CN111556868A - Radionuclide-labeled compound and developer containing the same - Google Patents
Radionuclide-labeled compound and developer containing the same Download PDFInfo
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- CN111556868A CN111556868A CN201980007415.2A CN201980007415A CN111556868A CN 111556868 A CN111556868 A CN 111556868A CN 201980007415 A CN201980007415 A CN 201980007415A CN 111556868 A CN111556868 A CN 111556868A
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B59/002—Heterocyclic compounds
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- 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
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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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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Abstract
The invention provides a radionuclide-labeled compound having both tau affinity and amyloid affinity; imaging of tau and/or amyloid proteins with radionuclide-labelled compoundsThe developer of (1); a radiopharmaceutical for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein, which comprises a radionuclide-labeled compound. A radionuclide-labeled compound represented by the following general formula (1) or a salt thereof. Wherein X represents a radioactive iodine atom,18F or11CH3Pyridine and oxazole are bonded by a carbon atom, and pyridine is bonded to imidazopyridine by a carbon atom.
Description
Technical Field
The present invention relates to a radionuclide-labeled compound and an imaging agent containing the same.
Background
In japan, where aging is becoming more severe, the number of cognitive impairment patients is increasing, and this is a serious social problem. According to statistics published by the japan overstrain research team in 2013, 15% of patients over 65 years old suffer from cognitive impairment, 462 thousands of patients with presumed cognitive impairment, and 400 thousands of patients with Mild Cognitive Impairment (MCI) as their reserve army. As for the details of cognitive disorder patients in this statistic, it has been reported that Alzheimer's Disease (AD) is as high as 67.6%, vascular cognitive disorder is as high as 19.5%, and Lewy body cognitive Disorder (DLB) is as high as 4.3% in the following order (non-patent document 1). In addition, in other statistics, it has been reported that Frontotemporal lobar degeneration (FTLD) patients account for about 20% of patients with cognitive impairment in the early stage and have AD frequently (non-patent documents 2 and 3). The same applies to the transition of the number of cognitive impairment patients in countries other than japan.
As described above, cognitive impairment is classified into various types of diseases, and in AD patients, some DLB patients, some FTLD patients, and the like, proteins called amyloid or tau accumulate in the brain several decades before onset of disease, leading to decline in cognitive function or death of nerve cells (non-patent documents 4, 5, and 6). Amyloid is accumulated in the brain of an AD patient, and tau is also accumulated (non-patent document 5). In 40% or more of DLB patients, amyloid or tau protein accumulates in the brain (non-patent documents 7 and 8). On the other hand, about half of FTLD patients accumulate only tau protein in the brain, and do not accumulate amyloid (cortical basal Degeneration (CBD), Progressive Supranuclear anesthesia (PSP), Pick's disease (PiD), and agrophilic cognitive disorder (AGD); FTLD-tau) (non-patent documents 2, 3, and 6). Further, it has been reported that neurofibrillary change (NFT) -type Senile cognitive impairment (SD-NFT) is a cognitive impairment in which tau protein is accumulated mainly in the hippocampal region but amyloid is not accumulated, and accounts for 1.7 to 5.6% of anatomical examination examples of elderly people with cognitive impairment (non-patent document 9).
In the past, many radiopharmaceuticals have been developed for imaging amyloid or tau, but these radiopharmaceuticals have high affinity only for either amyloid or tau (patent documents 1 to 4), and therefore cannot image both amyloid and tau accumulated in the brain at the same time. On the other hand, a radiopharmaceutical having a high affinity for both amyloid and tau can image both amyloid and tau accumulated in the brain at the same time. Therefore, such radiopharmaceuticals can simultaneously detect various cognitive disorder-related diseases including AD and FTLD-tau in which amyloid protein, tau protein, or both are accumulated in the brain, in a wide range of ways at an early stage before onset of disease, and contribute to early diagnosis and early treatment (non-patent documents 10 and 11).
Documents of the prior art
Patent document
Patent document 1: international publication No. 2005/016888 specification
Patent document 2: international publication No. 2008/078424 specification
Patent document 3: international publication No. 2007/063946 specification
Patent document 4: international publication No. 2014/097474 specification
Non-patent document
Non-patent document 1: the prevalence of cognitive disorders in the comprehensive research institute of cognitive disorder countermeasures against cognitive disorders and the countermeasures against life dysfunction against cognitive disorders in Toyota, Kyoho scientific research fee are on the order of 23-24 years comprehensive research report
Non-patent document 2: ratnavalli E, Brayne C, Dawson K, hoges jr, the prevalence of frontotemporal resolution, neurology.2002; 58: 1615-21.
Non-patent document 3: hoges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, KrilJJ, haliday gm. click surgery coatings in frontotemporal details. ann neurol.2004; 56: 399-406.
Non-patent document 4: lee VM, Goedert M, Trojanowski jq. neuroedinetrativatatahites. annu Rev neurosci.2001; 24: 1121-59.
Non-patent document 5: dextran, the pathological finding hypothesis of alzheimer's disease, its Paradigm Shift, kyngfu medical will, 2016; 125: 797-804.
Non-patent document 6: jicun, et al, jimura あき, university of medical and welfare before delivery, on Frontotemporal lobar degeneration (Frontotemporal lobar degeneration), particularly on MND and Frontotemporal lobar degeneration cognitive disorders accompanying motor system exosomes, 2009; 1: 1-22.
Non-patent document 7: shimada H, Shintoh H, Hirano S, Miyoshi M, Sato K, Tanaka N, Ota T, Fukushi K, Irie T, Ito H, Higuchi M, Kuwabara S, Suhara T. beta. -amino in Lewybody disease related to AIzheimer' S disease-like disease.Mov disease.2013; 28: 169-75.
Non-patent document 8: gomperts SN, Locascio JJ, makarez SJ, Schultz a, Caso C, Vasdev N, specling R, Growdon JH, Dickerson BC, Johnson k. tau PET imaging in the lewy body diseases, jama neuro 1.2016; 73: 1334-41.
Non-patent document 9: shantian zhenren, neurofibrillary-altered geriatric cognitive impairment, cognitive neuroscience 2015; 17: 32-9.
Non-patent document 10: villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tauimaging: early progress and future directions. Lancet neurol.2015; 14: 114-24.
Non-patent document 11: rowe CC and Villemagne VL Brain analog imaging. J NuclMed.2011; 52: 1733-40.
Disclosure of Invention
Technical problem to be solved by the invention
The present invention addresses the problem of providing a radionuclide-labeled compound having both tau affinity and amyloid affinity.
It is another object of the present invention to provide an imaging agent for imaging tau protein and/or amyloid protein, which contains a radionuclide-labeled compound.
It is another object of the present invention to provide a radiopharmaceutical for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein, which contains a radionuclide-labeled compound.
Means for solving the problems
Accordingly, the present inventors have studied compounds having both tau affinity and amyloid affinity, and as a result, have found that, among the compounds described in international publication No. 2007/63946 which discloses compounds having amyloid affinity, a compound represented by the following general formula (1) also has tau affinity and is useful as a developing agent for imaging tau and/or amyloid and a radiopharmaceutical for imaging diseases caused by aggregation of tau and/or amyloid, and completed the present invention.
Namely, the present invention provides the following [1] to [21 ].
[1] A radionuclide-labeled compound represented by the following general formula (1) or a salt thereof.
(wherein X represents a radioactive iodine atom,18F or11CH3，
The pyridine and the oxazole are bonded by a carbon atom,
the pyridine is bonded to the imidazopyridine by a carbon atom. )
[2] The radionuclide-labeled compound or a salt thereof according to [1], which is represented by the following general formula (2).
(wherein X represents a radioactive iodine atom,18F or11CH3。)
[3]According to [1]Or [2]]The radionuclide-labeled compound or a salt thereof, wherein X is123I、124I、125I or131I。
[4] An imaging agent comprising the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof, wherein the imaging agent is used for imaging tau protein and/or amyloid protein.
[5] An imaging agent comprising the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof, wherein the imaging agent is used for imaging tau protein.
[6] A radiopharmaceutical which comprises the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof and is used for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein.
[7] A radiopharmaceutical which comprises the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof and is used for image diagnosis of a disease caused by aggregation of tau protein.
[8] A compound represented by the following general formula (3) or a salt thereof.
(wherein R represents a trialkyltin alkyl group,
the pyridine and the oxazole are bonded by a carbon atom,
the pyridine is bonded to the imidazopyridine by a carbon atom. )
[9] The compound according to [8] or a salt thereof, which is represented by the following general formula (4).
(wherein R represents trialkylstannyl)
[10] Use of the radionuclide-labeled compound or a salt thereof according to any of [1] to [3] for producing an imaging agent for imaging tau protein and/or amyloid protein.
[11] Use of the radionuclide-labeled compound or a salt thereof according to any of [1] to [3] for producing a developer for imaging tau protein.
[12] Use of the radionuclide-labeled compound or a salt thereof according to any of [1] to [3] for producing a radiopharmaceutical for use in image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein.
[13] Use of the radionuclide-labeled compound or a salt thereof according to any of [1] to [3] for producing a radiopharmaceutical for use in image diagnosis of a disease caused by aggregation of tau protein.
[14] The radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof for imaging tau protein and/or amyloid protein.
[15] The radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof for imaging tau protein.
[16] The radionuclide-labeled compound or a salt thereof according to any of [1] to [3], which is used for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid.
[17] The radionuclide-labeled compound according to any of [1] to [3] or a salt thereof for use in image diagnosis of a disease caused by aggregation of tau protein.
[18] A method for imaging tau protein and/or amyloid protein, wherein the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof is administered.
[19] A method for imaging tau protein, which comprises administering the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof.
[20] A method for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid, comprising administering the radionuclide-labeled compound according to any one of [1] to [3] or a salt thereof.
[21] A method for diagnosing a disease caused by tau protein aggregation by administering the radionuclide-labeled compound or a salt thereof according to any one of [1] to [3 ].
Effects of the invention
The radionuclide-labeled compound represented by the general formula (1) or a salt thereof (the compound (1) of the present invention) has affinity for tau protein and amyloid protein. Therefore, the compound (1) of the present invention is useful as an imaging agent for imaging tau protein and/or amyloid protein. Further, the compound (1) of the present invention is useful as a radiopharmaceutical for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid.
Drawings
FIG. 1 shows a method for anatomically examining a brain tissue slice for a patient with Progressive Supranuclear Paralysis (PSP),125I-DRK092N and11ex vivo binding assay of C-PiB and immunostaining images showing accumulation of phosphorylated tau and amyloid in the brain of the patient.
FIG. 2 shows the use of healthy Humans (HC) and Alzheimer's diseaseAnatomical examination of brain tissue sections of Alzheimer's type cognitive impairment (AD) patients and amyloid precursor protein-forced expression (APP-Tg) mice,125I-DRK092N and11results of ex vivo binding assays for C-PiB.
Detailed Description
The present invention will be described in detail below.
In the general formula (1), X represents a radioactive iodine atom,18F or11CH3. That is, the compound (1) of the present invention is a radionuclide-labeled compound in which X is a radionuclide. The radioiodine atom represents a radioisotope of iodine, and is preferably a radioisotope of iodine123I、124I、125I or131I, more preferably123I。
In the general formula (1), pyridine and oxazole are bonded to each other through a carbon atom, and pyridine is bonded to imidazopyridine through a carbon atom. The imidazopyridine and oxazole on the pyridine may be any of ortho-, meta-or para-positions, preferably para. The binding of pyridine and imidazopyridine may be in any of the 2-, 3-, 5-or 6-positions of pyridine, preferably in the 5-position. The binding between pyridine and oxazole may be at any of the 2-, 3-, 5-or 6-positions of pyridine, may be at any of the 2-, 4-or 5-positions of oxazole, and preferably is at the 2-position of pyridine and the 5-position of oxazole. Therefore, the structure of the following general formula (2) is particularly preferable.
(wherein X represents a radioactive iodine atom,18F or11CH3。)
The compound (1) of the present invention can form a salt, and examples of such a salt include salts with a basic group such as a generally known amino acid. Examples of salts on the basic group include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.
The radionuclide-labeled compound (1) of the present invention can be synthesized by the method described in International publication No. 2007/063946. The radionuclide-labeled compound represented by the general formula (1) can be obtained by performing a radionuclide labeling reaction using the compound represented by the general formula (3) as a labeling precursor.
(wherein R represents trialkylstannyl, and X, pyridine and oxazole are as defined above.)
In the general formula (3), examples of the trialkyltin alkyl group represented by R include a tri (C)1-4Alkyl) stannyl, more preferably tributylstannyl or trimethylstannyl, and particularly preferably tributylstannyl. Here, as C1-4Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group and an n-butyl group.
The radionuclide labeling reaction can be carried out by reacting a compound represented by the general formula (3) with radioactive sodium iodide in the presence of an oxidizing agent such as sodium p-toluenesulfonamide.
The imaging agent or radiopharmaceutical of the present invention may be formulated so as to contain a buffer to bring the radionuclide-labeled compound of the general formula (1) to an appropriate pH, or may be formulated so as to be dissolved in water or physiological saline. In order to suppress the decomposition of the radionuclide-labeled compound by radiation, a stabilizer may be appropriately added to the preparation.
The radionuclide-labeled compound of the present invention has affinity for tau and amyloid, and is therefore useful as a compound for imaging tau and/or amyloid in the brain. That is, the radionuclide-labeled compound of the present invention is useful as an imaging agent for tau protein and/or amyloid protein. Therefore, if the radionuclide-labeled compound of the present invention is used, it is possible to perform image diagnosis of a disease in which tau protein and/or amyloid protein accumulates in the brain. Examples of the disease in which tau protein and/or amyloid accumulate in the brain include FTLD-tau or SD-NFT including AD, MCI, DLB, CBD, PSP, PiD and AGD, and examples of the disease in which tau protein accumulates in the brain include FTLD-tau or SD-NFT including CBD, PSP, PiD and AGD.
Examples
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples.
Example 1: synthesis of DRK092N labeled precursor (Compound 10)
Compound 10 was synthesized according to the scheme shown below.
Example 1-1: synthesis of Compound 2
50.9g of a diethyl ether solution 848mL of Compound 1 was cooled under an argon atmosphere, and 1.64mol/L of an n-BuLi hexane solution 131mL was added dropwise thereto at-62 ℃ over a period of 30 minutes. After stirring at this temperature for 30 minutes, 21.5g of dehydrated N, N-dimethylacetamide was added dropwise over 10 minutes. Aqueous ammonium chloride was added and stirred at room temperature for 2 days. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Compound 2 was used as it is in the following reaction without further purification.
Examples 1 to 2: synthesis of Compound 3
To 830mL of a toluene solution of Compound 2 were added 40.0g of 1, 2-ethanediol and 12.3g of p-toluenesulfonic acid monohydrate, and the resulting water was removed and refluxed for 20 hours. After cooling, an aqueous sodium carbonate solution was added and a small amount of ethyl acetate was added for extraction. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
The concentrated residue was purified by silica gel column chromatography (mobile phase: heptane/ethyl acetate 9/1 to 7/3), whereby 24.3g of compound 3 was obtained (yield: 46%).
1H-NMR(CDCl3)：8.48(1H，s)，7.63(1H，dd，J＝8.2，4.1Hz)，7.45(1H，dd，J＝8.2，4.1Hz)，4.08-4.05(2H，m)，3.81-3.75(2H，m)，1.67(3H，s).
Examples 1 to 3: synthesis of Compound 4
519mL of a diethyl ether solution of 24.2g of Compound 3 was cooled under an argon atmosphere, and 60.5mL of a 1.64mol/L n-BuLi hexane solution was added dropwise thereto at-68 ℃ over a period of 30 minutes. After stirring at this temperature for 30 minutes, dehydrated dmf18.8g was added dropwise over a period of 15 minutes. Aqueous sodium bicarbonate solution was added and stirred to reach room temperature. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (mobile phase: heptane/ethyl acetate 90/10 to 85/15), whereby 8.71g of compound 4 was obtained (yield 45%).
1H-NMR(CDC13)：10.09(1H，s)，8.91-8.90(1H，m)，7.99-7.94(2H，m)，4.11-4.09(2H，m)，3.82-3.78(2H，m)，1.69(3H，s).
Examples 1 to 4: synthesis of Compound 6
To 315mL of a diethyl ether solution of 8.50g of Compound 4 was added 21.6g of Compound 5 and 15.2g of potassium carbonate under an argon atmosphere, and the mixture was stirred for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (first, mobile phase: ethyl acetate only, second, mobile phase: toluene to ethyl acetate) to obtain 9.35g of compound 6 (yield 91%).
lH-NMR(CDCl3)：8.76(1H，d，J＝2.3Hz)，7.98(1H，s)，7.86(1H，dd，J＝8.2，2.3Hz)，7.71(2H，s)，7.65(2H，d，J＝8.2Hz)，4.10-4.08(2H，m)3.81-3.80(2H，m)1.69(3H，s).
Examples 1 to 5: synthesis of Compound 7
To 50mL of 9.25g of a THF solution of Compound 6, 1mo1/L of hydrochloric acid (50 mL) was added, and the mixture was stirred at 50 ℃ for 1 hour. After cooling, a saturated aqueous sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (mobile phase: ethyl acetate) to give 3.20g of Compound 7 (yield 42%).
1H-NMR(CDCl3)：9.17(1H，d，J＝2.3Hz)，8.32(1H，dd，J＝8.2，2.3Hz)，8.04(1H，s)，7.85(1H，s)，7.78(1H，d，J＝8.2Hz)，2.66(3H，s).
Examples 1 to 6: synthesis of Compound 8
To 65mL of a 3.10g dichloromethane solution of Compound 7 was added 9.50g triethylamine, followed by 5.04g bromotrimethylsilane at 0 ℃. After stirring at 0 ℃ for 30 minutes, stirring was carried out at room temperature for 18 hours. 2.20g of bromotrimethylsilane was added thereto, followed by stirring for 30 minutes, and 2.04g of trimethylsilane was further added thereto, followed by stirring for 30 minutes. Water was added to the reaction solution, followed by extraction with chloroform, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the concentrated residue was added 45mL of THF, and 2.93g of N-bromosuccinimide was added under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (mobile phase: heptane/ethyl acetate 2/1 to 4/3), whereby 1.92g of compound 8 was obtained (yield 43%).
1H-NMR(CDCl3)：9.22-9.21(1H，m)，8.36(1H，dd，J＝8.2，2.3Hz)，8.05(1H，s)，7.88(1H，s)，7.80(1H，d，J＝8.2Hz)，4.43(2H，s).
Examples 1 to 7: synthesis of Compound 9
To 15mL of a 1.88g acetonitrile solution of Compound 8 was added 1.55g of 2-amino-5-iodopyridine, and the mixture was refluxed for 2 hours. After cooling, filtration was carried out and the solid was washed with acetonitrile. The crude purified product was suspended and stirred in a mixed solution (15 mL of water, 15mL of methanol, and 7.5mL of a saturated aqueous solution of sodium hydrogencarbonate), and then filtered. The crude purified product was washed with water, methanol and ethyl acetate to obtain 1.89g of compound 9 (yield 69%).
1H-NMR(CDCl3)：9.22-9.21(1H，m)，8.96-8.97(1H，m)，8.57(1H，s)，8.50(1H，s)，8.43(1H，dd，J＝8.2，1.8Hz)，7.86(1H，d，J＝8.7Hz)，7.85(1H，s)，7.49(2H，s).
Examples 1 to 8: synthesis of Compound 10
To 0.33g of compound 9 in 16.5mL of 1, 4-dioxane was added 1.65mL of triethylamine and 0.99g of bis (tributyltin), 49.1mg of tetrakis (triphenylphosphine) palladium (0) under argon atmosphere, and the mixture was stirred at 100 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (mobile phase: heptane/ethyl acetate 4/1 to 3/2), whereby 0.14g of compound 10 was obtained (yield 30%).
1H-NMR(CDCl3)：9.15(1H，m)，8.40(1H，dd，J＝8.2，2.3Hz)，8.02(1H，s)，7.99(1H，s)，7.95(1H，s)，7.76(1H，d，J＝8.2Hz)，7.73(1H，s)，7.62(1H，d，J＝8.7Hz)，7.22(1H，d，J＝8.7Hz)，1.63-1.49(6H，m)，1.41-1.31(6H，m)，1.22-1.05(6H，m)，0.91(9H，t，J＝7.3Hz)。
(example 2)125I labeled Compound 9(125I-DRK092N)
Preparation of Using Compound 10 as a labeling precursor125Compound 9 is labeled.
In a 1.0mg/mL methanol solution of Compound 10 (60. mu.L), 0.3M phosphate buffer (pH5.5) 210. mu.L, [2]125I]To a 25. mu.L mixture of Sodium iodide solution (333MBq) was added 0.1mg/mL aqueous solution of Sodium p-toluenesulfonyl chloramide (Sodium p-toluenesulfonamide) 60. mu.L, and after standing at room temperature for 2 minutes, 300. mu.L of aqueous solution of Sodium metabisulfite 2.0mg/mL was added to complete the reaction, and the reaction was separated and purified by using a reverse phase column (SHISEIDO CAPCELLPAK C18 UG120, 6.0 × 150mm) and flowing 50% aqueous methanol solution, the resulting HPLC fraction was passed through a solid phase extraction column (Sep-Pak LightC18) to extract the retained labeled compound with ethanol, and ethanol and 50mmo1/L aqueous ascorbic acid solution were added in appropriate amounts to obtain a composition of 5.0mmo1/L aqueous ascorbic acid/90% aqueous ethanol solution of 37MBq/mL, and a solution of the objective substance was prepared, and developed by TLC (TLC solvent: 95% aqueous methanol solution, reverse phase plate Whatman 18. silica gel chromatography: 18F).
Example 3 in vivo distribution test in Normal mice
Mixing fructus Aurantii Immaturus with physiological salineObtained in example 2125I-DRK092N was diluted, and 200 μ L (108.4kBq) of 4 to 5 FVB mice (male 25 to 30g) aged 8 weeks in 1 group was administered from the tail vein per 1 mouse, decapitated and blood-collected after 2, 10, 30, and 60 minutes, and then organs were taken out, wet-weighed, and radioactivity was measured by a γ counter (PerkinElmer Wallac Wizard 3 "1480). The results are shown in Table 1. The Mean ± SD of the radioactivity of blood and each organ (percentage of the dose per unit weight (percentage of the injected dose per g of tissue,% of injection dose/g tissue, 1mL of blood regarded as 1g), and percentage of the dose of thyroid only (percentage of the injected dose,% of injection dose)) is shown in table 1.
[ TABLE 1]
Normal mice125In vivo distribution of I-DRKO92N
125I-DRK092N showed high brain metastasis, and rapid subsequent excretion from the brain was confirmed.
Example 4 Ex vivo binding assay for anatomic examination of brain tissue slices using progressive supranuclear anesthesia Process (PSP) patients
4-1: external autoradiography (In vitro autoradiography)
A20 μm thick brain slice was prepared from the postmortem brain of a PSP patient to whom the non-fixed freezing had been applied. The product obtained in example 2 was mixed with PBS125I-DRK092N was diluted to 0.5nM to prepare a culture solution, the brain slice was immersed in the culture solution, left to stand for 1 hour, washed with PBS for 2 minutes × 2 times, sealed in a developing plate (MS 2025E, manufactured by Fuji film Co., Ltd.) for 2 hours, and image reading and quantitative analysis were performed with a biological development analyzer (BAS 5000, manufactured by Fuji film Co., Ltd.)11The same experiment was carried out with C-PiB (gold standard for amyloid imaging agent, 1nM concentration in culture).
4-2: immunostaining
Staining of amyloid and phosphorylated tau was performed using anti-a β (6E10, signal Laboratories) antibody and anti-phosphorylated tau (AT8, Thermo Scientific) antibody. Brain sections used in vitro autoradiography were fixed in 4% paraformaldehyde solution (PFA) overnight and washed with PBS leaving 4% PFA. Sections for amyloid staining were treated with formic acid (2 minutes), sections for phosphorylated tau staining were treated with an autoclave (citric acid buffer (0.01M sodium citrate: 0.01M citric acid 5: 1), 121 ℃, 5 minutes), then washed with running water for 5 minutes, TSA blocking buffer (TSA Fluorescein System, NEL70000, Perkin Elmer) was added dropwise to all brain sections, and after standing for 1 hour, blocking buffer containing primary antibody (6E10, 1: 1000; AT8, 1: 1000) was added dropwise and left to stand overnight. The antibody was discarded once and washing with PBS was repeated 3 times for 5 minutes. A TSA blocking solution containing a secondary antibody (with Alexa-488 fluorochrome) was added dropwise thereto, and the mixture was allowed to stand for 1 hour. Thereafter, the fluorescence signal was amplified using a TSA sensitization kit (TSA fluorescence System, NEL70000, Perkin Elmer Co., Ltd.), blocked with an VECTASHILD blocking tablet (H-1000, vector laboratories Inc.) and observed under a microscope.
4-3: results
The results are shown in FIG. 1. FIGS. 1-a and 1-b are respectively a drawing using125I-DRK092N and11autoradiogram of the brain of PSP patients with C-PiB. FIGS. 1-c, 1-d are stained images of phosphorylated tau (AT8) and amyloid (6E10) in the brain of the same PSP patient, respectively. In the cortex125I-DRK092N binding was significantly more abundant than White Matter (WM), well consistent with the distribution of phosphorylated tau protein. In brain sections of the PSP patients, no amyloid accumulation was observed,11the C-PiB binding is also consistent with this result, indicating that FIG. 1-a shows125I-DRK092N specifically binds to tau protein aggregates entirely derived.
Example 5 Ex vivo binding assay for anatomic examination of brain tissue sections Using AD patients
After-death brains of persons (HC, healthy control group, health control) and AD patients who had not been subjected to fixed freezing and mice (APP-Tg, Tg2576, 24 months old) in which Amyloid Precursor Protein (APP) having amyloid accumulation had been forcibly expressed were sliced at a thickness of 20 μm, and the procedure was performed in the same manner as in example 4In a manner of125I-DRK092N and11in vitro autoradiography of C-PiB.
The results are shown in FIG. 2. In the brain with the same HC in the upper part125I-DRK092N (left, center) and11autoradiography of C-PiB (Right), middle segment in brain of the same AD patient125I-DRK092N (left, center) and11autoradiography of C-PiB (right), the lower panel in APP-Tg brain125Autoradiography of I-DRK 092N. In the human brains (HC and AD), usually, a region of interest is set in the cortex (white solid line) rich in AD pathology in the brains of AD patients, and in the APP-Tg mice, a region of interest is set in the cortex (white solid line) rich in amyloid accumulation and the thalamus (black solid line) free of amyloid accumulation, and the radioactivity per unit area in these regions is determined (analytical software: Multi Gauge V2.2). As a result, the ratio of radioactivity per unit area in the cortex of AD patients to HC was as high as about 2.1, indicating that AD pathology can be detected using radiolabeled DRK 092N. On the other hand, in APP-Tg, the ratio of radioactivity per unit area of temporal cortex to thalamus is up to about 2.1. From this, it was found that DRK092N also specifically binds to amyloid.
Claims (21)
1. A radionuclide-labeled compound represented by the following general formula (1) or a salt thereof,
wherein X represents a radioactive iodine atom,18F or11CH3，
The pyridine and the oxazole are bonded by a carbon atom,
the pyridine is bonded to the imidazopyridine by a carbon atom.
2. The radionuclide-labeled compound or a salt thereof according to claim 1,
which is represented by the following general formula (2),
wherein X represents a radioactive iodine atom,18F or11CH3。
3. The radionuclide-labeled compound or a salt thereof according to claim 1 or 2,
x is123I、124I、125I or131I。
4. A developer, characterized in that:
the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3, wherein the imaging agent is used for imaging tau protein and/or amyloid protein.
5. A developer, characterized in that:
the radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3, wherein the imaging agent is used for imaging tau protein.
6. A radiopharmaceutical, which comprises:
a radiopharmaceutical which comprises the radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3 and is used for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein.
7. A radiopharmaceutical, which comprises:
the radiopharmaceutical which comprises the radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3 and is used for image diagnosis of a disease caused by aggregation of tau protein.
8. A compound represented by the following general formula (3) or a salt thereof,
wherein R represents a trialkyltin alkyl group,
the pyridine and the oxazole are bonded by a carbon atom,
the pyridine is bonded to the imidazopyridine by a carbon atom.
9. The compound or salt thereof according to claim 8,
which is represented by the following general formula (4),
wherein R represents a trialkyltin alkyl group.
10. Use of the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3 for producing an imaging agent for imaging tau protein and/or amyloid protein.
11. Use of the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3 for producing an imaging agent for imaging tau protein.
12. Use of the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3 for the production of a radiopharmaceutical for use in image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein.
13. Use of the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3 for producing a radiopharmaceutical for use in image diagnosis of a disease caused by aggregation of tau protein.
14. The radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3,
for imaging tau and/or amyloid.
15. The radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3,
for imaging of tau proteins.
16. The radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3,
for the image diagnosis of diseases caused by the aggregation of tau proteins and/or amyloid proteins.
17. The radionuclide-labeled compound or a salt thereof according to any one of claims 1 to 3,
for the image diagnosis of diseases caused by tau protein aggregation.
18. A method for imaging tau protein and/or amyloid protein,
administering the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3.
19. A method of imaging tau protein, characterized in that,
administering the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3.
20. A method for image diagnosis of a disease caused by aggregation of tau protein and/or amyloid protein,
administering the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3.
21. A method for diagnosing a disease caused by tau protein aggregation by imaging,
administering the radionuclide-labeled compound or a salt thereof according to any of claims 1 to 3.
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| JP4738443B2 (en) * | 2007-05-30 | 2011-08-03 | 富士フイルムＲｉファーマ株式会社 | Imaging agents and therapeutic agents for diseases caused by aggregation and / or deposition of amyloid |
| WO2009155017A2 (en) * | 2008-05-30 | 2009-12-23 | Merck & Co., Inc. | Novel substituted azabenzoxazoles |
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| CN1867552A (en) * | 2003-08-13 | 2006-11-22 | 株式会社Bf研究所 | Probe for disease with amyloid deposit, amyloid-staining agent, remedy and preventive for disease with amyloid deposit and diagnostic probe and staining agent for neurofibril change |
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| TW201929909A (en) | 2019-08-01 |
| KR20200109335A (en) | 2020-09-22 |
| CN111556868B (en) | 2023-03-28 |
| WO2019138296A2 (en) | 2019-07-18 |
| WO2019138296A3 (en) | 2019-10-03 |
| JP2019123675A (en) | 2019-07-25 |
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