Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
• • 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
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/041—Heterocyclic compounds
  • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
  • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07B59/002—Heterocyclic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present disclosure is directed to imaging agents, 5 pharmaceutical compositions and methods for imaging myocardial
• kits comprising said imaging agent or precursor compounds linked or not 10 linked to an imaging moiety.
• Coronary artery disease is a leading cause of death in the Western world. Imaging techniques for diagnosis and prognosis are very i s important for the treatment of CAD to reduce the mortality. Imaging for evaluation the myocardial blood flow to determine the treatment necessary (often surgery) is a critical part of CAD healthcare. Currently Single Photon Emission Computer Tomography (SPECT) is the mainstay of CAD imaging but improved diagnostic methods are needed.
• SPECT Single Photon Emission Computer Tomography
• Heart cells myocardia, have a very high intracellular density
• MCI mitochondria complex I
• Respiratorius a pharmaceutical company based in Lund, Sweden, has been working on discovering novel bronchodilating drugs.
• a central part of Respiratorius' discovery work is screening small molecules that can relax human airway tissue ex vivo.
• a series of novel 1 ,8 naphthyridines were discovered as potent bronchorelaxing compounds (described in patent application WO/2010/097410).
• WO/2010/097410 Upon further pharmacological studies it was found that members of this class of compounds bound to and inhibited mitochondrial complex I.
• a bronchodilating compound belonging to a class of 1 ,8-naphthyridines also can inhibit mitochondrial function by relaxing the airway smooth muscle, alter mitochondrial function or bind to mitochondrial complex I. If the compounds are labelled with an imaging moiety a valuable diagnostic marker for myocardial perfusion imaging will be available.
• the invention relates to an imaging agent having the structure
• R is H, F, CF 3 , CI, R is a linker and X is an imaging moiety or an analogue or pharmaceutically salt of said imaging agent.
• the invention in a second aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising the imaging agent shown above and a
• the imaging agent and composition gives rise to a high cardiac uptake to non-target ratio with minimal redistribution. It will also result in better image quality and disease detection and diagnosis.
• the invention in a third aspect relates to a method of imaging a heart in a patient comprising: administering to the patient a diagnostically 5 effective amount of the imaging agent or pharmaceutical composition defined above, and obtaining an image of the heart of the patient.
• the invention in a final aspect relates to a diagnostic kit comprising a compound having the following formula wherein R is H, F, CF 3 , CI, R is a linker and X is a leaving group selected from the group consisting of tosylate, mesylate, triflate, nonaflate and halogen or an analogue of said compound and wherein said kit can be used to prepare an imaging agent as i s defined above.
• Fig 1 shows a synthetic pathway how to produce an imaging compound.
• “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
• An analogue is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure, such as a difference in the length of an alkyl chain), a molecular fragment, a structure that differs by one or more functional groups, a change in ionization.
• Structural analogues are often found using quantitative structure activity relationships (QSAR), with 5 techniques such as those disclosed in Remington (The Science and
• linking group refers to a portion of a molecule that serves as a spacer between two other portions of the molecule. Linking groups may also serve other functions as described 10 herein. Examples of linking groups include linear, branched, or cyclic
• the invention relates to an imaging agent having the structure
• R is H, F, CF 3 , CI, R is a linker and X is an imaging moiety
• R may be a straight alkyl, ethyleneglycol (ether) or polyethylenglycol.
• R is a linker and X is an imaging moiety.
• X is an imaging moiety.
• Another example being an imaging agent with the formula shown below:
• X may be a halogen isotope, such as a fluorine, bromine, chlorine 10 or iodine isotope.
• a halogen isotope such as a fluorine, bromine, chlorine 10 or iodine isotope.
• Examples includes 18 F, 19 F, 120 l, 121 l, 122 l, 123 l, 124 l, 125 l, 1 27 l, 131 l, 35 CI, 37 CI, 75 Br, 76 Br, 77 Br, 79 Br, 80 Br, 80m Br, 81 Br or 64 Cu.
• 18 F or 19 F is used.
• i pharmaceutically acceptable carrier, diluent, or buffer.
• “Pharmaceutically acceptable” means a non-toxic material that does not decrease the effectiveness of the biological activity of the active ingredients, i.e., the peptide(s), polypeptide(s) or variants thereof.
• Such pharmaceutically acceptable buffers, carriers or excipients are well-known 20 in the art (see Remington's Pharmaceutical Sciences, 18th edition, A.R Gennaro, Ed., Mack Publishing Company (1990) and handbook of
• buffer is intended to mean an aqueous solution
• diluent is intended to mean an aqueous or non-aqueous solution with the purpose of diluting the peptide in the pharmaceutical preparation.
• the diluent may be one or more of saline, water, human serum albumin, e.g., tris (hydroxymethyl) aminomethane (and its salts),
• the labelled compound may be present in from 1.0 to 50 millicuries, such as 1.0-10, 10-20, 20-30, 30-40, 40-50 millicuries
• compositions according to the invention may be administered systemically.
• Routes of administration include parenteral 5 (intravenous, subcutaneous, and intramuscular), oral, parenteral, vaginal and rectal.
• Suitable preparation forms are, for example dispersions, suspensions, aerosols, droples or injectable solution in ampule form and also preparations with protracted release of active compounds, in whose preparation excipients, diluents or carriers are customarily used as
• the imaging agents of the present invention may be used in methods of imaging, including methods of imaging in a patient.
• the method may comprise administering the imaging agent to the patient by injection (e.g., intravenous injection), infusion, or any other i s known method, and imaging the heart of the subject wherein an event of interest is located.
• the useful dosage to be administered and the particular mode of administration will vary depending upon such factors as age, weight, the diagnostic use contemplated, and the form of the formulation, for
• dosage is administered at lower levels and increased until the desirable diagnostic effect (e.g., production of an image) is achieved.
• the above-described imaging agents may
• 25 be administered by intravenous injection, usually in saline solution, at a dose of about 0.1 to about 100 mCi per 70 kg body weight (and all combinations and subcombinations of dosage ranges and specific dosages therein), or, in some embodiments, at a dose of about 0.5 to about 50 mCi. Imaging is performed using techniques well known to the
• Diagnostic kits of the present invention may comprise one or more vials 35 containing a sterile, non-pyrogenic, formulation comprising a
• a reagent e.g., contrast agent precursor
• a reagent of the present invention e.g., contrast agent precursor
• other components such as chelating agents, solvents, buffers, neutrlization aids, lyophilization aids, stabilization aids, solubilization aids and bacteriostats, as described more fully below.
• buffers useful in the preparation of 5 contrast agents and kits include, for example, phosphate, citrate,
• lyophilization aids useful in the preparation of contrast agents and kits include, for example, mannitol, 10 lactose, sorbitol, dextran, FICOLL.RTM. polymer, and polyvinylpyrrolidine (PVP).
• stabilization aids useful in the preparation of contrast agents and kits include, for example, ethanol, ascorbic acid, ethanol, cysteine, monothioglycerol, sodium bisulfite, i s sodium metabisulfite, gentisic acid, and inositol.
• solubilization aids useful in the preparation of contrast agents and kits include, for example, ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates, poly(oxyethylene)- 20 poly(oxypropylene)-poly(oxyethylene) block copolymers
• the compounds and compositions according to the invention may be used with imaging techniques such as positron emission tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
• PET imaging is a diagnostic examination that involves the acquisition of
• SPECT imaging is a 35 three-dimensional technique combined with computer assisted
• PET and SPECT images may be used to evaluate a variety of diseases, and are commonly used in the fields of oncology, cardiology, and neurology.
• imaging agents described herein may be synthesized by reacting at least a first component and a second component, such that a bond is formed there between.
• 18F labeled compounds may be synthesized by reacting two components via displacement of an
• leaving groups include sulfonic acid esters such as toluenesulfonate (tosylate, TsO-), methanesulfonate (mesylate, MsO-), or trifluoromethanesulfonate (triflate, TfO-), nonaflate or halogen.
• the leaving group may also be a halide, a phosphineoxide (via Mitsunobu i s reaction), or an internal leaving group (such as an epoxide or cyclic
• Purification is generally performed via salt removal by reverse- phase chromatography.
• methods of synthesizing the contrast agents may include the use of one or more reaction solvents.
• Representative reaction solvents include, for example, DMF, NMP, DMSO, THF, ethyl acetate,
• reaction solution 25 dichloromethane, and chloroform.
• the reaction solution may be kept
• the chemical transformations may be carried out at ambient temperatures and protected from oxygen and water with a nitrogen, argon or helium atmosphere.
• temporary protecting groups may be used to prevent other reactive functionality, such as amines, thiols, alcohols, phenols, and carboxylic acids, from participating or interfering in the reaction.
• Representative amine protecting groups include, for example, tert-butoxycarbonyl and trityl (removed under mild acidic conditions), 35 Fmoc (removed by the use of secondary amines such as piperidine), and benzyloxycarbonyl (removed by strong acid or by catalytic
• the trityl group may also used for the protection of thiols, phenols, and alcohols.
• carboxylic acid protecting groups include, for example, tert-butyl ester (removed by mild acid), benzyl ester (usually removed by catalytic hydrogenolysis), and alkyl esters such as methyl or ethyl (usually removed by mild base). All protecting groups may be removed at the conclusion of synthesis using the conditions described above for the individual protecting groups, and the final product may be purified by techniques which would be readily apparent to one of ordinary skill in the art, in combination with the teachings described herein.
• N-[[3-fluoro-4-(2-hydroxyethoxymethyl)phenyl]methyl]-2-methyl-1 ,8- naphthyridine-3-carboxamide 45 ⁇ oxalyl chloride (0.53 mmol) was added to a mixture of 50 mg 2- methyl-1 ,8-naphthyridine-3-carboxylic acid (0.27 mmol) in 3 ml CH2CI2 with one drop DMF. The reaction mixture was stirred for 1.5 h and then evaporated to dryness under reduced pressure. The residue was dissolved in 3 ml CH2CI2.

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• Proteomics, Peptides & Aminoacids (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• 2012
  • 2012-12-18 US US14/367,520 patent/US9295738B2/en not_active Expired - Fee Related
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