WO2011108236A1 - 放射性ヨウ素標識有機化合物またはその塩 - Google Patents
放射性ヨウ素標識有機化合物またはその塩 Download PDFInfo
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- WO2011108236A1 WO2011108236A1 PCT/JP2011/001075 JP2011001075W WO2011108236A1 WO 2011108236 A1 WO2011108236 A1 WO 2011108236A1 JP 2011001075 W JP2011001075 W JP 2011001075W WO 2011108236 A1 WO2011108236 A1 WO 2011108236A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to a radioactive iodine-labeled organic compound or a salt thereof.
- tauopathy a disease in which a structure containing a tau protein aggregate as a main constituent is expressed in the brain is called tauopathy.
- tauopathy a disease in which a structure containing a tau protein aggregate as a main constituent is expressed in the brain.
- tauopathy a disease in which a structure containing a tau protein aggregate as a main constituent is expressed in the brain.
- tauopathy a disease in which a structure containing a tau protein aggregate as a main constituent is expressed in the brain.
- tauopathy a disease in which a structure containing a tau protein aggregate as a main constituent is expressed in the brain is called tauopathy.
- typical tauopathy Alzheimer's disease, frontotemporal dementia, Pick's disease, basal ganglia degeneration, progressive supranuclear paralysis, and the like are known.
- tau protein aggregates are expressed in the brain of tauopathy patients, and such pathological degeneration is considered to play an important role in these disease symptoms. .
- many studies aimed at the diagnosis and treatment of tauopathy have been conducted with aggregated tau protein as the main target.
- various tau protein fibrosis inhibitors including rhodanine have been found as compounds having affinity for tau protein aggregates (Non-patent Documents 1 and 2).
- various quinoline derivatives and benzimidazole derivatives have been disclosed as biomarkers targeting tau protein aggregates (Non-patent Document 3, Patent Document 1, and Patent Document 2).
- the present invention has been made in view of the above circumstances, and an object thereof is to provide a novel radioactive organic compound having affinity for tau protein aggregates and a tauopathy diagnostic agent containing the compound.
- R 1 is a sulfur atom or a nitrogen atom
- R 2 is a substituent represented by the following formula (2) or the following formula (3)
- R 3 is radioactive iodine.
- an imaging agent comprising a compound represented by the above formula (1) or a salt thereof and used for imaging tau protein.
- an injection containing the compound represented by the above formula (1) or a salt thereof there is provided an injection containing the compound represented by the above formula (1) or a salt thereof.
- a radioactive iodine-labeled precursor comprising a compound represented by the following formula (4) or a salt thereof is provided.
- R 1 is a sulfur atom or a nitrogen atom
- R 2 is a substituent represented by the above formula (2) or the above formula (3)
- R 4 is an alkyl chain having a carbon number.
- a trialkylstannyl substituent having a length of 1 to 4 a trialkylammonium substituent having an alkyl chain having a length of 1 to 4 carbon atoms, or a triphenylstannyl substituent.
- an apparatus for producing a compound represented by the above formula (1) or a salt thereof by radioiodination of the above radioiodine labeled precursor Furthermore, according to the present invention, there is provided an apparatus for producing a compound represented by the above formula (1) or a salt thereof by radioiodination of the above radioiodine labeled precursor.
- a radioiodine-labeled organic compound having high selectivity for tau protein and high brain migration is provided.
- A is a figure which shows the fluorescent dyeing result by the compound 3
- B is a figure which shows the dyeing result by an anti- phosphorylated tau protein antibody.
- the present invention is a compound represented by the above formula (1) or a salt thereof, preferably a rhodanine derivative represented by the following formula (5) or a thiohydantoin derivative represented by the following formula (6): is there.
- the compound represented by the formula (5) corresponds to a compound in which R 1 is a sulfur atom and R 2 is a substituent represented by the above formula (2) in the above formula (1).
- R 2 is a 2- (4-imidazolyl) ethyl group or an ethoxycarbonylethyl group.
- the compound in which R 2 is an ethoxycarbonylethyl group is represented by the above formula (1), wherein R 1 is a nitrogen atom and R 2 is represented by the above formula (2). It corresponds to a compound which is a substituent.
- the compound in which R 2 is a 2- (4-imidazolyl) ethyl group is represented by the following formula (1), wherein R 1 is a nitrogen atom and R 2 is It corresponds to a compound which is a substituent represented by the formula (3).
- R 3 is radioactive iodine. It is not necessary to particularly limited radioactive iodine, preferably can be used 123 I, 124 I, 125 radioiodine selected from the group consisting of I and 131 I, and more preferably can be used 123 I . In short, any nuclide that can be used for nuclear medicine image diagnosis such as single photon emission computed tomography (SPECT) may be used.
- SPECT single photon emission computed tomography
- the compound represented by the formula (1) may form a salt, such as an acid addition salt such as an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromide, phosphate) Etc.), organic acid salts (eg acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonic acid) Salt, p-toluenesulfonate, etc.). Further, the compound represented by the formula (1) or a salt thereof may be a hydrate.
- an acid addition salt such as an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromide, phosphate) Etc.), organic acid salts (eg acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonic acid) Salt, p-
- the compound represented by the formula (1) or a salt thereof can be obtained by labeling the compound represented by the above formula (4) or a salt thereof with radioactive iodine.
- the compound represented by the formula (5) can be obtained by using a compound represented by the following formula (7) or a salt thereof as a radioactive iodine labeling precursor, and a compound represented by the formula (6).
- the compound represented by the above formula (7) corresponds to a compound in which R 1 is a sulfur atom and R 2 is a substituent represented by the above formula (2) in the above formula (4).
- R 2 is a 2- (4-imidazolyl) ethyl group or an ethoxycarbonylethyl group.
- the compound in which R 2 is an ethoxycarbonylethyl group is represented by the above formula (4), wherein R 1 is a nitrogen atom and R 2 is represented by the above formula (2). It corresponds to a compound which is a substituent.
- the compound in which R 2 is a 2- (4-imidazolyl) ethyl group has the above formula (4), wherein R 1 is a nitrogen atom and R 2 is the above It corresponds to a compound which is a substituent represented by the formula (3).
- R 4 is a trialkylstannyl substituent whose alkyl chain is 1 to 4 carbon atoms in length, and trialkyl whose alkyl chain is 1 to 4 carbon atoms in length.
- R 4 as the trialkylstannyl substituent, a trimethylstannyl substituent or a tributylstannyl substituent can be preferably used.
- any group that can be used for a precursor compound of a radioactive iodine-labeled compound may be used. Since this compound has a functional group represented by R 4 , it can be suitably used as a precursor of the radioactive iodine-labeled compound according to the present invention.
- 5- (3-bromophenyl) furan-2-carbaldehyde is dissolved in 1,4-dioxane, bistributyltin is added, and triethylamine and a catalytic amount of tetrakistriphenylphosphine palladium are added.
- This reaction solution is heated to reflux with stirring, and after the reaction, the solvent is distilled off under reduced pressure to obtain 5- (3- (tributylstannyl) phenyl) furan-2-carbaldehyde (FIG. 1, step 2).
- bistributyltin may be added in an equal amount or more with respect to 5- (3-bromophenyl) furan-2-carbaldehyde.
- glycine ethyl ester and approximately the same amount of ethyl isothiocyanatoacetate are dissolved in acetonitrile, and triethylamine is added and reacted at room temperature (25 ° C.) with stirring. After completion of the reaction, the solvent is distilled off for purification to obtain ethyl-2- (5-oxo-2-thioxoimidazolidin-1-yl) acetate (FIG. 1, step 3).
- Bistrialkyltin may be used.
- a reaction similar to the above may be performed using bistrimethyltin in Step 2 of FIG.
- step 4 in FIG. 1 may be performed.
- the radioactive iodine-labeled organic compound according to the present invention can be produced by using a production apparatus provided with at least a reaction vessel serving as a reaction field, and the device further comprises a member capable of shielding radiation emitted from the reaction vessel. It is preferable.
- the radioiodine labeled organic compound according to the present invention is synthesized by dissolving the labeled precursor compound synthesized in the above manner in an inert organic solvent, and obtaining a radioiodine labeled sodium iodide solution by a known method. Etc., and an acid and an oxidizing agent are added and reacted.
- the inert organic solvent for dissolving the label precursor compound various solvents having no reactivity with the label precursor and sodium iodide can be used, and preferably methanol can be used.
- the oxidizing agent is not particularly limited as long as it can oxidize iodine in the reaction solution, and preferably hydrogen peroxide or peracetic acid can be used.
- the addition amount of the oxidizing agent may be an amount sufficient to oxidize iodine in the reaction solution.
- the tau protein imaging agent according to the present invention like other generally known radiodiagnostic agents, water or physiological saline adjusted to an appropriate pH as required by the radioactive iodine-labeled organic compound according to the present invention, Or it can prepare as a liquid mix
- the concentration of the present compound needs to be not more than the concentration at which the stability of the blended present compound is obtained.
- the dosage form of the present compound is preferably an injection, and the dosage is not particularly limited as long as it is a concentration sufficient to image the distribution of the administered compound.
- 123 I-labeled compound in the case of 123 I-labeled compound, it can be used by intravenous administration or local administration of about 50 to 600 MBq per adult weighing 60 kg.
- the distribution of the administered compound can be imaged by a known method.
- 123 I-labeled compound it can be imaged using a SPECT apparatus.
- Tauopathy disease caused by accumulation of tau protein in the brain
- Alzheimer's disease, frontotemporal dementia, Pick's disease, basal ganglia Degenerative disease, progressive supranuclear palsy, etc. can be diagnosed noninvasively.
- glycine ethyl ester hydrochloride 140 mg, 1 mmol
- bis (carboxymethyl) trithiocarbonate 224 mg, 1 mmol
- 2-propanol 6 mL
- triethylamine 0.6 mL
- results of NMR analysis and mass spectrometry of the obtained Compound 1 were as follows.
- the results of NMR analysis and mass spectrometry show the results of measurement using a mass spectrometer of LCMS-2010 manufactured by JEOL Ltd., JNM400, manufactured by Shimadzu Corporation.
- 5- (3-Bromophenyl) furan-2-carbaldehyde (50 mg, 0.2 mmol) is dissolved in 1,4-dioxane (5 mL), and bis (tributyltin) (0.4 mL), tetrakistriphenylphosphine palladium ( 50 mg, 0.04 mmol) and triethylamine (4 mL) were added, and the mixture was heated to reflux with stirring for 3 hours.
- Example 5 (Z) -Ethyl-2- (5-oxo-2-thioxo-4-((5- (3- (tributylstannyl) phenyl) furan-2-yl) methylene) imidazolidine-1 -Yl) acetate synthesis (labeled precursor 2) 5- (3- (Tributylstannyl) phenyl) furan-2-carbaldehyde (10 mg, 0.022 mmol) synthesized in the same manner as in Example 4 and ethyl-synthesized in the same manner as in Example 2 2- (5-oxo-2-thioxoimidazolidin-1-yl) acetate (4.4 mg, 0.022 mmol) is dissolved in dichloromethane (3 mL), piperidine (5 ⁇ L) is added, and the mixture is stirred at room temperature (25 ° C.).
- Example 6 (Z) -3- (2- (1H-imidazol-4-yl) ethyl) -2-thioxo-5-((5- (3- (tributylstannyl) phenyl) furan-2- Yl) methylene) imidazolidin-4-one (labeled precursor 3) 5- (3- (Tributylstannyl) phenyl) furan-2-carbaldehyde (65 mg, 0.14 mmol) synthesized in the same manner as in Example 4 and 3- in the same manner as in Example 3 (2- (1H-imidazol-4-yl) ethyl) -2-thioxoimidazolidin-4-one (32 mg, 0.15 mmol) was dissolved in dichloromethane (7 mL), piperidine (20 ⁇ L) was added, and room temperature ( 25 ° C.) overnight.
- Example 7 Synthesis of 125 I-labeled substance Ethanol solutions (1 mg / mL) (50 ⁇ L) of labeled precursors 1 to 3 synthesized in Examples 4 to 6 were respectively prepared, and Na [ 125 I] (3. 7-7.4 MBq (0.1-0.2 mCi)) was added, and 1 mol / L hydrochloric acid (50 ⁇ L) and 3% by volume H 2 O 2 aqueous solution (50 ⁇ L) were added. After reacting at room temperature (25 ° C.) for 5 minutes, a saturated sodium hydrogen sulfite aqueous solution (100 ⁇ L) was added as a reducing agent to stop the reaction.
- Example 8 Radioactivity distribution experiment in a normal mouse
- the radioactive iodine labeled bodies 1 to 3 were each diluted with physiological saline containing 10% ethanol to prepare a sample solution.
- Each sample solution containing radioactive iodine-labeled compounds 1 to 3 was administered to each group of 5 5-week-old ddY mice (male 26-28 g) from the tail vein (6.66-18.5 kBq (0.18 -0.5 ⁇ Ci)) (100 ⁇ L) was administered, and after 2, 10, 30, 60 minutes, decapitation and blood collection, each organ was removed, and the radioactivity count was measured with a ⁇ counter.
- measurement by ⁇ counter those made using a Perkin Elmer WIZARD 3 1480.
- Tables 2-4 show the results of the radioactive iodine label 1.
- Table 3 shows the results of the radioactive iodine label 2.
- Table 4 shows the results of the radioactive iodine label 3. As shown in Tables 2 to 4, it was confirmed that each radioiodine labeled substance migrated into the brain immediately after administration.
- Example 9 Competitive inhibition experiment using thioflavin S (ThS) as a ligand Tau-441 expression vector (provided by Osaka City University graduate School of Medicine) was introduced into Escherichia coli (BL21) and cultured to extract tau protein. Purified. Heparin (0.1 mg / mL) was added to purified tau protein (1 mg / mL), and the mixture was added at 37 ° C. in 50 mmol / L MES buffer (pH 6.8, 100 mmol / L sodium chloride, 0.5 mmol / L EGTA). Incubated for days to produce aggregates. The formation of tau protein aggregates was confirmed by fluorescence assay with SDS-PAGE and Thioflavin S.
- Thioflavin S Thioflavin S
- the produced tau protein aggregate (final concentration 0.2 ⁇ mol / L), thioflavin S (Sigma Aldrich, final concentration 1.5 ⁇ mol / L), various concentrations of Compound 1, Compound 2 or Compound 3 solution (each Incubate a mixed solution (550 ⁇ L) with a final concentration of 0 to 2.7 ⁇ mol / L) for 30 minutes, and then, using a fluorometer (manufactured by Shimadzu Corporation, RF-5300PC), a fluorescence spectrum at an excitation wavelength of 440 nm is obtained. It was measured.
- a is a fluorescence spectrum of a sample (sample I) containing only thioflavin S at 1.5 ⁇ mol / L
- b is a sample A containing tau protein aggregate at 0.2 ⁇ mol / L. It is a fluorescence spectrum of a sample (sample II).
- c is a fluorescence spectrum of a sample containing 0.1 ⁇ mol / L of Compound 1 in Sample II
- d is a fluorescence spectrum of a sample containing Compound 1 in 0.3 ⁇ mol / L of Sample II.
- e is the fluorescence spectrum of the sample containing Compound 1 at 0.9 ⁇ mol / L in Sample II
- f is the fluorescence spectrum of the sample containing Compound 1 at 2.7 ⁇ mol / L in Sample II.
- c is a fluorescence spectrum of a sample containing 0.1 ⁇ mol / L of Compound 2 in Sample II
- d is a fluorescence of a sample containing Compound 2 of 0.3 ⁇ mol / L in Sample II
- E is a fluorescence spectrum of a sample containing Compound 2 in 0.9 ⁇ mol / L in Sample II
- f is a fluorescence spectrum of a sample containing Compound 2 in 2.7 ⁇ mol / L in Sample II. is there.
- c is the fluorescence spectrum of the sample containing 0.1 ⁇ mol / L of the compound 3 in the sample II
- d is the fluorescence spectrum of the sample containing 0.3 ⁇ mol / L of the compound 3 in the sample II
- e is the fluorescence spectrum of the sample containing 0.9 ⁇ mol / L of the compound 3 in the sample II
- f is the fluorescence spectrum of the sample containing 2.7 ⁇ mol / L of the compound 3 in the sample II.
- Example 10 Tau protein binding experiment using size exclusion chromatography Tau protein aggregate (final concentration 0.37 ⁇ mol / L, prepared in Example 9) or non-aggregated tau protein (final concentration 0.37 ⁇ mol) / L) and radioiodine labeled 1 (2.0 kBq (0.055 ⁇ Ci)), radioiodine labeled 2 (20 kBq (0.55 ⁇ Ci)) or radioiodine labeled 3 (2.0 kBq (0.055 ⁇ Ci)). Each of the mixed solutions is incubated for 1 to 1.5 hours and then subjected to size exclusion chromatography (PD-10 column (GE Healthcare Japan), eluent: phosphate buffered-saline (PBS)).
- PD-10 column GE Healthcare Japan
- PBS phosphate buffered-saline
- Radioactivity of the eluted fraction of protein aggregates or non-aggregated tau protein It was measured at the counter.
- PBS buffer and radioactive iodine label 1 2.0 kBq (0.055 ⁇ Ci)
- radio iodine label 2 2.0 kBq (0.055 ⁇ Ci)
- radio iodine label 3 2.0 kBq (0.
- the same experiment was performed using a mixed solution of 055 ⁇ Ci), and the radioactivity in the same fraction as that in which the tau protein aggregate fraction was eluted in the above experiment was measured with a ⁇ counter.
- FIG. 6 is a diagram showing the results using the radioactive iodine label 1.
- FIG. 7 is a diagram showing the results using the radioactive iodine label 2.
- FIG. 8 is a diagram showing the results of using the radioactive iodine label 3. 6-8, “aggregated tau” indicates the radioactivity of the tau protein aggregate fraction, “non aggregated tau” indicates the radioactivity of the non-aggregated tau protein elution fraction, and “buffer” is the control. Shows radioactivity.
- the radioactive iodine labeled body 1, the radioactive iodine labeled body 2 and the radioactive iodine labeled body 3 have the property of specifically binding to the tau protein aggregate.
- any of the radioactive iodine labeled bodies 1 to 3 has a property of quickly moving into the brain after intravenous administration.
- the radioactive iodine-labeled organic compound according to the present invention has a property of moving into the brain early after intravenous administration and binding to the tau protein aggregate. Therefore, it is suggested that the radioactive iodine-labeled organic compound according to the present invention can depict an aggregate of phosphorylated tau protein accumulated in the brain as a nuclear medicine image.
- Example 11 Evaluation experiment of binding property to amyloid ⁇ 0.5 mg of A ⁇ (1-42) peptide (purchased from Peptide Institute, Inc.) was dissolved in PBS buffer containing 2 mL of 1 mmol / L EDTA. And incubated at 37 ° C. for 42 hours to prepare A ⁇ 42 aggregates.
- chalcone derivative 4-dimethylamino-4′-iodochalcone (hereinafter referred to as chalcone derivative) was prepared according to the method described in the literature (Ono et al., Bioorg Med Chem, 15, 6802-6809, 2007). The experiment was performed (the amount of radioactivity in the sample: 0.85-0.37 kBq (0.023-0.01 ⁇ Ci)).
- Example 12 In vitro autoradiography experiment using brain sections derived from Alzheimer's disease patients Post-mortem brain sections (paraffin-embedded sections) of hippocampus of Alzheimer's disease patients were purchased from BioChain. The brain section was deparaffinized, and 10% ethanol-containing PBS solution (3.07 kBq / mL (0.083 ⁇ Ci / mL)) of radioactive iodine-labeled substance 3 was added and reacted for 1 hour. Thereafter, the mixture was washed successively with a saturated lithium carbonate 50 volume% ethanol aqueous solution (2 minutes ⁇ 2), a 50 volume% ethanol aqueous solution (2 minutes ⁇ 2), and purified water (30 seconds ⁇ 2).
- radioactivity distribution (FIG. 10a) of radioiodine labeled body 3 was consistent with the phosphorylated tau protein distribution (FIG. 10b) confirmed in the antibody-stained sections. From this result, it was shown that the radioactive iodine labeled body 3 has the property to bind to phosphorylated tau protein in the brain.
- any of the radioactive iodine labeled bodies 1 to 3 has a property of quickly moving into the brain after intravenous administration. Considering these results together, it is considered that the compound according to the present invention has a property of moving into the brain early after intravenous administration and binding to phosphorylated tau protein aggregates. Therefore, it is suggested that the radioactive iodine-labeled organic compound according to the present invention can depict an aggregate of phosphorylated tau protein accumulated in the brain as a nuclear medicine image.
- Example 13 Inhibition constants for tau protein and ⁇ -amyloid
- the dissociation constant (K d ) of thioflavin S used as a competitive ligand was first determined by a saturation experiment. That is, tau protein aggregate (final concentration 0.2 ⁇ mol / L, prepared in Example 9) or A ⁇ 42 aggregate (final concentration 2.2 ⁇ mol / L, prepared in Example 11), and thioflavine A mixed solution of S (0.1-12.8 ⁇ mol / L) with a 10% by volume ethanol aqueous solution was incubated for 30 minutes, and the fluorescence intensity was measured with a fluorescence plate reader (manufactured by Molecular Devices, FLEX STATION).
- the fluorescence intensity was measured at Ex 440 nm and Em 510 nm for tau protein aggregates, and at Ex 440 nm and Em 490 nm for A ⁇ 42 aggregates.
- a saturation curve was created using GraphPad Prism, and the K d value of thioflavin S was calculated.
- tau protein aggregates final concentration 0.2 ⁇ mol / L, prepared in Example 9
- a ⁇ 42 aggregates final concentration 10 ⁇ g / ml, prepared in Example 11
- thioflavin S 1.5 ⁇ mol / L
- a mixed solution of a test compound 0.6 nmol / L ⁇ 10 ⁇ mol / L
- a 10% by volume ethanol aqueous solution are incubated for 30 minutes, and a fluorescent plate reader (manufactured by Molecular Devices, FLEX STATION) is used.
- the Ki values of compounds 1, 2, and 3 are respectively 752, 864, and 469 nmol / L, and all of the derivatives showed higher binding to the tau protein aggregate than the A ⁇ 42 aggregate.
- Example 14 Evaluation of connectivity of neurogenic changes in human brain using brain sections derived from Alzheimer's disease patients Compound 3 using brain sections of Alzheimer's disease patients in order to evaluate the binding to changes in neurofibrils in human brain Fluorescence staining experiment was conducted. Postmortem brain sections (paraffin-embedded sections) of Alzheimer's disease patients purchased from BioChain, xylene (5 minutes x 2), ethanol, ethanol, 95 volume% ethanol aqueous solution, 85 volume% ethanol aqueous solution, 70 volume% ethanol aqueous solution ( It was deparaffinized by washing with 1 minute x 1).
- the section with the test compound (200 ⁇ mol / L / 50 volume% ethanol aqueous solution) was incubated for 1 hour and washed with 50 volume% ethanol. And observed with a fluorescence microscope. Further, the same section was stained with thioflavin S (0.125 wt%, 50 vol% ethanol aqueous solution) for 10 minutes. Thereafter, immunostaining was performed using an anti-phosphorylated tau protein antibody (AT8). The antigen was activated by autoclaving (121 ° C., 2 atm) in 0.01 mol / L citrate buffer for 15 minutes.
- FIG. 11A is a figure which shows the fluorescent dyeing result by the compound 3
- FIG. 11B is a figure which shows the dyeing
- the compound and tauopathy diagnostic agent according to the present invention can be used in the field of manufacturing radiopharmaceuticals.
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Abstract
Description
これまで、タウタンパク質凝集体に親和性を有する化合物として、ローダニンを初めとする種々のタウタンパク質線維化阻害剤が見出されている(非特許文献1、非特許文献2)。また、タウタンパク質凝集体をターゲットとしたバイオマーカーとして、種々のキノリン誘導体やベンゾイミダゾール誘導体が開示されている(非特許文献3、特許文献1、特許文献2)。
下記式(4)で表される化合物またはその塩からなる、放射性ヨウ素標識前駆体が提供される。
以下(Z)-エチル-2-(5-オキソ-2-チオキソ-4-((5-(3-(トリブチルスタニル)フェニル)フラン-2-イル)メチレン)イミダゾリジン-1-イル)アセテート(図1中のprecursor 2)を合成する場合を例にとり、本発明の一つの実施形態に係る、放射性ヨウ素標識有機化合物の前駆体化合物の合成法について、図面を参照しつつ説明する。
次に、本発明の別の一側面に係る、放射性ヨウ素標識有機化合物の製造方法について説明する。本発明に係る放射性ヨウ素標識有機化合物は、少なくとも反応場となる反応容器を備えた製造装置を用いて製造することができ、該装置は、反応容器から放出される放射線を遮蔽できる部材をさらに備えることが好ましい。本発明に係る放射性ヨウ素標識有機化合物の合成は、上記の要領にて合成した標識前駆体化合物を不活性有機溶媒に溶解し、これに公知の方法にて得られた放射性ヨウ素標識ヨウ化ナトリウム溶液等を加え、酸および酸化剤を加えて反応させることによって行うことができる。標識前駆体化合物を溶解させる不活性有機溶媒としては標識前駆体およびヨウ化ナトリウム等との間で反応性を有さない種々の溶媒を用いることができ、好ましくはメタノールを用いることができる。
酸化剤は、反応液中のヨウ素を酸化させることができるものであれば特に限定する必要はなく、好ましくは過酸化水素または過酢酸を用いることができる。酸化剤の添加量は、反応溶液中のヨウ素を酸化させるのに十分な量であれば良い。
本発明に係るタウタンパク質の画像化剤は、他の一般に知られている放射性診断剤と同様、本発明に係る放射性ヨウ素標識有機化合物を所望により適当なpHに調整された水または生理食塩水、あるいはリンゲル液等に配合させた液として調製することができる。この場合における本化合物の濃度は、配合された本化合物の安定性が得られる濃度以下とする必要がある。本化合物の投与形態は、注射剤が好ましく、投与量は、投与された化合物の分布を画像化するために十分な濃度であれば特に限定する必要はない。例えば、123I標識化合物の場合は、体重60kgの成人一人当り50~600MBq程度、静脈投与または局所投与して使用することができる。投与された本化合物の分布は、公知の方法にて画像化することができ、例えば123I標識化合物の場合はSPECT装置を用いて画像化することができる。このようにして得られた画像により、タウオパチー(タウタンパク質の脳内蓄積に起因する疾病)を診断することができ、例えば、アルツハイマー病、前頭側頭様型痴呆症、ピック病、大脳皮質基底核変性症、進行性核上麻痺等を非浸襲的に診断することが可能になる。
5-ホルミル-2-フランボロン酸(280mg,2mmol)、1,3-ジヨードベンゼン(660mg,2mmol)を1,2-ジメトキシエタン(15mL)に溶解させ、テトラキストリフェニルホスフィンパラジウム(114mg,0.1mmol)を加えた後、2mol/L炭酸ナトリウム(4.6mL)を加え、撹拌下3時間加熱還流させた。反応終了後、水(20mL)を加え、酢酸エチル(20mL×2)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水後、溶媒を減圧留去し、残渣を酢酸エチル/へキサン(3/7(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、5-(3-ヨードフェニル)フラン-2-カルバルデヒドを収量155mg(収率25.9%)で得た。
1HNMR(400MHz,DMSO) δ8.25(s,1H),7.88(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.80(s,1H),7.48(d,J=4.0Hz,1H),7.43(d,J=4.0Hz,1H),7.39(t,J=8.0Hz,1H),4.84(s,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)
MS(APCI)m/z 500[MH+]
グリシンエチルエステル塩酸塩(140mg,1mmol)とイソチオシアナト酢酸エチル(145mg,1mmol)をアセトニトリル(6mL)に溶解し、トリエチルアミン(0.6mL)を加え、室温(25℃)で10分間撹拌した。反応終了後、溶媒を減圧留去し、残渣を酢酸エチル/へキサン(1/1(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、エチル-2-(5-オキソ-2-チオキソイミダゾリジン-1-イル)アセテートを収量170mg(収率84.2%)で得た。
1HNMR(400MHz,DMSO-d6) δ8.34(s,1H),7.99(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.38(d,J=4.0Hz,1H),7.33(d,J=4.0Hz,1H),7.28(t,J=8.0Hz,1H),6.68(s,1H),4.61(s,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)
MS(APCI)m/z 483[MH+]
ヒスタミン(111mg,1mmol)とイソチオシアナト酢酸エチル(145mg,1mmol)をアセトニトリル(6mL)に溶解し、室温(25℃)で10分撹拌した。反応終了後、溶媒を減圧留去し、残渣をクロロホルム/メタノール(4/1(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、3-(2-(1H-イミダゾール-4-イル)エチル)-2-チオキソイミダゾリジン-4-オンを収量167mg(収率79.5%)で得た。
1HNMR(400MHz,DMSO-d6) δ12.1(br,s,1H),8.32(s,1H),7.98(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.58(s,1H),7.35(d,J=4.0Hz,1H),7.31(d,J=4.0Hz,1H),7.28(t,J=8.0Hz,1H),6.86(s,1H),6.55(s,1H),4.02(t,J=7.6Hz,2H),2.87(t,J=7.6Hz,2H)
MS(APCI)m/z 491[MH+]
5-ホルミル-2-フランボロン酸(676mg,4.8mmol)、3-ブロモヨードベンゼン(1132mg,4mmol)を1,2-ジメトキシエタン(30mL)に溶解させ、テトラキストリフェニルホスフィンパラジウム(228mg,0.2mmol)を加え、さらに2mol/L炭酸ナトリウム(9.6mL)を加え、撹拌下2時間加熱還流させた。反応終了後、水(20mL)を加え、酢酸エチル(20mL×2)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水後、溶媒を減圧留去し、残渣を酢酸エチル/へキサン(3/7(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、5-(3-ブロモフェニル)フラン-2-カルバルデヒドを収量306mg(収率25.9%)で得た。
実施例4と同様の方法にて合成した5-(3-(トリブチルスタニル)フェニル)フラン-2-カルバルデヒド(10mg,0.022mmol)と実施例2と同様の方法にて合成したエチル-2-(5-オキソ-2-チオキソイミダゾリジン-1-イル)アセテート(4.4mg,0.022mmol)をジクロロメタン(3mL)に溶解し、ピペリジン(5μL)加え、室温(25℃)で一晩撹拌した。反応終了後、溶媒を減圧留去し、残渣を酢酸エチル/へキサン(3/7(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、標識前駆体2を収量11mg(74.0%)で得た。
実施例4と同様の方法にて合成した5-(3-(トリブチルスタニル)フェニル)フラン-2-カルバルデヒド(65mg,0.14mmol)と実施例3と同様の方法にて合成した3-(2-(1H-イミダゾール-4-イル)エチル)-2-チオキソイミダゾリジン-4-オン(32mg,0.15mmol)をジクロロメタン(7mL)に溶解し、ピペリジン(20μL)を加え、室温(25℃)で一晩撹拌した。反応終了後、溶媒を減圧留去し、残渣をクロロホルム/メタノール(9/1(体積比))を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、標識前駆体3を収量42mg(収率45.9%)で得た。
実施例4~6にて合成した標識前駆体1~3のエタノール溶液(1mg/mL)(50μL)をそれぞれ調製し、Na[125I](3.7-7.4MBq(0.1-0.2mCi))を添加して1mol/L塩酸(50μL)、3体積%H2O2水溶液(50μL)を加えた。室温(25℃)で5分間反応させた後、還元剤として飽和亜硫酸水素ナトリウム水溶液(100μL)を加え、反応を停止させた。飽和炭酸水素ナトリウム水溶液(100μL)を加え、反応液を中和した後、酢酸エチルで目的物を抽出した。無水硫酸ナトリウムを充填したカラムを通し脱水した後、窒素ガスにより溶媒を留去した。125I標識したリガンドは、それぞれ対応する非放射性化合物を標品として、逆相HPLC(移動相(体積比);放射性ヨウ素標識体1,水:アセトニトリル=3:7、放射性ヨウ素標識体2,水:アセトニトリル=4:6、放射性ヨウ素標識体3,水:メタノール=25:75)を用いて精製した。放射性ヨウ素標識体1、2および3を放射化学的収率8~22%、放射化学的純度90%以上で得た。
放射性ヨウ素標識体1~3を、それぞれ10%のエタノール含む生理食塩水で希釈し、試料溶液とした。1群5匹の5週齢ddYマウス(雄26-28g)に、放射性ヨウ素標識体1~3を含む各試料溶液を、尾静脈より1匹あたり(6.66-18.5kBq(0.18-0.5μCi))(100μL)を投与し、2,10,30,60分後に断頭、採血後、各臓器を取り出し、γカウンターで放射能カウントを測定した。なお、本明細書において、γカウンターによる測定は、パーキンエルマー社製WIZARD31480を使用して行ったものである。
Tau-441発現ベクター(大阪市立大学大学院医学研究科より供与)を大腸菌(BL21)に導入後、培養し、タウタンパク質を抽出、精製した。精製したタウタンパク質(1mg/mL)にヘパリン(0.1mg/mL)を加え、50mmol/L MES緩衝液(pH6.8,100mmol/L塩化ナトリウム,0.5mmol/L EGTA)中37℃で3日間インキュベートし、凝集体を作製した。タウタンパク質凝集体の生成はSDS-PAGEおよびチオフラビンSによる蛍光アッセイにより確認した。
タウタンパク質凝集体(最終濃度0.37μmol/L、実施例9にて調製したもの)または非凝集タウタンパク質(最終濃度0.37μmol/L)と放射性ヨウ素標識体1(2.0kBq(0.055μCi))、放射性ヨウ素標識体2(20kBq(0.55μCi))または放射性ヨウ素標識体3(2.0kBq(0.055μCi))の混合溶液をそれぞれ1時間~1.5時間インキュベート後、サイズ排除クロマトグラフィー(PD-10カラム(GEヘルスケア・ジャパン株式会社製)、溶離液:phosphate buffered-saline(PBS))に付し、タウタンパク質凝集体または非凝集タウタンパク質の溶出画分の放射能をγカウンターで測定した。
対照として、PBS緩衝液と放射性ヨウ素標識体1(2.0kBq(0.055μCi))、放射性ヨウ素標識体2(2.0kBq(0.055μCi)または放射性ヨウ素標識体3(2.0kBq(0.055μCi)の混合溶液を用いて同様の実験を行い、上記実験でタウタンパク質凝集体画分が溶出されたのと同様のフラクションにおける放射能をγカウンターで測定した。
実施例8において、放射性ヨウ素標識体1~3は、いずれも静脈投与後速やかに脳内に移行する性質を有する事が示されている。この結果を合わせて考えると、本発明に係る放射性ヨウ素標識有機化合物は、静脈投与後早期に脳内に移行してタウタンパク質凝集体に結合する性質を有するものと考えられる。従って、本発明に係る放射性ヨウ素標識有機化合物は、脳内に蓄積したリン酸化タウタンパク質の凝集体を核医学画像として描出し得ることが示唆される。
Aβ(1-42)ペプチド((株)ペプチド研究所より購入)0.5mgを、2mLの1mmol/L EDTAを含むPBS緩衝液に溶解し、37℃で42時間インキュベートし、Aβ42凝集体を調製した。ガラスチューブに、10体積%エタノール水溶液(900μL)と、Aβ42凝集体(50μL,最終濃度30nmol/L)と、放射性ヨウ素標識体1、放射性ヨウ素標識体2または放射性ヨウ素標識体3(各50μL,0.018-0.097μCi)とを加え、3時間インキュベートした。セルハーベスター(ブランデル社製、M-24)を用いてB/F分離を行い、フィルター上の放射能をγカウンターにて計測した。用いた各試料における放射能カウントに対する上記フィルター上の放射能カウントの割合(%)を求め、Aβ42凝集体への各化合物の結合性を評価した。
対照として、4-ジメチルアミノ-4'-ヨードカルコン(以下、カルコン誘導体という)を、文献(Ono et al., Bioorg Med Chem, 15, 6802-6809, 2007)記載の方法に従って調製し、同様の実験を行った(試料中放射能量:0.85-0.37kBq(0.023-0.01μCi))。
アルツハイマー病患者の海馬の死後脳切片(パラフィン包埋切片)は、BioChain社より購入した。脳切片を脱パラフィン処理し、放射性ヨウ素標識体3の10%エタノール含有PBS溶液(3.07kBq/mL(0.083μCi/mL))を添加し、1時間反応させた。その後飽和炭酸リチウム50体積%エタノール水溶液(2分×2)、50体積%エタノール水溶液(2分×2)、精製水(30秒×2)で順次洗浄した。イメージングプレート上で48時間露光させた後、バイオイメージングアナライザー(形式:BAS-5000、富士写真フィルム株式会社製)を用い分析を行った。さらに隣接切片を用い、抗リン酸化タウタンパク質抗体(AT8、Thermo)による染色を行った。
実施例8において、放射性ヨウ素標識体1~3は、いずれも静脈投与後速やかに脳内に移行する性質を有する事が示されている。この結果を合わせて考えると、本発明に係る化合物は、静脈投与後早期に脳内に移行してリン酸化タウタンパク質凝集体に結合する性質を有するものと考えられる。従って、本発明に係る放射性ヨウ素標識有機化合物は、脳内に蓄積したリン酸化タウタンパク質の凝集体を核医学画像として描出し得ることが示唆される。
化合物1~3の阻害定数を算出するため、まず競合リガンドとして用いるチオフラビンSの解離定数(Kd)を飽和実験により求めた。すなわち、タウタンパク質凝集体(最終濃度0.2μmol/L、実施例9にて調製したもの)、またはAβ42凝集体(最終濃度2.2μmol/L、実施例11にて調製したもの)と、チオフラビンS(0.1-12.8μmol/L)の10体積%エタノール水溶液との混合溶液を30分間インキュベートし、蛍光プレートリーダー(モレキュラーデバイス社製、FLEX STATION)にて蛍光強度を測定した。タウタンパク質凝集体ではEx440nm、Em510nm、Aβ42凝集体ではEx440nm、Em490nmにおける蛍光強度を測定した。GraphPad Prismを用いて飽和曲線を作成し、チオフラビンSのKd値を算出した。
次に、タウタンパク質凝集体(最終濃度0.2μmol/L、実施例9にて調製したもの)またはAβ42凝集体(最終濃度10μg/ml、実施例11にて調製したもの)と、チオフラビンS(1.5μmol/L)、試験化合物(0.6nmol/L-10μmol/L)の10体積%エタノール水溶液との混合溶液を30分間インキュベートし、蛍光プレートリーダ(モレキュラーデバイス社製、FLEX STATION)にて、タウタンパク質凝集体ではEx440nm、Em510nm、Aβ42凝集体ではEx440nm、Em490nmにおける蛍光強度を測定しGraphPad Prism阻害曲線を作成し、先に求めたチオフラビンSのKd値を用いて、化合物1~3のKi値を算出した。
ヒト脳内神経原線維変化への結合性を評価するため、アルツハイマー病患者脳切片を用いた化合物3による蛍光染色実験を行った。BioChain社より購入したアルツハイマー病患者の死後脳切片(パラフィン包埋切片)をキシレン(5分間×2回)、エタノール、エタノール、95体積%エタノール水溶液、85体積%エタノール水溶液、70体積%エタノール水溶液(1分間×1回)で洗浄することで脱パラフィンした。次に、切片の自家蛍光を除去するため、0.3重量%過マンガン酸カリウム水溶液(20分間×1回)、PBS(リン酸緩衝生理食塩水)(2分間×2回)、1重量%二亜硫酸カリウム水溶液/1重量%シュウ酸水溶液(1分間×1回)、PBS(2分間×2回)、1重量%水素化ナトリウムホウ素水溶液(5分間×1回)、PBS(2分間×2回)の順で処理を行った。3重量%BSA含有PBS-0.1重量%tritonX100含有PBSによるブロッキングを3時間行った後、試験化合物(200μmol/L/50体積%エタノール水溶液)と切片を1時間インキュベートし50体積%エタノールで洗浄し、蛍光顕微鏡で観察した。さらに、同一切片をチオフラビンS(0.125重量%、50体積%エタノール水溶液)で10分間染色した。その後、抗リン酸化タウタンパク質抗体(AT8)を用いた免疫染色を行った。0.01mol/Lクエン酸緩衝液中オートクレーブ(121℃、2気圧)を15分間行うことで抗原の賦活化を行った。PBS-Tween20に2分間浸した後、3重量%BSA含有PBS-0.1重量%tritonX100含有PBSと室温(25℃)で1時間反応させ、AT8抗体溶液(サーモサイエンティフック社製)と室温(25℃)で一晩反応させた。PBS-Tween20で2分間×3回洗浄した後、抗マウスIgG(H+L)、ウサギ、ビオチン結合溶液(VECTOR Laboratories社製)と室温(25℃)で1時間反応させた。その後PBS-Tween20で2分間×3回洗浄した、ストレプトアビジンビオチンペルオキシダーゼ複合体溶液(VECTOR Laboratories社製)と室温(25℃)で1時間反応させた。PBS-Tween20で2分間×3回洗浄後、ジアミノベンジン溶液(トリス緩衝液)と室温(25℃)で1分間反応させた。蒸留水で1分間洗浄し反応を停止させ、封入後、顕微鏡で観察した。
Claims (12)
- 前記式(1)中、R1が硫黄原子であり、R2が前記式(2)で表される置換基である、請求項1に記載の化合物またはその塩。
- 前記式(1)中、R1が窒素原子であり、R2が前記式(2)で表される置換基である、請求項1に記載の化合物またはその塩。
- 前記式(1)中、R1が窒素原子であり、R2が前記式(3)で表される置換基である、請求項1に記載の化合物またはその塩。
- 前記放射性ヨウ素が、123I、124I、125Iおよび131Iよりなる群から選択されたものである、請求項1乃至4いずれか1項に記載の化合物またはその塩。
- 請求項1乃至5いずれか1項に記載された化合物またはその塩を含み、タウタンパク質の画像化に用いられる、画像化剤。
- 単光子放出コンピューター断層撮影(SPECT)に用いられる、請求項6に記載の画像化剤。
- タウオパチーの診断に用いられる、請求項6または7に記載の画像化剤。
- 請求項1乃至5いずれか1項に記載された化合物またはその塩を含む、注射剤。
- 請求項10に記載の放射性ヨウ素標識前駆体を放射性ヨウ素化し、請求項1乃至5いずれか1項に記載の化合物またはその塩を製造する方法。
- 請求項10に記載の放射性ヨウ素標識前駆体を放射性ヨウ素化し、請求項1乃至5いずれか1項に記載の化合物またはその塩を製造するための装置。
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JP2012503002A JP5073871B2 (ja) | 2010-03-01 | 2011-02-24 | 放射性ヨウ素標識有機化合物またはその塩 |
US13/582,047 US8476449B2 (en) | 2010-03-01 | 2011-02-24 | Radioactive iodine labeled organic compound or salt thereof |
CA2791491A CA2791491A1 (en) | 2010-03-01 | 2011-02-24 | Radioactive iodine-labeled organic compound or salt thereof |
EP11750349A EP2543666A1 (en) | 2010-03-01 | 2011-02-24 | Radioactive iodine labeled organic compound or salt thereof |
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EP (1) | EP2543666A1 (ja) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10080812B2 (en) | 2015-03-04 | 2018-09-25 | Kyoto University | Radioactive iodine labeled pyrido[1,2-a]benzoimidazole derivative compound |
US10081630B2 (en) | 2015-08-19 | 2018-09-25 | Kyoto University | Radioactive halogen-labeled pyrido [1,2-A] benzimidazole derivative compound |
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CN106045986B (zh) * | 2016-05-31 | 2019-12-06 | 广东工业大学 | 一种新型吩噻嗪衍生物及其制备方法与应用 |
CN106045987B (zh) * | 2016-06-21 | 2019-04-23 | 广东工业大学 | 一种具有多功能近红外荧光磁性纳米微粒及其制备和应用 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US10080812B2 (en) | 2015-03-04 | 2018-09-25 | Kyoto University | Radioactive iodine labeled pyrido[1,2-a]benzoimidazole derivative compound |
US10081630B2 (en) | 2015-08-19 | 2018-09-25 | Kyoto University | Radioactive halogen-labeled pyrido [1,2-A] benzimidazole derivative compound |
Also Published As
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EP2543666A4 (en) | 2013-01-09 |
US20120330024A1 (en) | 2012-12-27 |
JPWO2011108236A1 (ja) | 2013-06-20 |
EP2543666A1 (en) | 2013-01-09 |
JP5073871B2 (ja) | 2012-11-14 |
CA2791491A1 (en) | 2011-09-09 |
US8476449B2 (en) | 2013-07-02 |
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