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WO2013027694A1 - Sondes pour l'imagerie moléculaire permettant de diagnostiquer une maladie de conformation - Google Patents

Sondes pour l'imagerie moléculaire permettant de diagnostiquer une maladie de conformation Download PDF

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WO2013027694A1
WO2013027694A1 PCT/JP2012/070978 JP2012070978W WO2013027694A1 WO 2013027694 A1 WO2013027694 A1 WO 2013027694A1 JP 2012070978 W JP2012070978 W JP 2012070978W WO 2013027694 A1 WO2013027694 A1 WO 2013027694A1
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英郎 佐治
小野　正博
孟超 崔
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Kyoto University NUC
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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
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/66—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/10—The polymethine chain containing an even number of >CH- groups
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/14—Styryl dyes

Definitions

  • the present invention relates to a near-infrared fluorescent compound and a benzoxazole derivative. These compounds can be used for diagnosis of conformational diseases.
  • AD Alzheimer's disease
  • Senile plaque is the most characteristic brain lesion of AD, and its main component is amyloid ⁇ protein (A ⁇ ) having a ⁇ sheet structure. Imaging of senile plaques from outside the body is thought to lead to the establishment of an effective diagnostic method for AD, but imaging requires an amyloid imaging probe that specifically binds to A ⁇ .
  • Known amyloid imaging probes include radioactive probes used in PET and SPECT (Patent Document 1) and fluorescent probes using donor-acceptor type fluorescent molecules (Patent Document 2).
  • a compound used as an amyloid imaging probe is required to have high binding specificity for A ⁇ , high blood-brain barrier permeability, and rapid disappearance from the brain. Furthermore, the compound used as a fluorescent probe is also required to emit near-infrared light excellent in biological penetration.
  • the object of the present invention is to provide a novel compound having the above properties.
  • the present inventor has found that a compound having a benzoxazole skeleton has high binding specificity for A ⁇ , high permeability of the blood brain barrier, and rapid disappearance from the brain.
  • an aromatic ring compound having a dimethylamino group and a dicyanovinyl group emits near-infrared fluorescence, and completed the present invention.
  • any one of R 1 and R 2 is an electron donating group, the other is an electron withdrawing group, X and Y are the same or different, and are a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. And Z is an oxygen atom or a sulfur atom, and m represents an integer of 0 to 5.
  • X and Y are the same or different, and are a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom.
  • Z is an oxygen atom or a sulfur atom
  • m represents an integer of 0 to 5.
  • the electron donating group is a hydroxyl group, methoxy group, methyl group, amino group, methylamino group, dimethylamino group, methylaminophenyl group, or dimethylaminophenyl group
  • the electron withdrawing group is a nitro group, a nitrovinyl group
  • the compound or a pharmaceutically acceptable salt thereof according to (1) which is a cyano group, a dicyanovinyl group, a tricyanovinyl group, or a formyl group.
  • R 3 represents a hydroxy group, a C 1-3 alkoxy group, a C 1-3 alkoxy group containing a radioactive carbon atom, a halogen atom, a radioactive halogen atom, a chelate moiety bonded to a radioactive metal, or — (CH 2 CH 2 O) i -A [wherein i represents an integer of 1 to 10, and A represents a chelate moiety bonded to a halogen atom, a radioactive halogen atom, or a radioactive metal.
  • R 4 represents a hydroxy group, a methoxy group, — (CH 2 CH 2 O) j —OH [wherein j represents an integer of 1 to 10.
  • the radioactive halogen atom is 18 F, 123 I, 124 I or 125 I.
  • the compound or pharmaceutically acceptable salt thereof according to (3), wherein the chelate moiety bound to the radioactive metal is a chelate moiety that binds to 99m Tc or 68 Ga.
  • a composition for diagnosing conformation disease comprising the compound according to any one of (1) to (5).
  • the compound of the present invention has a high binding specificity for A ⁇ , it is useful for early and accurate diagnosis of conformational diseases such as AD.
  • the synthesis route of the near-infrared fluorescent compound of Example 1. The fluorescence spectrum of the near-infrared fluorescent compound of Example 1. The upper curve was measured in the presence of A ⁇ , and the lower curve was measured in the absence of A ⁇ . The figure which shows the result of the saturation binding assay to the A (beta) 42 aggregate of the near-infrared fluorescent compound of Example 1.
  • FIG. Fluorescent staining of a Tg model mouse brain tissue section using the near-infrared fluorescent compound of Example 1. Fluorescence imaging of Tg model mice using KR-5. Fluorescent staining of Tg model mouse brain tissue sections using KR-5.
  • the synthesis route of the near-infrared fluorescent compound of Example 2 (hereinafter sometimes referred to as “DANIR”).
  • Fluorescence spectra of near-infrared fluorescent compounds of Example 2 (A and B, DANIR-1; DC and D, DANIR-2; E and F, DANIR-3; G and H, DANIR-4; left, EX right, EM).
  • a and B DANIR-1; DC and D, DANIR-2; E and F, DANIR-3; G and H, DANIR-4; left, EX right, EM).
  • DANIR 2-4 Fluorescent staining of DANIR 2-4 on a section of brain tissue from AD human (93 years old,) female).
  • DANIR-2 A, Tx-red
  • DANIR-3 C, Cy5
  • DANIR-4 (E, Cy5.5).
  • A, C, E A ⁇ plaque
  • B, D, F NFTs (neurofibrillary tangles).
  • Reagents (a) dimethylamine, H 2 O; (b) malononitrile, pyridine, 2-propanol; (c) (1,3-dioxalan-2-ylmethyl) triphenylphosphonium bromide, NaH, 18-crown-6, THF. Fluorescent staining of brain sections of Tg2576 mice. A, C, E, G, I, and K are images stained with DTA-0, DTA-1, DFA-1, DTA-2, DFA-2, and DTA-3, respectively. B, D, F, H, J, and L are images obtained by staining adjacent sections of A, C, E, G, I, and K with thioflavin S, respectively.
  • R 1 and R 2 in general formula (I) may be either one of an electron donating group and the other an electron withdrawing group, but R 1 is an electron In the donor group, R 2 is preferably an electron withdrawing group.
  • R 1 in the general formula (I) may be in any position on the heterocyclic ring, but is preferably in the 6-position (position assuming that the heterocyclic ring is benzothiazole).
  • the electron donating group in formula (I) is preferably a hydroxyl group, a methoxy group, a methyl group, an amino group, a methylamino group, a dimethylamino group, a methylaminophenyl group, or a dimethylaminophenyl group, and more preferably Is a dimethylamino group.
  • the electron withdrawing group in the general formula (I) is preferably a nitro group, a nitrovinyl group, a cyano group, a dicyanovinyl group, a tricyanovinyl group, or a formyl group, and more preferably a dicyanovinyl group.
  • X in the general formula (I) is preferably nitrogen.
  • Y in the general formula (I) is preferably sulfur.
  • M in the general formula (I) may be an integer of 0 to 5, and is preferably 1 or 2.
  • m when m is 0, it means that R 2 is directly bonded to the heterocyclic ring.
  • Typical compounds among the compounds represented by the general formula (I) are shown in the following table.
  • “Me” represents a methyl group
  • “Dicyano” represents a dicyanovinyl group
  • “Tricyano” represents a tricyanovinyl group
  • “6-” represents a 6-position (complex of general formula (I)). It represents that the ring is a group at the position (assuming that it is benzothiazole).
  • preferred compounds include I-23 (KR-5), I-35 (KR-7), and I-47 (KR-9).
  • the compound represented by the general formula (I) can be synthesized by bonding an electron donating group and an electron withdrawing group directly or via an unsaturated carbon chain to a heterocyclic compound such as benzothiazole.
  • R 1 in the general formula (II) may be in any position on the benzene ring, but is preferably in the para position.
  • the electron donating group in the general formula (II) is preferably a hydroxyl group, a methoxy group, a methyl group, an amino group, a methylamino group, a dimethylamino group, a methylaminophenyl group, or a dimethylaminophenyl group, and more preferably Is a dimethylamino group.
  • the electron withdrawing group in the general formula (II) is preferably a nitro group, a nitrovinyl group, a cyano group, a dicyanovinyl group, a tricyanovinyl group, or a formyl group, and more preferably a dicyanovinyl group.
  • M in the general formula (II) may be an integer of 0 to 5, but is preferably 2 or 3.
  • m when m is 0, it means that R 2 is directly bonded to the benzene ring.
  • Typical compounds among the compounds represented by the general formula (II) are shown in the following table.
  • “Me” represents a methyl group
  • “Dicyano” represents a dicyanovinyl group
  • “Tricyano” represents a tricyanovinyl group
  • “p-” represents a para-position group.
  • preferred compounds include II-11 (DANIR-1), II-23 (DANIR-2), II-35 (DANIR-3), and II-47 (DANIR-4).
  • the compound represented by the general formula (II) can be synthesized by bonding an electron donating group and an electron withdrawing group to a compound having a benzene ring directly or via an unsaturated carbon chain.
  • C Compound represented by the general formula (III)
  • the “C 1-3 alkoxy group” is, for example, a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group. .
  • the “C 1-3 alkyl group” is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
  • halogen atom is, for example, F, Cl, Br, or I.
  • the “radiohalogen atom” is, for example, 18 F, 131 I, 125 I, 123 I, 124 I, 77 Br, or 76 Br.
  • the “radioactive carbon atom” is, for example, 11 C.
  • the “radioactive metal” is, for example, 99m Tc, 62 Cu, 67 Ga, or 68 Ga. As these radioactive metals, 99m Tc and 68 Ga are suitable.
  • a chelate moiety bonded to a radioactive metal is, for example, an N 2 S 2 type metal chelate moiety bonded to the radioactive metal.
  • R 3 in the general formula (III) is preferably a radioactive halogen atom, and more preferably 18 F, 123 I, 124 I or 125 I.
  • R 4 in the general formula (III) is preferably a group represented by —NRaRb, and more preferably a dimethylamino group or a methylamino group.
  • N in the general formula (III) may be an integer of 0 to 5, but is preferably 1, 2, or 3.
  • n when n is 0, it means that R 3 is directly bonded to the benzoxazole ring.
  • i is preferably 1, 2, or 3.
  • J in the formula: — (CH 2 CH 2 O) j —OH is preferably 1, 2, or 3.
  • K in the formula: — (CH 2 CH 2 O) k —F is preferably 1, 2, or 3.
  • preferred compounds include III-26 ([ 18 F] compound 7) and III-27 ([ 18 F] compound 15).
  • the compound represented by the general formula (III) can be synthesized according to the method described in the examples or according to a method in which those methods are appropriately modified or modified with reference to the description.
  • R 1 and R 2 (D) a compound represented by the general formula (IV) formula in (IV) is a one of an electron donating group, but the other may be an electron withdrawing group, R 1 is an electron In the donor group, R 2 is preferably an electron withdrawing group.
  • R 1 in the general formula (IV) may be in any position on the heterocycle, but is preferably in the 5-position (position when the heterocycle is assumed to be thiophene).
  • the electron donating group in the general formula (IV) is preferably a hydroxyl group, a methoxy group, a methyl group, an amino group, a methylamino group, a dimethylamino group, a methylaminophenyl group, or a dimethylaminophenyl group, and more preferably Is a dimethylamino group.
  • the electron withdrawing group in the general formula (IV) is preferably a nitro group, a nitrovinyl group, a cyano group, a dicyanovinyl group, a tricyanovinyl group, or a formyl group, and more preferably a dicyanovinyl group.
  • M in the general formula (IV) may be an integer of 0 to 5, and is preferably 1 or 2.
  • m when m is 0, it means that R 2 is directly bonded to a thiophene ring or the like.
  • Typical compounds among the compounds represented by the general formula (IV) are shown in the following table.
  • “Me” represents a methyl group
  • “Dicyano” represents a dicyanovinyl group
  • “Tricyano” represents a tricyanovinyl group
  • “5-” represents the 5-position (complex of general formula (IV)). It represents that the ring is a group at the position when it is assumed to be thiophene.
  • preferred compounds are IV-23 (DTA-1), IV-35 (DTA-2), IV-47 (DTA-3), IV-71 (DFA-1), IV-83 (DFA -2).
  • the compound represented by the general formula (IV) can be synthesized by bonding an electron donating group and an electron withdrawing group directly or via an unsaturated carbon chain to a compound having a thiophene ring or a furan ring.
  • (E) Composition for diagnosing conformation disease The composition containing the compounds represented by the general formulas (I) to (IV) described above can be used for diagnosis of conformation disease.
  • pharmaceutically acceptable salts can be used in place of the compounds represented by the general formulas (I) to (IV).
  • examples of pharmaceutically acceptable salts include alkali metal salts (sodium salt, potassium salt, lithium salt), alkaline earth metal salts (calcium salt, magnesium salt), sulfate, hydrochloride, nitrate, phosphate, etc. it can.
  • Conformation disease means a group of diseases caused by proteins that have become abnormal due to conformational transformation such as A ⁇ , tau protein, prion, etc.
  • AD hereditary cerebral dysemia with Down syndrome and Dutch amyloidosis (hereditary) cerebral hemorrhage with amyloidosis-Dutch type: HCHWA-D), Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), and type 2 diabetes.
  • diseases to be diagnosed include precursor symptoms of diseases that are generally not recognized as “diseases”. Examples of prodromal symptoms of such diseases include mild cognitive impairment (MCI) seen before the onset of AD.
  • MCI mild cognitive impairment
  • this composition is usually administered to a subject to be diagnosed or a laboratory animal, and then a brain image is taken and represented by the general formulas (I) to (IV) in the image. Based on the state (amount, distribution, etc.) of the compound to be produced.
  • the method of administration of the composition is not particularly limited and can be appropriately determined according to the type of compound, the type of labeling substance, etc., but is usually intradermal, intraperitoneal, intravenous, arterial or spinal fluid injection or Administer by infusion.
  • the dose of the composition is not particularly limited, and can be appropriately determined according to the type of compound, the type of labeling substance, etc.
  • the compound represented by general formulas (I) to (IV) is 1 It is preferable to administer 10 ⁇ 10 to 10 ⁇ 3 mg per day, and more preferably 10 ⁇ 8 to 10 ⁇ 5 mg.
  • this composition since this composition is usually administered by injection or infusion, it may contain components usually contained in injection solutions or infusion solutions.
  • Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.), antibacterial agents And local anesthetics (eg, procaine hydrochloride, dibucaine hydrochloride, etc.), buffer solutions (eg, Tris-HCl buffer solution, Hepes buffer solution, etc.), osmotic pressure regulators (eg, glucose, sorbitol, sodium chloride, etc.) .
  • liquid carriers for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.
  • All the compounds showed binding ability to A ⁇ aggregates in the order of nM, and the binding properties improved in the order of PP-BTA-1 ⁇ KR-5 ⁇ KR-9 ⁇ KR-7.
  • the bound and free radioactivity was then separated by vacuum filtration through a borosilicate glass fiber filter (Whatman GF / B) using an M-24 cell harvester (Brandel, Gaithersburg, MD).
  • the radioactivity of the filter containing bound 125 I ligand was measured with a ⁇ -counter (WALLAC / Wizard 1470, USA) with an efficiency of 70%. Under the assay conditions, the specific binding fraction accounted for 10% of the total radioactivity.
  • DANIR-3 Brain fluorescence imaging of DANIR-3 in vivo in normal and Tg mice (FIGS. 14 and 15) 50 ⁇ L of DANIR-3 (0.4 mg / kg, 20% DMSO, 80% propylene glycol) was injected into normal C57-BL6 and Tg-2576 (20 months) mice in vivo. Fluorescent signals from the brain were recorded by the Xenogen's IVIS 200 Imaging station at various times after injection and the data analyzed by Living Image Software. The ROI was drawn around the brain area and a time intensity curve was drawn.
  • Example 3 Benzoxazole Derivatives (1) General Review Unless otherwise indicated, all reagents were obtained commercially and used without further purification. Using a JEOL JNM-AL400 NMR spectrometer at 400 MHz, a 1 H-NMR spectrum was obtained in CDCl 3 solution using TMS as an internal standard. Chemical shifts are reported as ⁇ values relative to the internal standard TMS. Coupling constants are reported in Hertz. Multiplicity is defined by s (single line), d (double line), t (triple line), and m (multiple line). Mass spectra were obtained with Shimadzu GC MS-QP2010 Plus (APCI).
  • [18 F] 7 and [18 F] 15 procedure [18 F] labeled fluoride is produced by 18 O (p, n) 18 F reaction by JSW TypeBC3015 cyclotron, 18 O enriched water The solution was passed through a Sep-Pak Light QMA cartridge (Waters). The cartridge was dried in a stream of air and the 18 F - activity was eluted with K 2 CO 3 solution (33 mM). Kryptofix 222 (6-8 mg) was dissolved in [ 18 F] fluoride aqueous solution. The solvent was removed at 120 ° C. under a nitrogen stream. The residue was azeotroped twice with 0.3 mL anhydrous acetonitrile at 120 ° C. under a stream of nitrogen.
  • the bound and free radioactive fractions were then separated by vacuum filtration using a M-24 cell harvester (Brandel, Gaithersburg, MD) through a borosilicate glass fiber filter (Whatman GF / B). Radioactivity from the filter containing bound 125 I ligand was measured with a ⁇ -counter (WALLAC / Wizard 1470, USA) with 70% efficiency. Under the assay conditions, the specific binding fraction accounted for 10% of the total radioactivity.
  • Sections were incubated with radiolabeled tracer (10 ⁇ Ci / 100 ⁇ L) for 1 hour at room temperature, then washed with 50% ethanol for 1 hour and rinsed with water for 1 minute. After drying, the labeled sections were exposed to a Fujifilm imaging plate overnight. In vitro autoradiographic images were obtained using the BAS5000 scanner system (Fuji Film). The presence and location of plaques in the sections were confirmed by fluorescent staining with thioflavin S or immunohistochemical staining with BC05 (Wako), a monoclonal A ⁇ 1-42 antibody.
  • a ⁇ (1-42) aggregates PBS (pH 7.4) was used to prepare A ⁇ (1-42) at a concentration of 0.25 mg / mL.
  • An A ⁇ (1-42) aggregate solution was prepared by incubating at 37 ° C. for 42 hours. The aggregate solution was stored at ⁇ 80 ° C. until used for experiments.
  • DTA1-3 and DFA-1,2 had binding affinity for A ⁇ aggregates.
  • DTA-0 showed no binding affinity for A ⁇ aggregates.
  • the five compounds except DTA-0 selectively bound to amyloid plaques accumulated on model mouse brain slices. Moreover, when it stained with thioflavin S using the adjacent section
  • a ⁇ imaging reagents for the purpose of AD diagnosis, development support for therapeutic agents targeting A ⁇ , and disease state determination using A ⁇ accumulation in AD patients as an index.

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Abstract

L'objet de la présente invention concerne un composé émettant une lumière dans le proche infrarouge ayant la capacité de se lier très spécifiquement à l'Aβ, une perméabilité élevée à travers la barrière hémato-encéphalique, la capacité de disparaître rapidement du cerveau, et une bioperméabilité élevée. Un composé ayant un squelette benzoxazole et un composé aromatique contenant un groupe diméthylamino, un groupe dicyanovinyle, etc. sont également décrits. Dans la formule (I), soit R1 soit R2 est un groupe donneur d'électrons et l'autre est un groupe attracteur d'électrons; X et Y sont identiques ou différents et chacun représente un atome de carbone, un atome d'azote, un atome d'oxygène ou un atome de soufre; et m est un entier de 0 à 5.
PCT/JP2012/070978 2011-08-24 2012-08-20 Sondes pour l'imagerie moléculaire permettant de diagnostiquer une maladie de conformation Ceased WO2013027694A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108276296A (zh) * 2017-12-13 2018-07-13 潍坊润中精细化工有限公司 一种氰化物解毒剂的合成方法
KR20210107294A (ko) * 2020-02-24 2021-09-01 건국대학교 산학협력단 알부민 정량을 위한 근적외선 형광 센서

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531133A (ja) * 2000-04-13 2003-10-21 エイチエスシー リサーチ アンド ディベロップメント リミテッド パートナーシップ 細胞増殖を調節する新規化合物
JP2004506723A (ja) * 2000-08-24 2004-03-04 ユニバーシティー　オブ　ピッツバーグ アルツハイマー病の生前診断ならびにアミロイド沈着物のインビボ画像化および予防に用いるためのチオフラビン誘導体
WO2007041241A2 (fr) * 2005-09-30 2007-04-12 The Trustees Of Columbia University In The City Of New York Compositions et procedes permettant la detection des interactions ligand-recepteur
JP2008546804A (ja) * 2005-06-24 2008-12-25 ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア 造影剤として用いるためのリガンドの放射性標識ペグ化
JP2009516649A (ja) * 2005-10-31 2009-04-23 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害薬
JP2010189359A (ja) * 2009-02-20 2010-09-02 Kyoto Univ ベンゾチアゾール誘導体含有診断用組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531133A (ja) * 2000-04-13 2003-10-21 エイチエスシー リサーチ アンド ディベロップメント リミテッド パートナーシップ 細胞増殖を調節する新規化合物
JP2004506723A (ja) * 2000-08-24 2004-03-04 ユニバーシティー　オブ　ピッツバーグ アルツハイマー病の生前診断ならびにアミロイド沈着物のインビボ画像化および予防に用いるためのチオフラビン誘導体
JP2008546804A (ja) * 2005-06-24 2008-12-25 ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア 造影剤として用いるためのリガンドの放射性標識ペグ化
WO2007041241A2 (fr) * 2005-09-30 2007-04-12 The Trustees Of Columbia University In The City Of New York Compositions et procedes permettant la detection des interactions ligand-recepteur
JP2009516649A (ja) * 2005-10-31 2009-04-23 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害薬
JP2010189359A (ja) * 2009-02-20 2010-09-02 Kyoto Univ ベンゾチアゾール誘導体含有診断用組成物

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FERRIGHI,L. ET AL.: "Density-functional-theory study of the electric-field-induced second harmonic generation (EFISHG) of push-pull phenylpolyenes in solution", CHEMICAL PHYSICS LETTERS, vol. 425, no. 4-6, 2006, pages 267 - 272, XP027876658, DOI: doi:10.1016/j.cplett.2006.04.112 *
GRACZA,T. ET AL.: "New method of preparation of 5-(dimethylamino)-2-furylethylenes via furan vinamidinium salts", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 51, no. 4, 1986, pages 879 - 88 *
HROBARIK,P. ET AL.: "Computational design of benzothiazole-derived push-pull dyes with high molecular quadratic hyperpolarizabilities", PHYSICAL CHEMISTRY CHEMICAL PHYSICS, vol. 6, no. 3, 2004, pages 495 - 502 *
LAPORTE,S.L. ET AL.: "The application of malononitriles as microviscosity probes in pharmaceutical systems", PHARMACEUTICAL RESEARCH, vol. 12, no. 3, 1995, pages 380 - 6, XP002954839, DOI: doi:10.1023/A:1016252518401 *
LEE,H.S. ET AL.: "Chemometric studies on brain-uptake of PET agents via VolSurf analysis", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 29, no. 1, 2008, pages 61 - 68 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108276296A (zh) * 2017-12-13 2018-07-13 潍坊润中精细化工有限公司 一种氰化物解毒剂的合成方法
CN108276296B (zh) * 2017-12-13 2020-09-11 潍坊润中精细化工有限公司 一种氰化物解毒剂的合成方法
KR20210107294A (ko) * 2020-02-24 2021-09-01 건국대학교 산학협력단 알부민 정량을 위한 근적외선 형광 센서
KR102302318B1 (ko) 2020-02-24 2021-09-14 건국대학교 산학협력단 알부민 정량을 위한 근적외선 형광 센서

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