HK1134482A - Novel compounds with affinity for amyloid - Google Patents

Description

Novel compound having affinity for amyloid

Technical Field

[0001] The present invention relates to compounds for diagnosing cerebral degenerative diseases. More specifically, the present invention relates to compounds useful for detecting amyloid at a focal site in the diagnosis of alzheimer's disease and other diseases associated with amyloid accumulation.

Background

[0002] Diseases caused by the precipitation of fibrous proteins called amyloid in various organs or tissues in the body are collectively called amyloidosis. A common feature of amyloidosis is that a fibrous protein called amyloid, rich in β -sheet (sheet) structures, deposits systemically or locally at sites in various organs, such that dysfunction is triggered in the organ or tissue.

[0003] Alzheimer's disease (hereinafter referred to as AD) is a typical amyloidosis disease, which is known to be a disease causing dementia. As deposits of amyloid accumulate in the brain, the disease is fatal and, therefore, is said to be a disease of greater social interest than other amyloidosis disorders. In recent years, the number of AD patients in developed countries of aging society has rapidly increased, thus causing social problems.

[0004] From a histopathological point of view, AD is characterized by three pathological findings in the brain, namely the development of senile plaques, the formation of neurofibrillary tangles and extensive neuronal loss. Senile plaques have a structure mainly composed of amyloid, which is said to be evident in the initial stages of the onset of AD, and thus, the pathological phenomenon is found in the brain about 10 or more years before clinical symptoms occur.

[0005] Diagnosis of AD involves the assessment of various cognitive functions (e.g., Hasegawa scale, ADAS-JCog, and MMSE) with the aid of a combination of image diagnoses such as CT and MRI. However, the methods based on the evaluation of cognitive functions have a low diagnostic sensitivity in the early stage of onset, and furthermore, there is a problem that the diagnostic result is susceptible to the innate cognitive function of an individual. Currently, when AD patients are still present, it is practically impossible to perform definitive diagnosis of AD because definitive diagnosis requires biopsy of the diseased part (non-patent document 1).

[0006] Meanwhile, a report indicates that amyloid constituting senile plaques is an aggregate of amyloid β protein (hereinafter referred to as a β). Meanwhile, many reports indicate that a β aggregates form β -layer structures leading to neurocytotoxicity. Based on these findings, a so-called "amyloid interlock reaction hypothesis" has been proposed, which suggests that brain precipitation of a β causes downstream phenomena, i.e., formation of neurofibrillary tangles and neuronal loss (non-patent document 2).

[0007] Based on these facts, in vivo detection of AD using a compound having a high affinity for amyloid as a marker has been recently attempted.

Such probes for image diagnosis of amyloid in brain are mostly hydrophobic low molecular weight compounds having high affinity with amyloid and high brain transferability, and are used with various radioactive substances such as¹¹C、¹⁸F and¹²³and I, marking. For example, there is a report that,¹¹c or radiohalogen labelled compounds include various thioflavine derivatives such as 6-iodo-2- [ 4' - (N, N-dimethylamino) phenyl]Benzothiazole (hereinafter referred to as TZDM) and 6-hydroxy-2- [ 4' - (N-methylamino) phenyl]Benzothiazole (hereinafter referred to as 6-OH-BTA-1) (patent document 1, non-patent document 3); stilbene compounds such as (E) -4-methylamino-4 '-hydroxystilbene (hereinafter referred to as SB-13) and (E) -4-dimethylamino-4' -iodostilbene (hereinafter referred to as m-I-SB) (patent document 2, non-patent document 4, non-patent document 5); benzoxazole derivatives such as 6-iodo-2- [ 4' - (N, N-dimethylamino) phenyl]Benzoxazoles (hereinafter IBOX) and 6- [2- (fluoro) ethoxy]-2- [2- (2-dimethylaminothiazol-5-yl) ethenyl]Benzoxazoles (non-patent document 6, non-patent document 7); DDNP derivatives such as 2- (1- {6- [ (2-fluoroethyl) (methyl)Radical) amino]-2-naphthyl } ethylene) malononitrile (hereinafter referred to as FDDNP) (patent document 4, non-patent document 8); and imidazopyridine derivatives such as 6-iodo-2- [ 4' - (N, N-dimethylamino) phenyl]Imidazo [1, 2-a ]]Pyridine (hereinafter referred to as IMPY) (patent document 3, non-patent document 9). Further, as for some probes for image diagnosis, human body image studies have been conducted, and it has been reported that there is a significant accumulation of radioactivity in the brain of AD patients as compared with normal persons (non-patent document 10, non-patent document 11, non-patent document 12, non-patent document 13).

International publication WO2007/002540 discloses a series of compounds containing a group having affinity with amyloid, to which a site labeled with a radioisotope is linked via ethylene glycol or polyethylene glycol (patent document 5).

International publication WO2007/063946 discloses a series of compounds that are linked to a five-membered aromatic heterocyclic group to prevent their metabolism in the brain.

[0008] [ patent document 1] JP-T-2004-506723

[ patent document 2] JP-T-2005-504055

[ patent document 3] JP-T-2005-512945

[ patent document 4] JP-T-2002-

[ patent document 5] International publication WO2007/002540

[ patent document 6] International publication WO2007/063946

[ non-patent document 1] J.A.Hardy & G.A.Higgins, "Alzheimer's disease: the Amyloid Cascade Hypothesis. ", Science, 1992, 256, p.184-185

[ non-patent document 2] G.McKhann et al, "Clinical diagnostics of Alzheimer's disease: report of the NINCDS-ADRDA word Group of underscores of Department of Health and Human Services task force on Alzheimer's disease ", Neurology, 1984, 34, p.939-944

[ non-patent document 3] Z. -P.ZHuang et al, "Radiodinated styrylbenzenes and Thioflavins as Probes for amylin dAggereggates", J.Med.chem., 2001, 44, p.1905-1914

[ non-patent document 4] Masahiro Ono et al, "11C-laboratory styrene derivatives as A β -aggregate-specific PET imaging agents for Alzheimer's disease", nucleic Medicine and Biology, 2003, 30, p.565-571

[ non-patent document 5] H.F.Kung et al, "Novel Stilbenes as probes for analog devices", J.American Chemical Society, 2001, 123, P.12740-12741

[ non-patent document 6] Zhi-Ping Zhuang et al, "IBOX (2- (4' -dimethyl-aminophenyl) -6-iodobendoxazole): a ligand for imaging amyloid peptides in the brain ", nucleic acids and Biology, 2001, 28, p.887-894

[ non-patent document 7]Furumoto Y et al, "A" and "B", "¹¹C]BF-227：A New¹¹C-Labeled 2-Ethenylbenzoxazole Derivative for Amyloid-βPlaques Imaging.”，European Journal of Nuclear Medicine andMolecular Imaging，2005，32，Sup.1，P759

[ non-patent document 8] Eric D.Agdeppa et al, "2-Dialkylamino-6-acryloylinnonitrile treated naphthanes (DDNP Analogs): novel Diagnostic and Therapeutic Toolsin Alzheimer's disease ", Molecular Imaging and Biology, 2003, 5, p.404-417

[ non-patent document 9] Zhi-Ping Zhuang et al, "Structure-Activity relationship of Imidazo [1, 2-a ] pyridines as Ligands for detecting β -Amyloid plants in the brain", J.Med.chem, 2003, 46, p.237-243

[ non-patent document 10] W.E.Kluk et al, "Imaging brand amyloid Alzheimer's disease with Pittsburgh Compound-B.", Ann.Neurol.2004, 55, p.306-319

[ non-patent document 11] Nicolaas P.L.G.Verhoeff et al, "In-vivo imaging of Alzheimer Disease β -Amyloid With [11C ] SB-13 PET.", American Journal of Geriatric Psychiatry, 2004, 12, p.584-595

[ non-patent document 12] Hiroyuki Arai et al, "[ 11C ] -BF-227 AND PETTO Visualize Amyloid in Alzheimer's diseases Patients", Alzheimer's & Dementia: the Journal of The Alzheimer' S Association, 2006, 2, Sup.1, S312

[ non-patent document 13] Christopher M.Clark et al, "imagingAmyloid with I123 IMPY SPECT" Alzheimer's & Dementia: the journal of The Alzheimer' S Association, 2006, 2, Sup.1, S342

Disclosure of Invention

Problems to be solved by the invention

[0009] As described above, it was disclosed that each compound can be used as a probe for image diagnosis of amyloid, and clinical use thereof was sought.

The results of the experiment in the normal mouse show that the use of [ alpha ], [ alpha ]¹²⁵I]Labeled TZDM, IBOX and m-I-SB were all transferred into the brain 2 minutes after administration. However, clearance of these compounds from normal tissues is insufficient and gradually accumulates in the brain with the passage of time after administration (JP-T-2005-. A problem arises when clearance from normal tissue is inadequate: sufficient contrast cannot be obtained at the site of amyloid accumulation (contrast). [¹¹C]The labeled SB-13 was shown in rat experiments to have clearance from normal tissue, but the clearance rate was not said to be sufficiently rapid (Masahiro Ono et al, Nuclear medicine)ne and Biology，2003，30，p.565-571)。

[0010]Also, it is disclosed as using [, ]¹²⁵I]As a result of experiments with labeled compounds, a compound having an imidazopyridine skeleton such as IMPY has a property of transferring to the brain and accumulating on amyloid after administration, and it also has an excellent property of being rapidly cleared from normal tissues, which is different from the above-mentioned compound. However, IMPY is a compound that is positive in the back-mutation assay. In order to use such a compound as a probe for image diagnosis, the dosage and administration manner must be sufficiently considered (International publication WO 03/106439).

FDDNP was also reported to be positive in the back-mutation assay. (International publication WO 03/106439).

[0011] As described above, although each compound has been disclosed as a probe for image diagnosis targeting amyloid, no compound has been found that has been confirmed to have clinically tolerable properties.

[0012] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a compound which is effective as a probe for image diagnosis of a target amyloid protein, and a diagnostic agent for alzheimer's disease comprising the compound.

Means for solving the problems

[0013] The present inventors have found that a group of compounds useful as diagnostic probes for images targeting amyloid can be obtained by directly labeling a compound having an imidazopyridine-phenyl skeleton with a radioactive halogen, thereby completing the present invention.

[0014] Specifically, according to one aspect of the present invention, there is provided a compound represented by the following formula (1):

[0015]

[0016]

or a salt thereof, and a diagnostic agent for Alzheimer's disease comprising the compound represented by the above formula (1) or a salt thereof.

[0017]In the formula (1), A¹、A²、A³And A⁴Each independently represents carbon or nitrogen, and it is necessary that at least one of them represents carbon. Preferably, A¹、A²、A³And A⁴Three or more of them represent carbon, and more preferably they all represent carbon. In the formula (1), R¹And A¹、A²、A³Or A⁴The carbons shown are attached. R¹The bonding site of (A) is preferably A³The carbon indicated, i.e., the 6-position carbon.

[0018]In the formula (1), R¹May be a group selected from hydrogen, hydroxyl, carboxyl, sulfate, amino, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and alkoxy substituents having 1 to 4 carbon atoms. R¹Preferably a hydroxyl, alkyl substituent having 1 to 4 carbon atoms or alkoxy substituent having 1 to 4 carbon atoms, more preferably a hydroxyl, methyl or methoxy substituent.

[0019]R²May be a radioactive halogen substituent, preferably selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹the radiohalogen substituents of I are more preferably selected from¹⁸F、⁷⁶Br、¹²³I and¹²⁵a radioactive halogen substituent of I.

[0020] According to a preferred embodiment of the present invention, there is provided a compound represented by the following formula (1'):

[0021]

[0022] or a salt thereof, and a diagnostic agent for Alzheimer's disease comprising the compound represented by the above formula (1') or a salt thereof.

In the formula (1'), R¹And R²Each represents the same group as the above formula (1).

[0023] According to another aspect of the present invention, there is provided a compound represented by the following formula (2):

[0024]

[0025] or a salt thereof, and a diagnostic agent for Alzheimer's disease comprising the compound represented by the above formula (2) or a salt thereof.

[0026]In the formula (2), A⁵、A⁶、A⁷And A⁸Each independently represents carbon or nitrogen, and it is necessary that at least one of them represents carbon. Preferably, A⁵、A⁶、A⁷And A⁸Three or more of them represent carbon, and more preferably they all represent carbon. In the formula (2), R³And A⁵、A⁶、A⁷Or A⁸The carbons shown are attached. R³The bonding site of (A) is preferably A⁷The carbon indicated, i.e., the 6-position carbon.

[0027]In the formula (2), R³May be a radioactive halogen substituent, preferably selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹the radiohalogen substituents of I are more preferably selected from¹⁸F、⁷⁶Br、¹²³I and¹²⁵a radioactive halogen substituent of I.

[0028]R⁴May be a group selected from hydrogen, carboxyl, sulfate, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and methoxy substituents. R⁴Is preferably a toolAn alkyl substituent having 1 to 4 carbon atoms or an alkoxy substituent having 1 to 4 carbon atoms, more preferably a methyl substituent or a methoxy substituent.

[0029] According to a preferred embodiment of the present invention, there is provided a compound represented by the following formula (2'):

[0030]

[0031] or a salt thereof, and a diagnostic agent for Alzheimer's disease comprising the compound represented by the above formula (2') or a salt thereof.

In the formula (2'), R³And R⁴Each represents the same group as the above formula (2).

[0032] According to another aspect of the present invention, there is provided a compound represented by the following formula (3):

[0033]

[0034] or a salt thereof.

[0035]In formula (3), A¹、A²、A³And A⁴Each independently represents carbon or nitrogen, and it is necessary that at least one of them represents carbon. Preferably, A¹、A²、A³And A⁴Three or more of them represent carbon, and more preferably they all represent carbon. In the formula (3), R¹And A¹、A²、A³Or A⁴The carbons shown are attached. R¹The bonding site of (A) is preferably A³The carbon indicated, i.e., the 6-position carbon.

[0036]In the formula (3), R⁵Can be selected from hydrogen, hydroxyl, carboxyl, sulfate, amino, nitro,Cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms, and alkoxy substituents having 1 to 4 carbon atoms. R⁵Preferably a hydroxyl, alkyl substituent having 1 to 4 carbon atoms or alkoxy substituent having 1 to 4 carbon atoms, more preferably a hydroxyl, methyl or methoxy substituent.

[0037]R⁶Is a group selected from the group consisting of non-radioactive halogen substituents, nitro groups, trialkylstannyl substituents having 1 to 4 carbon atoms in the alkyl chain, triphenylstannyl groups and trialkylammonium groups having 1 to 4 carbon atoms in the alkyl chain.

As the non-radioactive halogen substituent, a halogen capable of serving as a target of a nucleophilic substitution reaction using radioactive fluorine or radioactive iodine may be used, and chlorine, iodine, or bromine may be preferably used.

[0038] According to a preferred embodiment of the present invention, there is provided a compound represented by the following formula (3'):

[0039]

[0040] or a salt thereof.

In the formula (3'), R⁵And R⁶Each represents the same group as the above formula (3).

[0041] According to another aspect of the present invention, there is provided a compound represented by the following formula (4):

[0042]

[0043] or a salt thereof.

[0044]In formula (4), A⁵、A⁶、A⁷And A⁸Each independently represents carbon or nitrogen, and it is necessary that at least one of them represents carbon. Preferably, A⁵、A⁶、A⁷And A⁸Three or more of them represent carbon, and more preferably they all represent carbon. In the formula (4), R⁷And A⁵、A⁶、A⁷Or A⁸The carbons shown are attached. R⁸The bonding site of (A) is preferably A⁷The carbon indicated, i.e., the 6-position carbon.

[0045]In the formula (4), R⁷Is a group selected from the group consisting of non-radioactive halogen substituents, nitro groups, trialkylstannyl substituents having 1 to 4 carbon atoms in the alkyl chain, triphenylstannyl groups and trialkylammonium groups having 1 to 4 carbon atoms in the alkyl chain.

As the non-radioactive halogen substituent, a halogen capable of serving as a target of a nucleophilic substitution reaction using radioactive fluorine or radioactive iodine may be used, and chlorine, iodine, or bromine may be preferably used.

[0046]R⁸May be a group selected from hydrogen, carboxyl, sulfate, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and methoxy substituents. R⁸Preferably an alkyl substituent having 1 to 4 carbon atoms or an alkoxy substituent having 1 to 4 carbon atoms, more preferably a methyl substituent or a methoxy substituent.

[0047] According to a preferred embodiment of the present invention, there is provided a compound represented by the following formula (4'):

[0048]

[0049] or a salt thereof.

In the formula (4'), R⁷And R⁸Each represents the same group as the above formula (4).

Effects of the invention

[0050] The present invention provides a novel compound having affinity for amyloid, and therefore can provide a diagnostic agent for alzheimer's disease comprising the compound.

Drawings

[0171] FIG. 1 is a scheme for the synthesis of 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a ] pyridine.

FIG. 2 is a synthetic route for 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine.

FIG. 3 is a synthetic route for 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine.

FIG. 4 is a scheme for the synthesis of 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine.

FIG. 5 is a synthetic route to 2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a ] pyridine.

FIG. 6 is a scheme for the synthesis of 6-tributylstannyl-2- (4' -fluorophenyl) imidazo [1, 2-a ] pyridine.

FIG. 7 is a graph showing the relationship between the amyloid concentration and the radioactive concentration in the sample solution.

FIG. 8(a) is a view of the state of injection¹²³I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Autoradiograms of brain sections after pyridine, fig. 8(b) is a fluorescence micrograph of thioflavin T-stained samples (magnified image of the site of amyloid suspension injection).

FIG. 9(a) is a view of the state of injection [ 2]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Autoradiogram of pyridine postbrain sections, fig. 9(b) is a fluorescence micrograph of thioflavin T-stained samples (magnified image of the site of amyloid suspension injection).

FIG. 10(a) is a view of the state of injection [ 2]¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Autoradiograms of pyridine postbrain sections, fig. 10(b) is a fluorescence micrograph of thioflavin T-stained samples (magnified image of the site of amyloid suspension injection).

Detailed Description

[0051] (method for synthesizing precursor Compound of Radioactive halogen-labeled Compound)

Hereinafter, a method for synthesizing a precursor compound of a radiohalogen-labeled compound according to one embodiment of the present invention will be described by taking 2- (4' -tributylstannyl phenyl) -6-methoxyimidazo [1, 2-a ] pyridine as an example.

[0052] First, 2-bromo-3-hydroxypyridine is reacted with methyl iodide in the presence of sodium methoxide to synthesize 2-bromo-3-methoxypyridine. Then nitrated with a mixed acid of concentrated sulfuric acid and concentrated nitric acid to convert it into 2-bromo-3-methoxy-6-nitropyridine, and then, reductive elimination of the bromo group and reduction of the nitro group were performed with palladium on carbon to synthesize 2-amino-5-methoxypyridine (FIG. 1, steps 1 to 3). In this series of reactions, the reaction conditions can be set according to conventional methods, for example according to the methods described in the documents Journal g.lombardino, Journal of Medicinal Chemistry, 1981, 24, p.39-42.

[0053] The resulting 2-amino-5-methoxypyridine was reacted with 2-bromo-4 ' -bromoacetophenone to brominate the 4 ' -position, thereby synthesizing 2- (4 ' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine (FIG. 1, step 4). This step can be performed according to the following method.

[0054] First, 2-bromo-4 '-bromoacetophenone and 2-amino-5-methoxypyridine are dissolved in an inert solvent such as acetonitrile, and then they are reacted with each other at a reflux temperature for 2 to 6 hours to prepare a hydrobromide salt of 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine as a white precipitate. The inert solvent used in this case may be acetonitrile or other solvents commonly used in the same reaction, such as methanol and acetone. The reaction temperature may be a temperature that allows reflux, for example 90 ℃ when the solvent is acetonitrile. The amount of the solvent used may be an amount sufficient to effect the reaction, but it should be noted that if the solvent is too much, precipitation of the reaction product is difficult to obtain. For example, when the reaction is carried out using 2-bromo-4' -bromoacetophenone in an amount corresponding to 10mmol, the amount of the solvent used may be about 40 to 50 mL.

[0055] Subsequently, the reaction solution was filtered to recover a precipitate. The white precipitate was suspended in a methanol/water (1:1) mixture. Then, a saturated aqueous solution of sodium bicarbonate was added thereto in a very large excess amount relative to the above suspension precipitate to release 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine as a precipitate. The newly generated precipitate was filtered to recover crystalline 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine, which is the target compound of this step. The amount of the water/methanol mixed liquid is not particularly limited as long as it is sufficient to effect the reaction. However, it should be noted that if the amount of the mixed liquid is too large, precipitation of crystals is disturbed. For example, when 2-bromo-4' -bromoacetophenone is used in an amount corresponding to 10mmol, a water/methanol mixture may be used in an amount of about 40 to 100 mL. The amount of sodium hydrogencarbonate is not particularly limited as long as it is in a very large excess relative to the above-mentioned precipitate as a reaction substrate. For example, when the reaction is carried out under the above conditions, the amount of the saturated aqueous solution of sodium hydrogencarbonate added to the reaction solution may be about 25 mL.

[0056] The resulting 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine is dissolved in dioxane, triethylamine is added to the solution, followed by bis (tributyltin) and a catalytic amount of tetrakis (triphenylphosphine) palladium. The reaction mixture was heated at about 90 ℃ to effect a reaction, and then the solvent was distilled off and purified by chromatography to obtain 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a ] pyridine (fig. 1, step 5) as the target compound. At this time, the amount of bis (tributyltin) used may be an amount satisfying the condition of excess relative to the reaction substrate, specifically, it may be about 1.5 times as much as the molar ratio relative to the reaction substrate, 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine.

[0057] When a compound is obtained in which the substituent at the 4' -position is a trialkylstannyl substituent other than the tributylstannyl substituent, various di (trialkyltin) s suitable for the purpose may be used in step 5 in place of di (tributyltin). For example, when a compound having a trimethylstannyl substituent as a substituent at the 4' -position is synthesized, the same reaction as described above can be performed using bis (trimethyltin) in step 4.

[0058] Compounds can be obtained in which the substituent attached to the imidazopyridine ring is a hydroxy substituent, for example by: the 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine obtained in the above-mentioned step 4 is reacted with boron tribromide or the like to effect demethylation, followed by the reaction of the above-mentioned step 5. For compounds in which the substituent attached to the imidazopyridine ring is a methyl substituent or an ethoxy substituent, 2-amino-5-methoxypyridine may be replaced with 2-amino-5-methylpyridine and 2-amino-ethoxypyridine, respectively, in step 4 above.

[0059] The compound having a carbon atom other than the 6-position carbon as the bonding site of the functional group on the imidazopyridine ring can be obtained by using each compound having a different bonding site such as an alkoxy substituent on the pyridine ring instead of the 2-amino-5-methoxypyridine in step 4. For example, when the bonding site of the functional group is the 8-position carbon of the imidazopyridine ring, 2-amino-3-methoxypyridine may be used instead of 2-amino-5-methoxypyridine in step 4.

[0060] In addition, the labeling site of the radioactive halogen is a labeled precursor compound of an imidazopyridine ring, for example, 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine can be synthesized by the following method.

[0061] First, 4 '-hydroxyacetophenone is reacted with copper bromide according to a conventional method to prepare 2-bromo-4' -hydroxyacetophenone, for example, according to the method described in King, L.Carroll and Ostrum, G.Kenneth, Journal of Organic Chemistry, 1964, 29(12), p.3459-3461 (FIG. 3, step 1). This is reacted with 2-amino-5-iodopyridine in an inert solvent such as acetonitrile, and the resulting precipitate is purified to obtain 2- (4' -hydroxyphenyl) -6-iodoimidazo [1, 2-a ] pyridine (FIG. 3, step 2). The conditions of this step may be the same conditions as described in step 4 of fig. 1.

[0062] Then, the obtained 2- (4' -hydroxyphenyl) -6-iodoimidazo [1, 2-a ] pyridine is dissolved in a mixed solution of methanol and dioxane, and trimethylsilyldiazomethane is added thereto to carry out a reaction. The solvent was distilled off, and the residue was purified to synthesize 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine (fig. 3, step 3). In this step, the amount of trimethylsilyldiazomethane may be not less than the amount of 2- (4' -hydroxyphenyl) -6-iodoimidazo [1, 2-a ] pyridine.

[0063] The obtained 6-iodo-2- (4 '-methoxyphenyl) imidazo [1, 2-a ] pyridine was dissolved in dioxane, and triethylamine was added to the solution, followed by addition of bis (tributyltin) and a catalytic amount of tetrakis (triphenylphosphine) palladium, and a reaction was performed to obtain 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine as a target compound (fig. 4, step 1). The conditions of this step may be the same conditions as described in step 5 of fig. 1.

[0064] (method for synthesizing a radiohalogen-labeled Compound)

Next, a method for producing a radiohalogen-labeled compound according to another aspect of the present invention will be described by taking a radioiodine-labeled compound as an example.

[0065]Synthesis of a radioiodine-labeled compound is carried out by dissolving the labeled precursor compound prepared as described above in an inert organic solvent, and adding thereto the labeled precursor compound obtained by a known method¹²³I]Sodium iodide solution, etc., and an acid and an oxidizing agent are added thereto to carry out a reaction. Inert organic compounds as precursors for dissolving labelsSolvent, with a labeling precursor and [125I ] can be used]Various unreactive solvents such as sodium iodide, and methanol can be preferably used.

[0066] As the acid, various acids can be used, and hydrochloric acid is preferred.

The oxidizing agent is not particularly limited as long as it can oxidize iodine in the reaction solution, and is preferably hydrogen peroxide or peracetic acid. The amount of the oxidizing agent to be added may be an amount sufficient to oxidize iodine in the reaction liquid.

[0067]Compounds labeled with a radioactive halogen other than iodine can be synthesized by labeling a labeled precursor suitable for the purpose of synthesis with a radioactive halogen suitable for the purpose. For example, to synthesize 2- (4' - [ solution ]¹⁸F]Fluorophenyl) -6-methoxyimidazo [1, 2-a]Pyridine, the labeled precursor 2- (4' -nitrophenyl) -6-methoxyimidazo [1, 2-a ] can be reacted in the presence of a phase transfer catalyst and potassium carbonate]Pyridine and [ alpha ], [ alpha¹⁸F]Fluoride ion (fluoride ion).

[0068] (methods of preparing and Using the diagnostic Agents of the invention)

The diagnostic agent of the present invention may be prepared as a solution prepared in the same manner as other well-known radioactive diagnostic agents and comprising the radioactive halogen-labeled compound of the present invention mixed in water, a physiological saline solution or ringer's solution, optionally adjusted to an appropriate pH. At this time, the concentration of the compound of the present invention should be adjusted to not more than a concentration at which the stability of the compound of the present invention is ensured. There is no particular limitation on the dose of the compound of the present invention as long as it is sufficient to obtain a distribution image of the administered agent. For example, in the case of iodine-123 labeled compounds and fluorine-18 labeled compounds, about 50 to 600MBq/60kg of adult body weight may be administered intravenously or topically. The distribution of the administered agent can be visualized (imaged) by known methods. For example, an iodine-123 labeled compound may be imaged by a SPECT device, and a fluorine-18 labeled compound may be imaged by a PET device.

[0069] The present invention is described in more detail below by way of examples, comparative examples and reference examples. However, these examples do not limit the scope of the present invention.

[0070]Example 1: 2- (4' -tributylstannyl phenyl) -6-methoxyimidazo [1，2-a]Synthesis of pyridine

[0071] 100.0g (equivalent to 0.575mol) of 2-bromo-3-hydroxypyridine was dissolved in 310mL of dimethyl sulfoxide, and 575mL (equivalent to 0.575mol) of a 1mol/L sodium methoxide-methanol solution was added thereto. The reaction solution was then heated to 90 ℃ to distill off methanol. After the reaction liquid was cooled to 10 ℃ or lower, 93.9g (equivalent to 0.662mol) of methyl iodide was added, followed by stirring at room temperature for 20.5 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with chloroform 2 times. The combined chloroform layers were washed with 1mol/L sodium hydroxide solution, and then washed 2 times with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, 65.4g (equivalent to 0.348mol) of 2-bromo-3-methoxypyridine was obtained (FIG. 1, step 1).

[0072] 262mL of concentrated sulfuric acid was cooled to-2 ℃ and 262mL of 90% concentrated nitric acid was carefully added thereto. Subsequently, 65.3g (corresponding to 0.347mol) of 2-bromo-3-methoxypyridine were carefully added thereto. After the reaction mixture was stirred in the ice bath for 10 minutes, the mixture was stirred at room temperature for 30 minutes, then heated to 55 ℃, and stirred for another 1.5 hours. After the reaction solution was cooled, the reaction solution was poured little by little into crushed ice to cause precipitation. The precipitate was filtered and washed with water and then dried over phosphorus pentoxide under reduced pressure to give 55.7g (equivalent to 0.239mmol) of 2-bromo-3-methoxy-6-nitropyridine (FIG. 1, step 2).

[0073] 55.6g (equivalent to 0.239mol) of 2-bromo-3-methoxy-6-nitropyridine was dissolved in 1700mL of ethanol, and 37.3g (50% humidity) of 10% palladium on carbon was added thereto under an argon flow. 283mL of hydrazine monohydrate is then added dropwise to this mixture. After refluxing the reaction mixture for 70 minutes, the reaction was cooled to room temperature. Then, after filtering off the palladium on carbon, the residue was washed with ethanol, and the washing solution and the filtrate were combined. The combined solution was concentrated under reduced pressure. 1300mL of water and 130mL of concentrated aqueous ammonia were then added to the concentrate, and the resulting mixture was extracted 8 times with chloroform. The combined chloroform layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was distilled off under reduced pressure to obtain 26.2g (equivalent to 0.211mol) of 2-amino-5-methoxypyridine (FIG. 1, step 3).

[0074] 844mg (equivalent to 3.0mmol) of 2-bromo-4' -bromoacetophenone and 378mg (equivalent to 3.0mmol) of 2-amino-5-methoxypyridine are dissolved in 25mL of acetonitrile. The resulting solution was heated to reflux in an oil bath at 105 ℃ for 3.5 hours. After the reaction, the reaction solution was cooled to room temperature, and the precipitate was recovered by filtration. The filtered precipitate was washed with acetonitrile and dried under reduced pressure to give crude crystals. The resulting crude crystals were suspended in a mixture of 7mL of water and 7mL of methanol. Then, about 7mL of a saturated sodium bicarbonate solution was added thereto, and the mixture was sonicated with a sonicator for 5 minutes. The precipitate was filtered, washed well with water, and dried under reduced pressure to give 640mg (equivalent to 2.11mmol) of 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine (FIG. 1, step 4).

[0075] 463mg (equivalent to 1.5mmol) of 2- (4' -bromophenyl) -6-methoxyimidazo [1, 2-a ] pyridine are dissolved in 25mL of dioxane, to which 2mL of triethylamine are added. Then, 1.15mL (equivalent to 2.25mmol) of bis (tributyltin) and 19mg (catalytic amount) of tetrakis (triphenylphosphine) palladium were added thereto. After the reaction mixture was stirred at 90 ℃ for 15 hours, the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: hexane/ethyl acetate 5/1 → 4/1). The crude product was purified by preparative HPLC (HPLC apparatus: LC-908 (trade name; manufactured by Nippon analytical industries, Ltd.), 2 JAIGEL2H (trade name; manufactured by Nippon analytical industries, Ltd.) in series and chloroform as a mobile phase to obtain 419mg (equivalent to 0.82mmol) of 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a ] pyridine (FIG. 1, step 5).

[0076] The results of NMR measurement of the obtained 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a ] pyridine (internal standard: tetramethylsilane) are shown below.

[0077] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: chloroform-d 1, resonance frequency: 500 MHz): δ 7.89-7.84(m, 2H), 7.81(s, 1H), 7.66-7.63(m, 1H), 7.57-7.46(m, 3H), 6.96(dd, J ═ 9.7, 2.4Hz, 1H), 3.83(s, 3H), 1.64-1.47(m, 6H), 1.34 (hexamer, J ═ 7.3Hz, 6H), 1.15-1.00(m, 6H), 0.89(t, J ═ 7.3Hz, 9H).

[0078]¹³C-NMR (solvent: chloroform-d 1, resonance frequency: 125 MHz): δ 149.29, 146.02, 142.90, 141.71, 136.84, 133.52, 125.23, 119.66, 117.73, 109.16, 107.47, 56.20, 29.12, 27.38, 13.69, 9.62.

[0079]Example 2: [ ¹²⁵ I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a] Synthesis of pyridine

[0080]To 75. mu.L of 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a]To a methanol solution of pyridine (concentration: 1mg/mL) were added 100. mu.L of 1mol/L hydrochloric acid, 10. mu.L of 1mmol/L sodium iodide, and 160MBq of [125I ]]Sodium iodide solution (80. mu.L volume) and 20. mu.L of 10% (w/v) hydrogen peroxide. The mixture was allowed to stand at 50 ℃ for 10 minutes, and then subjected to HPLC under the following conditions to obtain [ 2], [¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine fraction.

[0081] HPLC conditions:

a chromatographic column: phenomenex Luna C18 (trade name; manufactured by Phenomenex Co., Ltd.; size: 4.6X 150mm)

Mobile phase: 0.1% trifluoroacetic acid/acetonitrile 20/80 → 0/100(17 min, linear gradient)

Flow rate: 1.0 mL/min

A detector: an ultraviolet visible absorption photometer (detection wavelength: 282nm) and a radioactivity counter (model: STEFFI, manufactured by Raytest Co., Ltd.)

[0082]To this fraction, 10mL of water was added. The resulting solution was passed through a reverse phase column (trade name; Sep-Pak (registered trade name) Light C8 bridges, manufactured by Waters Corp.; filling amount of filler: 130mg) so that the column was adsorbed and collected [, [ 2]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine. The column was washed with 1mL of water, and then 1mL of diethyl ether was passed therethrough to elute¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine. The radioactivity (radioactivity) of the compound obtained was 27MBq (at the end of the synthesis). Further, as a result of TLC analysis under the following conditions, the radiochemical purity of this compound was 97%.

[0083] TLC analysis conditions:

TLC plate: RP-18F254 (trade name; manufactured by Merck)

Developing phase: chloroform/methanol/triethylamine 100/1/2

A detector: bio-image analyzer BAS-2500 (model: BAS-2500; manufactured by Fuji film Co., Ltd.)

[0084]Example 3: [ ¹²⁵ I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a] Synthesis of pyridine

[0085]To 75. mu.L of 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a]To a methanol solution of pyridine (concentration: 1mg/mL), 100. mu.L of 1mol/L hydrochloric acid, 10. mu.L of 1mmol/L sodium iodide, 32MBq [ alpha ], [ solution ] was added¹²⁵I]Sodium iodide solution (20. mu.L in volume) and 20. mu.L of 10% (w/v) hydrogen peroxide. The mixture was allowed to stand at 50 ℃ for 10 minutes and then subjected to HPLC under the same conditions as in example 2 to obtain [ 2]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine fraction.

[0086]To this fraction, 10mL of water was added. The resulting solution was passed through a reverse phase column (trade name; Sep-Pak (registered trade Mark) Light C8 bridges, Waters corporation)Preparing; filling amount of the filler: 130mg) so that the column adsorbs and collects¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine. The column was rinsed with 1mL of water, and then 1mL of ethanol was passed therethrough to elute¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine. The radioactivity of the compound obtained was 15MBq (immediately after the synthesis). Further, as a result of TLC analysis under the same conditions as in example 2, the radiochemical purity of this compound was 92%.

[0087]Example 4: 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine compound Synthesis of (non-radioactive iodinated form)

[0088] 100mg (equivalent to 0.20mmol) of 2- (4' -tributylstannylphenyl) -6-methoxyimidazo [1, 2-a ] pyridine obtained in example 1 are dissolved in 2.0mL of dichloromethane, to which 37mg (equivalent to 0.29mmol) of iodine are added. After the reaction mixture was stirred at 0 ℃ for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium thiosulfate solution were added thereto, and extracted with dichloromethane 3 times. The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 2/1) to obtain 44.5mg (equivalent to 0.13mmol) of 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine (fig. 2, step 1).

[0089] The results of NMR measurement of the obtained 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine (internal standard: tetramethylsilane) are shown below.

[0090] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: chloroform-d 1, resonance frequency: 500 MHz): δ 7.75-7.71(m, 3H), 7.64-7.62(m, 2H), 7.59(d, J ═ 1.8Hz, 1H), 7.49(d, J ═ 10.1Hz, 1H), 6.96(dd, J ═ 10.1, 1.8Hz, 1H), 3.81(s, 3H).

[0091]¹³C-NMR (solvent: chloroform-d 1, resonance frequency: 125MHz)：δ 149.80，144.94，143.27，138.12，133.91，127.88，120.56，118.05，109.72，107.79，93.45，56.57。

[0092]Example 5: 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine compound Synthesis of (non-radioactive iodinated form)

[0093] 50mL of ethyl acetate was added to 28.17g (equivalent to 126mmol) of cupric bromide to obtain a suspension, and a mixture of 8.18g (equivalent to 60.0mmol) of 4' -hydroxyacetophenone in 50mL of ethyl acetate and 50mL of chloroform was added thereto. The resulting mixture was then heated to reflux. After 5 hours, the reaction was cooled to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and activated carbon was added to perform a decoloring operation. Then, the resulting solution was filtered and concentrated. The resulting crude product was purified by flash column chromatography on silica gel (eluent: chloroform/methanol-20/1) and recrystallized from ethyl acetate/petroleum ether to give 7.25g (equivalent to 33.7mmol) of 2-bromo-4' -hydroxyacetophenone (fig. 3, step 1).

[0094] 441mg (equivalent to 2.0mmol) of 2-bromo-4' -hydroxyacetophenone and 449mg (equivalent to 2.0mmol) of 2-amino-5-iodopyridine were dissolved in 15mL of acetonitrile. The resulting solution was heated to reflux in an oil bath for 5 hours at 110 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, and the precipitate was collected by filtration. The precipitate was washed with acetonitrile and dried under reduced pressure, and the resulting crude crystal was suspended in a mixture of 10mL of water and 10mL of methanol. About 10mL of a saturated sodium bicarbonate solution was then added thereto, and the mixture was sonicated with a sonicator for 5 minutes. The precipitate was recovered by filtration from the resulting mixture, washed well with water, and dried under reduced pressure to obtain 0.53g (equivalent to 1.56mmol) of 2- (4' -hydroxyphenyl) -6-iodoimidazo [1, 2-a ] pyridine (FIG. 3, step 2).

[0095] 0.40g (equivalent to 1.2mmol) of 2- (4' -hydroxyphenyl) -6-iodoimidazo [1, 2-a ] pyridine is dissolved in a mixture of 30mL of methanol and 50mL of dioxane, and 1.2mL (equivalent to 2.4mmol) of trimethylsilyldiazomethane (2M in hexane) is added thereto. The reaction mixture was stirred at room temperature for 24.5 hours, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give 223mg (equivalent to 0.64mmol) of 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine (FIG. 3, step 3).

[0096] The results of NMR measurement of the obtained 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine are shown below (internal standard: tetramethylsilane).

[0097] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: chloroform-d 1, resonance frequency: 500 MHz): δ 8.37-8.34(m, 1H), 7.88-7.84(m, 2H), 7.72(s, 1H), 7.40(d, J ═ 9.4Hz, 1H), 7.31(dd, J ═ 9.4, 1.6Hz, 1H), 6.99-6.95(m, 2H), 3.86(s, 3H).

[0098]¹³C-NMR (solvent: chloroform-d 1, resonance frequency: 125 MHz): δ 159.86, 146.32, 144.18, 132.32, 130.28, 127.41, 125.90, 118.32, 114.22, 106.88, 74.76, 55.33.

[0099]Example 6: 6-Tributylstannyl-2- (4' -methoxyphenyl) imidazo [1，2-a]Synthesis of pyridine

[0100] 87.6mg (equivalent to 0.25mmol) of 6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine obtained in example 5 was dissolved in 10mL of dioxane, and 2mL of triethylamine was added thereto. Then, 190. mu.L (equivalent to 0.375mmol) of di (tributyltin) and 20mg (catalytic amount) of tetrakis (triphenylphosphine) palladium were added thereto. After the reaction mixture was stirred at 90 ℃ for 21.5 hours, the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: hexane/ethyl acetate 3/1). The crude product was purified by preparative HPLC (HPLC apparatus: LC-908 (trade name; manufactured by Nippon analytical industries, Ltd.), 2 JAIGEL2H (trade name; manufactured by Nippon analytical industries, Ltd.) in series and chloroform as a mobile phase) to obtain 53mg (equivalent to 0.10mmol) of 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine (FIG. 4, step 1).

[0101] The results of NMR measurement of the obtained 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a ] pyridine (internal standard: tetramethylsilane) are shown below.

[0102] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: chloroform-d 1, resonance frequency: 500 MHz): δ 8.01-7.93(m, 1H), 7.92-7.87(m, 2H), 7.74(s, 1H), 7.60-7.56(m, 1H), 7.18-7.09(m, 1H), 6.99-6.94(m, 2H), 3.84(s, 3H), 1.66-1.46(m, 6H), 1.35 (hexamer, J ═ 7.3Hz, 6H), 1.19-1.02(m, 6H), 0.91(t, J ═ 7.3Hz, 9H).

[0103]¹³C-NMR (solvent: chloroform-d 1, resonance frequency: 125 MHz): δ 159.45, 145.56, 145.01, 131.00, 129.95, 127.22, 126.70, 121.69, 116.80, 114.06, 106.24, 55.23, 28.94, 27.24, 13.59, 9.74.

[0104]Example 7: [ ¹²³ I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a] Synthesis of pyridine

[0105]To 50. mu.L of 6-tributylstannyl-2- (4' -methoxyphenyl) imidazo [1, 2-a)]To a methanol solution of pyridine (concentration: 1mg/mL) were added 50. mu.L of 1mol/L hydrochloric acid, 10. mu.L of 1mmol/L sodium iodide, 318MBq of¹²⁵I]Sodium iodide solution (50. mu.L volume) and 10. mu.L of 10% (w/v) hydrogen peroxide. The mixture was allowed to stand at 50 ℃ for 10 minutes and then subjected to HPLC under the same conditions as in example 2 to obtain [ 2]¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine fraction.

[0106]To this fraction, 10mL of water was added. The resulting solution was passed through a reverse phase column (trade name; Sep-Pak (registered trade name) Light C18 bridges, manufactured by Waters Corp.; filling amount of filler: 130mg) so that the column was adsorbed and collected [, [ 2]¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine. The column was rinsed with 1mL of water and then allowed to drain1mL of diethyl ether was passed to elute¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine. The radioactivity of the compound obtained was 86MBq (immediately after the synthesis). Further, as a result of TLC analysis under the same conditions as in example 2, the radiochemical purity of this compound was 98%.

[0107]Example 8: 2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine (non-radioactive) Radiofluorinated forms) synthesis

[0108] 40mL of ethyl acetate were added to 3.70g (corresponding to 16.6mmol) of copper bromide to obtain a suspension, to which 1.0mL (corresponding to 8.27mmol) of 4' -fluoroacetophenone was added. The resulting mixture was then heated to reflux. After 3 hours, the reaction mixture was cooled to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform/methanol 10/1) to obtain 1.82g (equivalent to 8.39mmol) of 2-bromo-4' -fluoroacetophenone (fig. 5, step 1).

[0109] 1.82g (corresponding to 8.39mmol) of 2-bromo-4' -fluoroacetophenone and 1.29g (corresponding to 5.87mmol) of 2-amino-5-iodopyridine are dissolved in 40mL of acetonitrile. The resulting solution was heated to reflux in an oil bath at 110 ℃ for 1.5 hours. After the reaction, the reaction solution was cooled to room temperature, and the precipitate was recovered by filtration. The precipitate was then washed with acetonitrile and dried under reduced pressure, and the resulting crude crystal was suspended in a mixture of 20mL of water and 10mL of methanol. About 30mL of a saturated sodium bicarbonate solution was then added thereto, and the mixture was sonicated with a sonicator for 5 minutes. The precipitate was recovered by filtration from the resulting mixture, washed well with water, and dried under reduced pressure to obtain 1.28g (equivalent to 3.79mmol) of 2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a ] pyridine (FIG. 5, step 2).

[0110] NMR measurement results of the obtained 2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a ] pyridine are shown below (internal standard: tetramethylsilane).

[0111] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: dimethylformamide-d 7, resonance frequency: 500 MHz): δ 9.06(s, 1H), 8.44(s, 1H), 8.01-7.98(m, 2H), 7.22(d, J ═ 9.6Hz, 1H), 7.57(d, J ═ 9.6Hz, 1H), 7.38-7.34(m, 2H).

[0112]Example 9: 6-Tributylstannyl-2- (4' -fluorophenyl) imidazo [1，2-a]Synthesis of pyridine

[0113] 338mg (equivalent to 1.00mmol) of 2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a ] pyridine obtained in example 8 was dissolved in 4.0mL of dioxane, and 2mL of triethylamine was added thereto. Then, 0.76mL (equivalent to 1.5mmol) of bis (tributyltin) and 76.3mg (catalyst amount) of tetrakis (triphenylphosphine) palladium were added thereto. After the reaction mixture was stirred at 90 ℃ for 18 hours, the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: hexane/ethyl acetate 5/1) to give 310mg (equivalent to 0.618mmol) of 6-tributylstannyl-2- (4' -fluorophenyl) imidazo [1, 2-a ] pyridine (fig. 6, step 1).

[0114] The results of NMR measurement of the obtained 6-tributylstannyl-2- (4' -fluorophenyl) imidazo [1, 2-a ] pyridine (internal standard: tetramethylsilane) are shown below.

[0115] NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)

¹H-NMR (solvent: chloroform-d 1, resonance frequency: 500 MHz): δ 7.98(s, 1H), 7.94-7.90(m, 2H), 7.77(s, 1H), 7.60-7.58(m, 1H), 7.17-7.10(m, 3H), 1.64-1.48(m, 6H), 1.35 (hexameric peak, J ═ 7.3Hz, 6H), 1.19-1.05(m, 6H), 0.91(t, J ═ 7.3Hz, 9H).

[0116]¹³C-NMR (solvent: chloroform-d 1, resonance frequency: 125 MHz): δ 162.7(d,¹J_CF＝246.7Hz)，145.7，144.3，131.4，130.3(d，⁴J_CF＝2.9Hz)，130.1，127.7(d，³J_CF＝8.6Hz)，122.2，117.1，115.6(d，²J_CF＝21.1Hz)，106.9，29.0，27.3，13.7，9.8。

[0117]example 10: [ ¹²³ I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine (II) Synthesis of pyridine

[0118]To 6-tributylstannyl-2- (4' -fluorophenyl) imidazo [1, 2-a)]To 60. mu.L of a methanol/dimethyl sulfoxide solution of pyridine (mixing ratio: 9/1) (concentration: 1mg/mL) were added 40. mu.L of 1mol/L hydrochloric acid, 15. mu.L of 1mmol/L sodium iodide, 12. mu.L of 150.1MBq [, [ 2]¹²⁵I]Sodium iodide and 15. mu.L of 10% (w/v) hydrogen peroxide. The mixture was allowed to stand at 50 ℃ for 10 minutes and then subjected to HPLC under the following conditions to obtain 2- (4' -fluorophenyl) -6-, [ 2], [2- ]¹²⁵I]Iodoimidazo [1, 2-a]Pyridine fraction.

[0119] HPLC conditions:

a chromatographic column: phenomenex Luna C18 (trade name; manufactured by Phenomenex Co., Ltd.; size: 4.6X 150mm)

Mobile phase: 0.1% trifluoroacetic acid/acetonitrile 20/80 → 0/100(17 min)

Flow rate: 1.0 mL/min

A detector: an ultraviolet visible absorption photometer (detection wavelength: 282nm) and a radioactivity counter (model: STEFFI, manufactured by Raytest Co., Ltd.)

[0120]To this fraction, 10mL of water was added. The resulting solution was passed through a Sep-Pak C8 column (trade name; Sep-Pak (registered trade name) Light C8 cards, manufactured by Waters Co., Ltd.; packing amount of packing: 130mg) so that the column was adsorbed and collected [, [ 2] ]¹²³I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine. The column was washed with 1mL of water, and then 1mL of diethyl ether was passed therethrough to elute 2- (4' -fluorophenyl) -6-, [ 2], [2- ]¹²⁵I]Iodoimidazo [1, 2-a]Pyridine. The radioactivity of the compound obtained immediately after the synthesis was 28.8 MBq.

[0121]Reference example 1: [ ¹²⁵ I]Synthesis of IMPY

[0122]Synthesized for logP according to the following procedure_{Octanol (I)}The [ 2] used in the comparative example for measuring and evaluating the accumulation in the brain¹²³I]-IMPY。

[0123]6-Tributylstannyl-2- [ 4' - (N, N-dimethylamino) phenyl ] was synthesized according to the method described in literature (Zhi-Ping Zhuang et al, J.Med.chem., 2003, 46, p.237-243)]Imidazo [1, 2-a ]]Pyridine, and dissolved in methanol (concentration: 1 mg/mL). To 53. mu.L of the resulting solution, 75. mu.L of 1mol/L hydrochloric acid, 60 to 70. mu.L of 2-¹²³I]Sodium iodide, 10. mu.L of a 1mmol/L sodium iodide solution, 15. mu.L of 10% (w/v) hydrogen peroxide. After the mixture was allowed to stand at 50 ℃ for 10 minutes, the solution was subjected to HPLC under the same conditions as described in example 2 to obtain [ 2], [¹²⁵I]-an IMPY fraction.

[0124]To this fraction, 10mL of water was added. The resulting solution was passed through a reverse phase column (trade name; Sep-Pak (registered trade name) Light C18 bridges, manufactured by Waters Corp.; filling amount of filler: 130mg) so that the column was adsorbed and collected [, [ 2]¹²³I]-IMPY. The column was washed with 1mL of water, and then 1mL of diethyl ether was passed therethrough to elute¹²⁵I]-IMPY. The radioactivity of the obtained compound immediately after the synthesis was 41-57 MBq. Further, as a result of TLC analysis under the same conditions as described in example 2, the radiochemical purity of this compound was 93%.

[0125]Example 11: determination of binding to amyloid

[0126] The compounds of the invention were tested for affinity to amyloid by the in vitro binding assay described below.

[0127] (method)

(1) Mixing A beta_1-42(manufactured by Wako pure chemical industries, Ltd.) was dissolved in a phosphate buffer solution (pH7.4) and shaken at 37 ℃ for 72 hours to obtain a suspension of 1mg/mL of aggregated A β (hereinafter, referred to as amyloid in this example) (hereinafter, referred to as amyloid suspension in this example))。

[0128](2) According to the literature (Naiki, H. et al, laboratory investigation,74p.374-383(1996)) based on fluorescence spectrophotometry using thioflavin T (manufactured by Fluka corporation), to confirm that the agglutinated a β obtained in (1) is amyloid (measurement conditions: excitation wavelength 446nm, fluorescence wavelength 490 nm).

[0129](3) The [ 2] synthesized by the method described in example 3 was diluted with a phosphate buffer solution (pH7.4) containing 1% bovine serum albumin¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine in ethanol (radioactive concentration: 27MBq/mL) to prepare 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ]]The total amount of pyridine corresponds to a solution with a concentration of 2 nmol/L.

[0130] (4) to each well of a 96-well microplate, 50. mu.L of the solution prepared as in (3) above and a solution obtained by dissolving an amyloid suspension in a phosphate buffer solution (pH7.4) containing 1% bovine serum albumin (the concentration of amyloid can be adjusted depending on the amyloid concentration in the sample solution) were added to 50. mu.L, and then 150. mu.L of a phosphate buffer solution containing 1% bovine serum albumin was added to prepare an amyloid solution having final concentrations of 25, 62.5, 250, 625 and 1000nmol/L (corresponding to a total amount of 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine of 400 pmol/L).

[0131](5) The microplate was shaken at the indicated speed (400rpm) at 22 ℃ for 3 hours. The mixture in each well was then passed through a glass fiber filter (trade name; Mulutiscreen)^TM-FC, manufactured by Millipore) filtration to separate from free [ solution ]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Separation of amyloid-binding protein in pyridine¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine.

[0132] (6) the glass fiber filter used for filtering the sample solution was washed (0.5 mL. times.5) with a phosphate buffer solution (pH7.4) containing 1% bovine serum albumin, and then the radioactivity count (hereinafter referred to as A) of the glass fiber filter was measured using an AutowellGamma system (model: ARC-301B, manufactured by Aloka Co., Ltd.).

[0133] (7) in addition, the same operation as described in (3) was carried out using the methanol solution of 2- (4 '-iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine (non-radioiodinated form) prepared in example 4 to prepare a 2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a ] pyridine solution at a concentration of 15. mu. mol/L. To each well of a 96-well microplate containing 50. mu.L of the solution prepared in (3), 50. mu.L of a solution obtained by dissolving an amyloid suspension in a phosphate buffer solution (pH7.4) containing 1% bovine serum albumin (the concentration of amyloid can be adjusted depending on the amyloid concentration in the sample solution) and 100. mu.L of a phosphate buffer solution (pH7.4) containing 1% bovine serum albumin were added to prepare amyloid solutions at final concentrations of 25, 62.5, 250, 625 and 1000 nmol/L. The same operations as in (5) and (6) above were carried out to measure the radioactivity count (hereinafter referred to as B) remaining in the glass fiber filter of the microplate.

[0134](8) Using the radioactive counts measured in the above (6) and (7), the value of [ 2] which binds specifically to amyloid is calculated according to the formula (1)¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Radioactivity of pyridine was counted and evaluated in relation to the amount of amyloid added.

[0135]

Radioactivity count ═ A-B (1)

[0136] (results)

The relationship between the radioactive count calculated in (8) above and the concentration of amyloid in the sample solution is shown in FIG. 5. As shown in the figure, the radioactivity count calculated in (8) above tends to increase with increasing amyloid concentration. Under the conditions of this experiment, amyloid and compounds that bind to amyloid remain in the glass fibers. Counting from radioactivity substantially calculated in (8) aboveThe radioactivity count remaining on the glass fibers that were not bound to amyloid was subtracted from the values. The radioactive count on the glass fiber measured in this example can be referred to as a value reflecting the amount of the compound that specifically binds to amyloid. Therefore, the fact that the value of the radioactive count calculated in the above (8) increases with the increase in the amyloid concentration strongly indicates that [ alpha ], [ beta ] -cyclodextrin¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine is a compound that binds to amyloid.

The above result indicates that the value of [ alpha ], [ alpha ]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine can bind to amyloid.

[0137]Examples 12 to 14, comparative example 1: partition coefficient based on octanol extraction Measurement of

[0138]The partition coefficient (hereinafter referred to as logP) was measured by octanol extraction which is generally known as an indicator of the penetration of a compound through the blood-brain barrier (hereinafter referred to as BBB)_{Octanol (I)})。

[0139] (method)

The [ 2], [ prepared in example 7] was diluted with a physiological saline solution containing 10mg/mL of ascorbic acid, respectively¹²³I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]A solution of pyridine in ether (example 12), the product prepared in example 2¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]A solution of pyridine in ether (example 13), the product prepared in example 10¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]A solution of pyridine in diethyl ether (example 14) and the product prepared in reference example 1¹²⁵I]IMPY in ether (comparative example 1), adjusted to a radioactive concentration of 20-30 MBq/ml. To 2mL of octanol were added 10. mu.L each of the prepared sample solutions, and 2mL of 10mmol/L phosphate buffer solution (pH7.4) was added, followed by stirring for 30 seconds. After the mixture was centrifuged by a low speed centrifuge (2000 rpm. times.60 minutes), 1mL of the octyl alcohol layer and the aqueous layer were each sampled and the respective contents were measured by an Autowell Gamma System (model: ARC-301B, manufactured by Aloka)And (6) counting the radioactivity. Using the measured radioactivity counts, logP is calculated according to equation (2)_{Octanol (I)}。

[0141] (results)

The results are shown in Table 1. As shown in the table, all compounds showed logP_{Octanol (I)}The values are all between 1 and 3. logP of compounds known to be able to permeate the BBB_{Octanol (I)}Values ranged from 1 to 3 (Douglas D.Dischino et al, J.Nucl.Med., (1983), 24, p.1030-1038). From the above results, all compounds have the same BBB permeability as IMPY.

[0142]Table 1: logP of the Compounds of the invention_{Octanol (I)}Value of

Experiment of	Compound (I)	logPOctanol (I)Value of
			Comparative example 1	[123I]-IMPY	1.9
Example 12	[125I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine compound	1.7
			Example 13	[123I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine compound	2.3
Example 14	[123I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine compound	2.3

[0143]Examples 15 to 16, by weightComparative example 2: metastatic and clearance into the brain (Qing) Division ratio) was determined

[0144]Use of¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine and [ alpha ], [ alpha¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine, and the change with time of radioactive accumulation in the brain of male Wistar rats (7 weeks old) was measured.

[0145] (method)

The product of example 2¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]A physiological saline solution of pyridine (example 15) containing 10mg/mL of ascorbic acid, and the product of example 10¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine (example 16) in a physiological saline solution containing 10mg/mL ascorbic acid (0.05 mL each (radioactive concentration 20-30MBq/mL) was injected into the tail vein of male Wistar rats (7 weeks old) under thiopentan anesthesia. These rats were sacrificed by bleeding from the abdominal aorta 2, 5, 30 and 60 minutes after injection, and the brains were removed and measured for brain quality, and then radioactivity of the brains (hereinafter, referred to as "A" in this example) was measured by a single channel analyzer (model: SP-20, manufactured by Utility industries, Ltd.). In addition, the radioactivity of the remaining part of the whole body was measured in the same manner as described above (hereinafter, referred to as B in this example). Using these measurement results, the amount of radioactivity accumulated (% ID/g) per unit brain mass at each time point was calculated according to the following formula (3) (example 15 and example 16).

Further, the term "2" prepared in reference example 1 is prepared¹²⁵I]A solution of IMPY dissolved in a physiological saline solution containing 10mg/mL of ascorbic acid (radioactive concentration 20-30 MBq/mL). The same operation as described above was performed to calculate the amount of radioactivity accumulated (% ID/g) per unit brain mass at each time point (comparative example 2).

At each time point, three animals were used in example 15, example 16 and comparative example 2.

[0147] (results)

The results are shown in Table 2. As shown in Table 2, at a time point of 2 minutes after the injection, [ 2]¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine (example 15) and [, [ 2]¹²³I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine (example 16) shows the same as¹²³I]IMPY (comparative example 2) accumulated equally and then showed a tendency to rapidly disappear within 60 minutes. These results suggest [ alpha ], [ alpha ] a¹²³I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine and [ alpha ], [ alpha¹²³I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine and [ alpha ], [ alpha¹²³I]IMPY, as well, has excellent transferability to the brain and can be cleared rapidly from the brain.

[0148] Table 2: after intravenous injection, the compounds of the invention accumulate radioactivity in the brain (rats)

[0149]Example 17: [ ¹²⁵ I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a] Imaging (visualization) confirmation of amyloid in brain by pyridine

[0150] The following experiment was conducted to examine whether amyloid in the brain can be imaged by the compound of the present invention.

[0151] (method)

(1) Mixing A beta_1-42(Wako pure chemical industries, Ltd.) was dissolved in a phosphate buffer (pH7.4) and shaken at 37 ℃ for 72 hours to obtain a suspension of aggregated A.beta.at 1mg/mL (hereinafter, referred to as an amyloid suspension in this example).

[0152] (2) under Sulfotuzin anesthesia, 2.5. mu.L (equivalent to 25. mu.g) of the above amyloid suspension was injected into amygdala on the side of male Wistar rats (7 weeks old). As a control, 2.5. mu.L of phosphate buffered saline (pH7.4) was injected into the amygdala on the other side of the rat. The rats were examined 1 day after injection of the amyloid suspension and phosphate buffered saline solution (ph 7.4).

[0153](3) Will 2¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine was dissolved in a physiological saline solution containing 10mg/mL of ascorbic acid to obtain a sample solution (in which the radioactive concentration was 32 MBq/mL). The sample solution was injected into the rat through the tail vein under the condition of thiopentan sodium anesthesia (dose: 0.5mL, radioactivity given: equivalent to 16 MBq).

[0154] (4) the brain was removed 60 minutes after the injection, and a brain section having a thickness of 10 μm was prepared using a microtome (model: CM3050S, manufactured by LEICA Co., Ltd.). The brain slice was exposed on an imaging plate for 20 hours, and then image analysis was performed by using a bio-image analyzer (model: BAS-2500; manufactured by Fuji photo film Co., Ltd.).

[0155] (5) after completion of image analysis with a bio-image analyzer, pathological staining was carried out with thioflavin T and imaging was carried out by using a fluorescence microscope (manufactured by Nikon Co., Ltd.; model: TE 2000-U; excitation wavelength: 400-. This confirmed that amyloid was precipitated on the section (fig. 8 b).

[0156] (results)

Fig. 8 shows an autoradiogram and thioflavine T-stained image of brain sections from rats injected intracerebrally with amyloid. As shown in the figure, significant radioactive accumulation was observed in the amygdala on the side injected with the amyloid suspension. From the results of thioflavin T staining of the radioactive accumulation site, the presence of amyloid at the accumulation site was confirmed. On the other hand, no significant accumulation of radioactivity was observed in the amygdala on the side of the saline solution injection compared to other sites. These results suggest [ alpha ], [ alpha ] a¹²³I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine has the property of accumulating amyloid in the brain and the ability to image amyloid in the brain.

[0157]Example 18: [ ¹²³ I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a] Imaging confirmation of amyloid in brain with pyridine

[0158] The following experiment was conducted to examine whether amyloid in the brain can be imaged by the compound of the present invention.

[0159] (method)

Except for using the term¹²³I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]The same operation as in example 17 was carried out except that pyridine was dissolved in a physiological saline solution containing 10mg/mL ascorbic acid as a sample solution (radioactive concentration: 20MBq/mL), and [125I ] was observed]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]The ability of pyridine to image amyloid in the brain (dose: 0.5mL, radioactivity given: equivalent to 10 MBq).

[0160] (results)

Fig. 9 shows an autoradiogram and thioflavine T-stained image of brain sections from rats injected intracerebrally with amyloid. As shown in the figure, significant radioactive accumulation was observed in the amygdala on the side injected with the amyloid suspension. From the results of thioflavin T staining at the radioactive accumulation site, the presence of amyloid at the accumulation site was confirmed. On the other hand, no significant accumulation of radioactivity was observed in the amygdala on the side of the saline solution injection compared to other sites. These results suggest [ alpha ], [ alpha ] a¹²⁵I]-2- (4' -iodophenyl) -6-methoxyimidazo [1, 2-a]Pyridine has the property of accumulating amyloid in the brain and the ability to image amyloid in the brain.

[0161]Example 19: [ ¹²³ I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine (II) Amyloid in brain proteinVisualization confirmation of white

[0162] The following experiment was conducted to examine whether amyloid in the brain can be imaged by the compound of the present invention.

[0163] (method)

Except for using the term¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]The same operation as in example 17 was carried out except that pyridine was dissolved in a physiological saline solution containing 10mg/mL ascorbic acid solution to prepare a sample solution (radioactive concentration: 24MBq/mL), and observation was carried out¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]The ability of pyridine to image amyloid in the brain (dose: 0.5mL, radioactivity given: equivalent to 12 MBq).

[0164] (results)

Fig. 10 shows an autoradiogram and thioflavine T-stained image of brain sections from rats injected intracerebrally with amyloid. As shown in the figure, significant radioactive accumulation was observed in the amygdala on the side injected with the amyloid suspension. From the results of thioflavin T staining at the radioactive accumulation site, the presence of amyloid at the accumulation site was confirmed. On the other hand, no significant accumulation of radioactivity was observed in the amygdala on the side of the saline solution injection compared to other sites. These results suggest [ alpha ], [ alpha ] a¹²⁵I]-2- (4' -fluorophenyl) -6-iodoimidazo [1, 2-a]Pyridine has the property of accumulating amyloid in the brain and the ability to image amyloid in the brain.

[0165]Example 20: determination of metastatic and clearance into the brain

[0166]Use of¹²³I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine, and the change with time of radioactive accumulation in the brain of male Wistar rats (7 weeks old) was measured.

[0167] (method)

Except that the [ 2] prepared in example 7 is used¹²⁵I]-6-iodo-2- (4'-methoxyphenyl) imidazo [1, 2-a]Pyridine was dissolved in a physiological saline solution containing 10mg/mL ascorbic acid (radioactive concentration: 20-30MBq/mL) to prepare a sample solution, and the change with time of radioactive accumulation in the brain of the rat was measured in the same manner as in examples 15 and 16.

[0168] (results)

The results are shown in Table 3. As shown in Table 3, at a time point of 2 minutes after the injection, [ 2]¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]The pyridine shows the harmony with¹²⁵I]IMPY (see comparative example 2) also accumulated and then showed a tendency to rapidly clear within 60 minutes. These results suggest [ alpha ], [ alpha ] a¹²⁵I]-6-iodo-2- (4' -methoxyphenyl) imidazo [1, 2-a]Pyridine and [ alpha ], [ alpha¹²⁵I]IMPY, as well, has excellent transferability to the brain and rapid clearance from the brain.

[0169] Table 3: after intravenous injection, the compounds of the invention accumulate radioactivity in the brain (rats)

Industrial applicability

[0170] The compounds of the invention may be used in the field of diagnostic agents.

Claims (22)

1. A compound represented by the following formula (1) or a salt thereof:

wherein A is¹、A²、A³And A⁴Each independently represents carbon or nitrogen,

R¹is selected from hydrogen, hydroxyl, carboxyl, sulfate, amino, nitro, cyano, non-radioactive halogen substituent, alkyl substituent with 1-4 carbon atomsA group having an alkoxy substituent of 1 to 4 carbon atoms, and

R²is a substituent of a radioactive halogen, and is,

with the proviso that A¹、A²、A³And A⁴At least one of (A) represents carbon, R¹And A¹、A²、A³Or A⁴The carbons shown are attached.

2. The compound or salt according to claim 1, wherein A is¹、A²、A³And A⁴At least three of which represent carbon.

3. The compound or salt according to claim 2, wherein A is¹、A²、A³And A⁴All represent carbon.

4. A compound or salt thereof according to any one of claims 1-3, wherein R²Is selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹a radioactive halogen substituent of I.

5. A compound represented by the following formula (2) or a salt thereof:

wherein A is⁵、A⁶、A⁷And A⁸Each independently represents carbon or nitrogen,

R³is a radioactive halogen substituent, and

R⁴is a group selected from the group consisting of hydrogen, carboxyl, sulfate, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and methoxy substituents,

with the proviso that A⁵、A⁶、A⁷And A⁸At least one of (A) represents carbon, R³And A⁵、A⁶、A⁷Or A⁸The carbons shown are attached.

6. A compound or a salt thereof according to claim 5, wherein A⁵、A⁶、A⁷And A⁸At least three of which represent carbon.

7. A compound or a salt thereof according to claim 6, wherein A⁵、A⁶、A⁷And A⁸All represent carbon.

8. A compound or salt thereof according to any one of claims 5-7, wherein R³Is selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹a radioactive halogen substituent of I.

9. A compound represented by the following formula (3) or a salt thereof:

wherein A is¹、A²、A³And A⁴Each independently represents carbon or nitrogen,

R⁵is a group selected from the group consisting of hydrogen, hydroxy, carboxy, sulfate, amino, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and alkoxy substituents having 1 to 4 carbon atoms, and

R⁶is a group selected from the group consisting of non-radioactive halogen substituents, nitro groups, trialkylstannyl substituents having 1 to 4 carbon atoms in the alkyl chain, triphenylstannyl groups and trialkylammonium groups having 1 to 4 carbon atoms in the alkyl chain,

with the proviso that A¹、A²、A³And A⁴At least one of (A) represents carbon, R⁵And A¹、A²、A³Or A⁴The carbons shown are attached.

10. The compound or salt according to claim 9, wherein a is¹、A²、A³And A⁴At least three of which represent carbon.

11. A compound or salt thereof according to claim 10, wherein a¹、A²、A³And A⁴All represent carbon.

12. A compound represented by the following formula (4) or a salt thereof:

wherein A is⁵、A⁶、A⁷And A⁸Each independently represents carbon or nitrogen,

R⁷is a group selected from the group consisting of a non-radioactive halogen substituent, a nitro group, a trialkylstannyl substituent having 1 to 4 carbon atoms in the alkyl chain, a triphenylstannyl group and a trialkylammonium group having 1 to 4 carbon atoms in the alkyl chain, and

R⁸is a group selected from the group consisting of hydrogen, carboxyl, sulfate, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and methoxy substituents,

with the proviso that A⁵、A⁶、A⁷And A⁸At least one of (A) represents carbon, R⁷And A⁵、A⁶、A⁷Or A⁸The carbons shown are attached.

13. A compound or salt thereof according to claim 12, wherein a⁵、A⁶、A⁷And A⁸At least three of which represent carbon.

14. A compound or salt thereof according to claim 13, wherein a⁵、A⁶、A⁷And A⁸All represent carbon.

15. A diagnostic agent for Alzheimer's disease, comprising a compound represented by the following formula (1) or a salt thereof:

wherein A is¹、A²、A³And A⁴Each independently represents carbon or nitrogen,

R¹is a group selected from the group consisting of hydrogen, hydroxy, carboxy, sulfate, amino, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and alkoxy substituents having 1 to 4 carbon atoms, and

R²is a substituent of a radioactive halogen, and is,

with the proviso that A¹、A²、A³And A⁴At least one of (A) represents carbon, R¹And A¹、A²、A³Or A⁴The carbons shown are attached.

16. The diagnostic agent for alzheimer's disease according to claim 15, wherein a¹、A²、A³And A⁴At least three of which represent carbon.

17. The diagnostic agent for alzheimer's disease according to claim 16, wherein a¹、A²、A³And A⁴All represent carbon.

18. The diagnostic agent for alzheimer's disease according to any one of claims 15-17, wherein R²Is selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹a radioactive halogen substituent of I.

19. A diagnostic agent for Alzheimer's disease, comprising a compound represented by the following formula (2) or a salt thereof:

wherein A is⁵、A⁶、A⁷And A⁸Each independently represents carbon or nitrogen,

R³is a radioactive halogen substituent, and

R⁴is a group selected from the group consisting of hydrogen, carboxyl, sulfate, nitro, cyano, non-radioactive halogen substituents, alkyl substituents having 1 to 4 carbon atoms and alkoxy substituents having 1 to 4 carbon atoms,

with the proviso that A⁵、A⁶、A⁷And A⁸At least one of (A) represents carbon, R³And A⁵、A⁶、A⁷Or A⁸The carbons shown are attached.

20. The diagnostic agent for alzheimer's disease according to claim 19, wherein a⁵、A⁶、A⁷And A⁸At least three of which represent carbon.

21. The diagnostic agent for alzheimer's disease according to claim 20, wherein a⁵、A⁶、A⁷And A⁸All represent carbon.

22. The diagnostic agent for alzheimer's disease according to any one of claims 19-21, wherein R³Is selected from¹⁸F、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹a radioactive halogen substituent of I.