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• • 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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to the use of a specific compound, as described in detail below, having a high affinity to the peripheral benzodiazepine receptor for imaging cardiac and cardiovascular diseases for which inflammation and/or mitochondrial dysfunction and any other pathophysiological process leading to PBR activation are major contributing factor .
• CVD cardiovascular disease
• Heart Diseases of the heart (cardio) Diseases of the blood vessels (vascular)
• the heart diseases to be considered are coronary artery disease, ischemic or other cardiomyopathy, inflammatory valvular heart disease, inflammatory pericardial disease,, heart failure of different origin, myocarditis.
• the blood vessel disorders to be considered are arteriosclerosis and atherosclerosis of any vessel, high blood pressure, stroke, aneurysm, peripheral arterial disease, vasculitis, venous incompetence, venous thrombosis, lymphedema.
• Kidney diseases to be considered are ischemia-reperfusion injury, acute and/or chronic renal failure, nephrosclerosis, autoimmune diseases affecting the kidneys. Autoimmune diseases to fall under the patent e.g. rheumatoid arthritis, MS and others.
• PBRs are expressed in blood cells, e.g. platelets, lymphocytes, and mononuclear cells.
• this receptor is part of the mitochondrial transition pore and known to be expressed in heart cells as well, i.e. striated cardiac muscle cells and vascular smooth muscle cells, mast cells as well as endothelial cells.
• Inflammation and/or mitochondrial dysfunction are involved in most of the cardiovascular diseases as well as in many other cardiac, vascular and kidney diseases. Therefore, as a consequence of any injury (trauma, ischemia) immune cells bearing the peripheral benzodiazepine receptor infiltrate into the respective organs, i.e. heart, kidneys, vascular wall, and upregulate the PBR receptor upon activation.
• PBR central benzodiazepine receptor
• Leducq et al JPET, vol 306, N°3, 828-837, 2003 discloses that peripheral benzodiazepine receptors play a major role in the regulation of cardiac ischemia- reperfusion injury.
• SSR180575 a pyridazazino-indol derivative is seen as a novel peripheral benzodiazepine receptor ligand.
• phenyloxyaniline derivatives having a high affinity for peripheral benzodiazepine receptor can be used for imaging cardiovascular diseases for which inflammation and/or mitochondrial dysfunction are/is a major contributing factor
• the object of the present invention is to provide the use of the compound which is useful as a ligand for PBR 1 having a strong affinity and a high selectivity and, in an external measurement of PBR where a sufficient signal has not been obtained until now, to label a ligand of PBR having a high affinity and a high selectivity with a positron nuclide whereby measurement of PBR in a living body is made possible for imaging cardiovascular diseases and more particularly vessel, heart and kidney diseases for which inflammation and/or mitochondrial dysfunction are major contributing factor.
• diseases are e.g.
• aneurysms e.g. athersclerosis, cardiomyopathy and some other heart diseases, heart failure, inflammatory valvular disease, coronary artery disease, endocarditis, atheroma, arteriosclerosis, inflammatory diseases of the heart, e.g. myocarditis, inflammatory cardiomyopathy, renal diseases, autoimmune diseases and nephrosclerosis.
• the invention concerns the use of compound of formula 1 for imaging vessel, heart, and kidney diseases for which inflammation and/or mitochondrial dysfunction are major contributing factor.
• X1 and X2 are independently from each other a hydrogen atom or a halogen atom
• R1 and R2 are independently from each other a hydrogen atom, alkyl group having 1 to 10 carbon(s), a halogen-substituted alkyl group having 1 to 10 carbon(s) or radioisotope
• R3 is a halogen substituted alkyl group having 1 to 5 carbon(s) or a radioisotope thereof.
• the halogen atom in R3 is a fluorine atom, an iodine atom or a bromine atom and, more preferably, a fluorine atom or an iodine atom.
• the radioisotope in the present invention is 11 C, 18 F, 123 1 and more preferably 18 F.
• Kidney diseases are selected from ischemia-reperfusion injury, acute and/or chronic renal failure, nephrosclerosis, autoimmune diseases affecting the kidneys.
• the diseases are selected from myocarditis, atheroma, arteriosclerosis.
• the compound 1 is
• [ 18 F]FMDAA1106) or N-[2-(2-[ 18 F]fluoro)ethyl-5-methoxybenzyl]-N-(5-fluoro-2-phenoxyphenyl)acetamide hereinafter, referred to as [ 18 F]FEDAA1106.
• the alkyl group having 1 to 10 carbon(s) means a linear or branched alkyl group and its examples are a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an n-heptyl group.
• the halogen-substituted alkyl group having 1 to 10 carbon(s) means a linear or branched alkyl group where 1 to 3 halogen atom(s) is/are substituted for a hydrogen atom(s) and, preferably, it is an alkyl group substituted with fluorine or iodine atom(s). Examples thereof are a fluoromethyl group, a 2-fluoroethyl group, an 2-iodoethyl group, a 5-fluoroheptyl group and a 6-bromohexyl group.
• the halogen-substituted alkyl group having 1 to 5 carbon(s) means a linear or branched alkyl group where 1 to 3 halogen atom(s) is/are substituted for a hydrogen atom(s) and, preferably, it is an alkyl group substituted with fluorine or iodine atom(s). Examples thereof area fluoromethyl group, a 2-fluoroethyl group, an 2-iodoethyl group and a 5-fluoroheptyl group.
• the invention relates to the use of compound of formula 1 for imaging peripheral inflammatory disease, characterized by infiltration of white blood cells, e.g. osteomyelitis or rheumatoid arthritis for which inflammation and/or mitochondrial dysfunction are/is a major factor of incidence.
• white blood cells e.g. osteomyelitis or rheumatoid arthritis for which inflammation and/or mitochondrial dysfunction are/is a major factor of incidence.
• the invention relates to the use of compound of formula 1 for imaging autoimmune diseases.
• the autoimmune disease is selected from Multiple sclerosis, rheumatoid arthritis, Amyotrophic lateral sclerosis (ALS), and others
• N-(2-fluoromethyl-5-methoxybenzyl)-N-(5-fluoro-2- phenoxyphenyl)acetamide (hereinafter, referred to as FMDAA1106)
• An oily sodium hydride (60%) (5.1 mg) was added to a solution of N-(2-hydroxy-5- methoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (hereinafter, referred to as DAA1123) (18 mg) in N,N-dimethylformamide (DMF; 1.0 mL) followed by stirring at 0[deg.] C, 10 mg of fluoromethyl iodide (FCH2I) were added thereto and the mixture was further stirred at 0[deg.] C.
• DMF N,N-dimethylformamide
• [ 18 F]fluorine ([ F]F) was produced by irradiation of 18 MeV proton using 20 atom.% H218 O. After the irradiation, [ 18 F]F was recovered from a target, separated from [ 18 O]H2O by an anion-exchange resin Dowex 1-X8, mixed with acetonitrile (CH3CN, 1.5 mL) containing Kryptofix 2.2.2. (25 mg) and transferred from an irradiation chamber to a synthetic cell.
• FEDAA1106 Production of N-[2-(2-fluoro)ethyl-5-methoxybenzyl]-N-(5-fluoro-2- phenoxyphenyl)acetamide (hereinafter, referred to as FEDAA1106)
• FCH2CH2OTs 1-fluoro-2- tosyloxyethane
• FCH2I fluoromethyl iodide
• a compound which is useful as a ligand for PBR having a strong affinity and a high selectivity In an external measurement of PBR where a sufficient signal has not been obtained until now, a ligand of PBR having a high affinity and a high selectivity is labeled with a positron nuclide whereby measurement of PBR in a living body is now possible.

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• 2007
  • 2007-05-30 EP EP07010701A patent/EP1997515A1/en not_active Withdrawn
• 2008
  • 2008-05-21 JP JP2010509713A patent/JP2010528073A/ja not_active Withdrawn
  • 2008-05-21 CA CA002687729A patent/CA2687729A1/en not_active Abandoned
  • 2008-05-21 EP EP08758650A patent/EP2155263A2/en not_active Withdrawn
  • 2008-05-21 US US12/602,238 patent/US20100178248A1/en not_active Abandoned
  • 2008-05-21 WO PCT/EP2008/004042 patent/WO2008145283A2/en not_active Ceased
  • 2008-05-29 TW TW097119789A patent/TW200914055A/zh unknown
  • 2008-05-30 AR ARP080102269A patent/AR066768A1/es unknown

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