaric acid is a byproduct at certain stages in the arginine-urea cycle and purine biosynthesis.
  • a deficiency of fumaric acid leads to the accumulation of metabolic half-products that may be responsible for causing the skin lesions of psoriasis.
  • provided herein is a method of monitoring a deficiency in fumaric acid.
  • a method of monitoring a deficiency in the accumulation of metabolic half -products of fumaric acid is provided herein.
  • succinic acid is an entry pathway for other metabolites into the cycle and is involved in a variety of important biological actions.
  • succinic acid comprises an enzymatic activity.
  • Succinic acid is combined with protein to rebuild muscle fiber and nerve endings, and helps fight infection.
  • provided herein is a method of monitoring a deficiency characterized by low levels of succinic acid in the urine.
  • the acetic acid subunit of acetyl CoA is combined with oxaloacetate to form a molecule of citrate.
  • a method of monitoring citrate formation is provided herein.
  • a method of monitoring citric acid levels are provided herein.
  • low citric acid levels cause fatigue, poor digestion, cold and flu infections, asthma, hypertension and cholesterol deposits in blood vessels.
  • pyruvic acid is either reduced to lactate in the cytoplasm, or oxidized to acetyl CoA.
  • a method of monitoring acetyl CoA is also provided herein.
  • pantothenic acid is required for the synthesis of coenzyme A.
  • panthenine pantothenate bound to cysteamine reduces elevated levels of free radicals or singlet oxygen in the blood.
  • provided herein is a method of measuring the oxidation of 13 C- enriched substrates in the TCA cycle and/or their entry via anaplerotic pathways.
  • a method of measuring the flux from malate or oxaloacetate into acetyl-CoA via pyruvate is a method of measuring the flux from malate or oxaloacetate into acetyl-CoA via pyruvate.
  • a method of measuring gluconeogenesis based on measuring the flux from malate or oxaloacetate into acetyl-CoA via pyruvate.
  • provided herein is a method of measuring a flux in an isolated biological sample.
  • a method of measuring a flux in an isolated organ sample In another embodiment, provided herein is a method of measuring a flux in an isolated tissue.
  • measuring a flux in an isolated biological sample comprises the use of a nonlinear least squares analysis of hyperpolarized hydroxyethylpropionate labeling kinetics from [1- 13 C] metabolites.
  • 13 C enriched substrates are metabolized and the 13 C label is transferred to various metabolic intermediates.
  • the rate of incorporation of 13 C label is determined by the flux through the TCA cycle.
  • metabolite pool sizes remain constant over the time course of the measurements, the number of unknowns reduces to the number of endogenous and exogenous influxes and the flux through the transaminase reactions.
  • the intermediate pool sizes are defined in order for fluxes to be calculated.
  • the 13 C-labeled hyperpolarized hydroxyethylpropionate enter the network as an influx and is assumed to be the principle sources of energy and of 13 C label in the system.
  • provided herein is a method of monitoring the amounts of cellular energy required. In another embodiment, provided herein is a method of monitoring disruption of the Krebs' cycle. In another embodiment, provided herein is a method of monitoring disruption of the Krebs' cycle by monitoring metabolites of the Krebs' cycle. In another embodiment, provided herein is a method of monitoring disruption of the Krebs' cycle by monitoring the end products of the Krebs' cycle.
  • the invention relates to a method for providing a prognosis of a disease mediated by the TCA cycle, in a subject, comprising: administering to said subject a contrast agent that comprises a hyperpolarized [1- 13 C] propionic acid and detecting said contrast agent, thereby detecting a metabolite in the TCA cycle to provide prognosis of said disease.
  • the invention relates to a method for treating a disease mediated by a metabolite in the TCA cycle in a subject, the method comprising: administering to said subject a contrast agentthat comprises a hyperpolarized [1- 13 C] propionic acid; detecting said contrast agent, thereby detecting said metabolite in the TCA cycle; and treating said condition.
  • a metabolic flux is analyzed by using 13 C NMR spectroscopy to monitor the labeling of aspartate, glutamate and methymalonate.
  • a metabolic flux is analyzed by using 13 C NMR spectroscopy to monitor the labeling of aspartate, glutamate and methymalonate.
  • a metabolite as described herein is measured by using C NMR spectroscopy monitoring the labeling of aspartate, glutamate and methymalonate.
  • the biological sample is blood. In another embodiment, the biological sample is sera. In another embodiment, the biological sample is plasma. In another embodiment, the biological sample is saliva. In another embodiment, the biological sample is sperm. In another embodiment, the biological sample is urine. In another embodiment, the biological sample is mucous. In another embodiment, the biological sample is cerebral spinal fluid.
  • a method of determining the progression of a disease associated with the TCA cycle or its intermediates comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-administration period, a biological sample is collected from a subject and TCA metabolic flux is analyzed and compared the TCA metabolic flux from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic flux level is different than the standard by more than a predetermined threshold, the subject has a disease disorder; or , (b) if the standard is taken from a subject or pool of subjects correctly diagnosed with having a disease and the level of the metabolic flux is different than the standard by more than a predetermined threshold, the subject's disease progression is determined.
  • a method of determining the prognosis of a subject developing a disease associated with the TCA cycle or its intermediates comprising the step of administering to a subject a hyperpolarized propionate, whereby following a predetermined post-
  • a biological sample is collected from a subject and TCA metabolic flux is analyzed and compared the TCA metabolic flux from a standard, whereby: (a) if the standard is taken from a healthy subject or pool of subjects and the metabolic flux level is different than the standard by more than a predetermined threshold, the subject has a disease disorder; or , (b) if the standard is taken from a subject or pool of subjects correctly diagnosed with having a disease and the level of the metabolic flux is different than the standard by more than a predetermined threshold, the subject's prognosis is determined.
  • a method of isolating a labeled propionate in a purified form suitable for parenteral administration comprises acid hydrolysis of CH 3 CH 2 C 51 OOCH 2 CH 2 OH.
  • the method comprises enzymatic hydrolysis of CH S CH I C 11 OOCH 2 CH 2 OH.
  • the method comprises purification of the propionate by rapid ion exchange chromatography.
  • the Ti relaxation time of C is increased at elevated temperatures.
  • hydrolysis and ion exchange chromatography is performed at elevated temperatures and the product is rapidly cooled prior to administration.
  • hydrolysis and ion exchange chromatography is performed at elevated temperatures and the product is rapidly cooled prior to administration by injection,
  • composition of the invention may be conveniently formulated with conventional pharmaceutical or veterinary carriers or excipient.
  • the composition may contain one or more pharmaceutical acceptable additives and/or excipients e.g. buffers; solubilisers such as cyclodextrins; or surfactants such as Pluronic, Tween or phospholipids. Further; stabilisers or antioxidants such as ascorbic acid, gentisic acid or para-aminobenzoic acid and also bulking agents for lyophilisation such as sodium chloride or mannitol may be added.
  • the formulation of the present invention further comprises a base.
  • the base used in the pharmaceutical composition of this invention may be one of those which are known as bases of suppositories.
  • base include oils and fats comprising triglycerides as main components such as cacao butter, palm fat, palm kernel oil, coconut oil, fractionated coconut oil, lard and WITEPSOL ® ., waxes such as lanolin and reduced lanolin; hydrocarbons such as Vaseline, squalene, squalane and liquid paraffin; long to medium chain fatty acids such as caprylic acid, lauric acid, stearic acid and oleic acid; higher alcohols such as lauryl alcohol, cetanol and stearyl alcohol; fatty acid esters such as butyl stearate and dilauryl malonate; medium to long chain carboxylic acid esters of glycerin such as triolein and tristearin; glycerin- substituted carboxylic acid esters such as glycerin acetoacetate; and polyethylene glycols and its derivatives such as macrogols and cetomacrogol. They may be used either singly or in combination
  • composition of this invention may further include a surface-active agent, preservative, and coloring agent, which are ordinarily used in suppositories.
  • the composition may also include a binder conjugated to the deformable particle, where the binder has a preferential affinity for a biochemical marker (e.g., antibody, receptor, ligand, or small molecule).
  • a biochemical marker e.g., antibody, receptor, ligand, or small molecule.
  • the binder may be covalently attached to other molecules.
  • the present invention also provides a pharmaceutical composition comprising an effective amount (e.g. an amount effective for enhancing Image contrast in an in vivo imaging procedure) of the composition or a salt thereof, together with one or more pharmaceutically acceptable adjuvants, excipients or diluents.
  • a polarised composition of the invention may be administered (either alone or with additional components such as additional MR imaging agents) in liquid form.
  • Other suitable forms such as gas or solids may also be used.
  • the retention of polarisation in a liquid medium vis-a-vis a gas medium is significantly greater.
  • T 1 and T 2 are in general shorter for the liquid, the T 2 effect due to diffusion is 10 5 times less significant for the liquid.
  • the composition of the invention may be administered to a subject "parenterally", for example, by intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection or infusion.
  • composition of the invention may, following administration, detect a metabolite at regions of interest, such as heart tissue, liver tissue, tumor tissue or others, to enhance imaging of those regions of interest.
  • regions of interest such as heart tissue, liver tissue, tumor tissue or others.
  • Parenterally administrable forms should of course be sterile and free from physiologically unacceptable agents and should have low osmolality to minimize irritation or other adverse effects upon administration and, thus, the formulation should preferably be isotonic or slightly hypertonic.
  • composition of the invention is to be injected, it may be convenient to inject simultaneously at a series of administration sites such that a greater proportion of the vascular tree may be visualized before the polarization is lost through relaxation.
  • suitable routes of administration include oral, rectal, transmucosal, transnasal, intestinal as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections
  • hyperpolarized hydroxyethylpropionate labeled on the carboxyl carbon of compositions of the present invention is mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • additives customary for this purpose such as vehicles, stabilizers, or inert diluents
  • the preparation is administered in a local rather than systemic manner, for example, via injection of the preparation directly into a specific region of a patient's body.
  • the 13 C-labeled propionic acid is administered by an intravenous injection and enters various tissues such as the heart, liver and probably most other organs.
  • 13 C-labeled propionic acid enters the TCA cycle by formation of succinyl-CoA and is metabolized to succinate, fumarate. malate, oxalloacetate, citrate, isocitrate, ⁇ -ketoglutarate and back to succinyl-CoA.
  • flux through this metabolic pathway is monitored by 13 C NMR spectroscopy by monitoring the labeling of aspartate, glutamate and methymalonate using well known algorithms.
  • the composition for use in in vivo imaging, may conveniently be administered at a concentration sufficient to yield a 1 micromolar to 1 OM concentration of the MR imaging agent in the imaging zone; however the precise concentration and dosage will of course depend upon a range of factors such as toxicity, the organ targeting ability of the composition and the administration route.
  • the dosages of the composition of the invention used according to the method of the present invention will vary according to the precise nature of the composition used, of the tissue or organ of interest and of the measuring apparatus. Preferably the dosage should be kept as low as possible while still achieving a detectable contrast effect. In general, the maximum dosage will depend on toxicity constraints.

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Abstract

L'invention concerne une composition hydrogénée qui comprend du [1-13C]acide propionique hyperpolarisé. En outre, l'invention concerne des procédés de détection ou de diagnostic de déséquilibres dans le cycle de l'acide tricarboxylique (ATC) ou ses intermédiaires, par administration d'un [1-13C]acide propionique hyperpolarisé.
PCT/US2009/039467 2008-04-03 2009-04-03 Compositions et procédés pour détecter un flux métabolique d'acide tricarboxylique (atc) WO2009124250A1 (fr)

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WO2015063020A1 (fr) * 2013-10-28 2015-05-07 Bracco Imaging Spa Procédé de préparation de composés carboxylate hyperpolarisés
WO2015073803A1 (fr) * 2013-11-14 2015-05-21 The University Of Queensland Troubles neurodégénératifs et procédés de traitement et de diagnostic de ceux-ci
US9717705B2 (en) 2006-12-04 2017-08-01 Institut National De La Sante Et De La Recherche Medicale Anaplerotic therapy of huntington disease and other polyglutamine diseases
US10111848B2 (en) 2012-12-13 2018-10-30 National Institute Of Health And Medical Research Triheptanoin for the treatment of glucose transport 1 deficiency

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9717705B2 (en) 2006-12-04 2017-08-01 Institut National De La Sante Et De La Recherche Medicale Anaplerotic therapy of huntington disease and other polyglutamine diseases
US10220014B2 (en) 2006-12-04 2019-03-05 Inserm (Institut National De La Sante Et De La Recherche Medicale) Anaplerotic therapy of huntington disease and other polyglutamine diseases
US10111848B2 (en) 2012-12-13 2018-10-30 National Institute Of Health And Medical Research Triheptanoin for the treatment of glucose transport 1 deficiency
WO2015063020A1 (fr) * 2013-10-28 2015-05-07 Bracco Imaging Spa Procédé de préparation de composés carboxylate hyperpolarisés
US10369236B2 (en) 2013-10-28 2019-08-06 Bracco Imaging S.P.A. Process for the preparation of hyperpolarized carboxylate compounds
US10695448B2 (en) 2013-10-28 2020-06-30 Bracco Imaging S.P.A. Process for the preparation of hyperpolarized carboxylate compounds
WO2015073803A1 (fr) * 2013-11-14 2015-05-21 The University Of Queensland Troubles neurodégénératifs et procédés de traitement et de diagnostic de ceux-ci
US9833430B2 (en) 2013-11-14 2017-12-05 The University Of Queensland Neurodegenerative disorders and methods of treatment and diagnosis thereof

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