JP2009120590A - Novel amyloid affinity compound - Google Patents

Abstract

Disclosed are a compound effective as an imaging diagnostic probe targeting amyloid and a reagent for detecting amyloid deposited in a living tissue containing the compound.
A compound represented by the following formula and a reagent for detecting amyloid deposited in a living tissue containing the compound.

In the formula, R ¹ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group, and R ² is ⁷⁶ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I. Or a radioactive halogen selected from the group consisting of ¹³¹ I, m is an integer of 1 to 4; This compound has an affinity for amyloid deposited in a living tissue, and also has a good clearance from normal tissue. According to the present invention, it has become possible to obtain a novel amyloid affinity compound and a detection reagent for amyloid deposited in living tissue, which have a good ability to visualize amyloid in vivo.
[Selection figure] None

Description

The present invention relates to a compound used for diagnosis of head degenerative diseases. More specifically, the present invention relates to a compound useful for detecting amyloid at a lesion site in the diagnosis of a disease in which amyloid accumulates such as Alzheimer's disease.

Diseases that develop when fibrous proteins called amyloid are deposited 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 structure is deposited in various organs or regions throughout the body, causing functional abnormalities in the organs and tissues.

Alzheimer's disease (hereinafter referred to as AD), which is a typical disease of amyloidosis, is known as a disease causing dementia. Since this disease is a disease in which amyloid gradually deposits in the brain and causes death, it can be said that it is a disease with high social interest compared to other amyloidosis. In recent years, in advanced countries, the number of AD patients has rapidly increased with the aging of society, which has become a social problem.

According to histopathology, AD is associated with the appearance of senile plaques, neurofibrillary changes (neurofibrillary).
tangles) and three brain pathological findings of extensive neuronal loss. Senile plaques are structures containing amyloid as a major component, and are considered to be pathological findings in the brain that appear in the first stage of AD onset, that is, more than 10 years before clinical symptoms appear.

Diagnosis of AD is performed by performing various cognitive function evaluations (for example, Hasegawa scale, ADAS-JCog, MMSE, etc.) after supplementarily combining image diagnosis such as CT and MRI. However, such a method based on the evaluation of cognitive function has a drawback that the diagnostic sensitivity is low in the early stage of onset, and further, the diagnosis result is easily affected by the cognitive function inherent in each individual. Moreover, since a biopsy of a diseased part is indispensable for a definitive diagnosis, it is virtually impossible to make a definitive diagnosis of AD during the lifetime of a patient (Non-patent Document 1).

On the other hand, amyloid composing senile plaques has been reported to be an aggregate of amyloid β protein (hereinafter referred to as Aβ), and the aggregate of Aβ can exhibit neuronal cytotoxicity by taking a β sheet structure. It has been reported by many studies. Based on these findings, the so-called “amyloid cascade hypothesis” has been proposed in which the deposition of Aβ in the brain is triggered, and the formation of neurofibrillary tangles and neuronal loss occur as downstream phenomena (non-patented). Reference 2).

Based on such facts, attempts have recently been made to detect AD in vivo using a compound having high affinity for amyloid as a marker.
Many of these intracerebral amyloid imaging probes have a high affinity for amyloid and a hydrophobic low-molecular compound having a high ability to migrate to the brain, such as various radionuclides such as ¹¹ C, ¹⁸ F and ¹²³ I. The compound labeled with Specific examples include 6-iodo-2- [4 ′-(N, N-dimethylamino) phenyl] benzothiazole (hereinafter referred to as TZDM) and 6-hydroxy-2- [4 ′-(N-methylamino) phenyl. ] Various thioflavin derivatives (Patent Literature 1, Non-Patent Literature 3) including benzothiazole (hereinafter referred to as 6-OH-BTA-1), (E) -4-methylamino-4′-hydroxystilbene (hereinafter referred to as “Ethylose”) , 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), 6-iodo-2- [4 ′-(N, N-dimethylamino) phenyl] benzoxazole (hereinafter referred to as IBOX), 6- [2- (fluoro) ethoxy] -2- [2- ( -Dimethylaminothiazol-5-yl) ethenyl] benzoxazole and other benzoxazole derivatives (Non-patent document 6, Non-patent document 7), 2- (1- {6-[(2-fluoroethyl) (methyl) Amino] -2-naphthyl} ethylidene) malononitrile (hereinafter referred to as FDDNP) and other DDNP derivatives (Patent Document 4, Non-Patent Document 8) and 6-iodo-2- [4 ′-(N, N-dimethylamino) ) Compounds in which imidazopyridine derivatives (Patent Document 3, Non-Patent Document 9) such as phenyl] imidazo [1,2-a] pyridine (hereinafter referred to as IMPY) are labeled with ¹¹ C or radioactive halogen have been reported. Yes. Furthermore, human imaging studies have been conducted on some of these diagnostic imaging probes, and it has been reported that AD patients show radioactive accumulation in the brain that is clearly different from normal cases (Non-patent Document 10). Non-patent document 11, Non-patent document 12, Non-patent document 13).
In addition, International Publication No. 2007/002540 pamphlet discloses a series of compounds in which a side chain containing ethylene glycol or polyethylene glycol is bonded to an amyloid affinity group to increase fat solubility (Patent Document 5). .
Furthermore, in the pamphlet of International Publication No. 2007/063946, a series of compounds in which a 5-membered aromatic heterocyclic group is bonded for the purpose of suppressing metabolism in the brain are disclosed (Patent Document 6).

JP-T-2004-506723 JP 2005-504055 Gazette JP 2005-512945 A Japanese translation of PCT publication No. 2002-523383 International Publication No. 2007/002540 Pamphlet International Publication No. 2007/063946 Pamphlet J. A. Hardy & G. A. Higgins, “Alzheimer ’s Disease: The Amyloid Cascade Hypohesis.”, Science, 1992, 256, p.184-185 G. McKhann et al., “Clinical diagnosis of Alzheimer ’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer ’s Disease.”, Neurology, 1984, 34, p.939-944 Z.-P. Zhuang et al., “Radioiodinated Styrylbenzenes and Thioflavins asProbes for Amyloid Aggregates.”, J. Med. Chem., 2001,44, p.1905-1914 MasahiroOno et al., “11C-labeled stilbene derivatives as Aβ-aggregate-specific PET imagingagents for Alzheimer ’s disease.”, Nuclear Medicine and Biology, 2003, 30, p.565-571 H. F. Kung et al., “Novel Stilbenes as Probes for amyloid plaques.”, J. American Chemical Society, 2001,123, p.12740-12741 Zhi-Ping Zhuanget al., “IBOX (2- (4’-dimethylaminophenyl) -6- iodobensoxazole): a ligand for imaging amyloidplaques in the brain.”, Nuclear Medicine and Biology, 2001, 28, p.887-894 Furumoto Y et al., “[11C] BF-227: A New 11C-Labeled 2-Ethenylbenzoxazole Derivative for Amyloid-β Plaques Imaging.”, European Journal of Nuclear Medicine and Molecular Imaging, 2005, 32, Sup.1, P759 EricD. Agdeppa et al., “2-Dialkylamino-6-Acylmalononitrile Substituted Naphthalenes (DDNP Analogs): Novel Diagnostic and Therapeutic Tools in Alzheimer ’s Disease,” Molecular Imaging and Biology, 2003, 5, p.404-417 Zhi-Ping Zhuanget al., “Structure-Activity Relationship of Imidazo [1,2-a] pyridinesas Ligands for Detectingβ-AmyloidPlaques in the Brain.”, J. Med. Chem, 2003, 46, p.237-243 W. E. Klunk et al., “Imaging brain amyloidin Alzheumer ’s disease with Pittsburgh Compound-B.”, Ann. Neurol., 2004, 55, p.306-319 Nicolaas P. L. G. Verhoeffet al., “In-Vivo Imaging of Alzheimer Disease β-Amyloid With [11C] SB-13 PET.”, American Journal of Geriatric Psychiatry, 2004, 12, p.584-595 HiroyukiArai et al., "[11C] -BF-227 AND PET to Visualize Amyloidin Alzheimer's Disease Patients", Alzheimer's & Dementia: The Journalof the Alzheimer's Association, 2006, 2, Sup.1, S312 ChristopherM. Clark et al., "Imaging Amyloid with I123 IMPY SPECT", Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 2006, 2, Sup.1, S342

As described above, various compounds have been disclosed as diagnostic imaging probes for amyloid and are being studied for clinical application.
TZDM, compounds labeled with iodine IBOX and m-I-SB in ^[125 I] are results of experiments with normal mice, the time point of two minutes after the injection, all transferred into brain . However, these compounds do not have sufficient clearance from normal tissues, and show a tendency to gradually accumulate in the brain with the passage of time after administration (Japanese Patent Publication No. 2005-512945, Zhi-Ping Zhuang et al. al., Nuclear Medicine
and Biology, 2001, 28, p. 887-894, HF Kung et al., J. Am. Chem. Soc., 2001,
123, p.12740-12741). If the clearance from the normal tissue is not sufficient, there is a problem that sufficient contrast cannot be obtained at the amyloid accumulation site. The compound labeled with [ ¹¹ C] of SB-13 has been shown to have clearance from normal tissues by experiments using rats, but the clearance rate is not sufficiently high (Masahiro Ono) et al., Nuclear Medicine and Biology, 2003, 30,
p.565-571).

On the other hand, compounds having an imidazopyridine skeleton such as IMPY have the property of moving into the brain after administration and accumulating in amyloid, and, unlike the above-mentioned compounds, have excellent properties such as quick clearance from normal tissues. It has been clarified as a result of an experiment using a [ ¹²⁵ I] -labeled compound. However, IMPY is a compound that shows a positive result in a reverse mutation test, and in order to use this compound as an imaging diagnostic probe, it is necessary to pay sufficient attention to its dosage and dosage form. (International Publication No. 03/106439 Pamphlet)
FDDNP has also been reported to be positive in the reverse mutation test. (International Publication No. 03/106439 Pamphlet)

Although various compounds have been disclosed as diagnostic imaging probes targeting amyloid, the present invention has been made in view of the above situation that no compound has been confirmed to have the ability to withstand clinical use. Therefore, an object of the present invention is to obtain a compound effective as a diagnostic imaging probe targeting amyloid and a detection reagent for amyloid deposited in a living tissue containing the compound.

As a result of intensive studies, the inventors of the present invention are effective as diagnostic imaging probes targeting amyloid by a compound having an imidazopyridine-phenyl skeleton and having a phenyl group carbon bonded with a radiohalogen via an alkenyloxy group. And the present invention has been completed.

According to one aspect of the present invention, the following formula (1):

Or a salt thereof, and a reagent for detecting amyloid deposited in a living tissue, comprising the compound.

Here, the living tissue can be various tissues known to deposit amyloid in amyloidosis. Representative examples of such biological tissues include the brain, heart, lungs, pancreas, bones, joints, and the like, and the most representative biological tissues include the brain. Typical amyloidosis in the case of the brain is Alzheimer's disease and Lewy body dementia.

In Formula (1), R ¹ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group, and R ² is ⁷⁶ Br, ¹²³ I, ¹²⁴ I. , ¹²⁵ I or ¹³¹ I selected from the group consisting of radioactive halogen, m is an integer of 1-4.

According to another aspect of the present invention, the following formula (2):

Or a salt thereof is provided.

In the formula (2), R ³ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group, R ⁴ is a non-radioactive halogen substituent, an alkyl chain The trialkylstannyl substituent or the triphenylstannyl substituent whose carbon number is 1-4, m is an integer of 1-4.

According to the present invention, it has become possible to obtain a novel amyloid affinity compound and a detection reagent for amyloid deposited in living tissue, which have a good ability to visualize amyloid in vivo.

(Synthesis of labeled precursor compound)
Hereinafter, the case of synthesizing (E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine will be described as an example. A method for synthesizing the compound according to the invention will be described.

In the synthesis of (E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine, first, 4′-hydroxy Reaction of acetophenone and cupric bromide yields 2-bromo-4′-hydroxyacetophenone (FIG. 1, step 4). This reaction can be performed using conventional methods, such as the literature (King L. Carroll & Ostrum G. Kenneth,
Journal of Organic Chemistry, 1964, 29 (12), p.3459-3461).

Next, 2-bromo-4′-hydroxyacetophenone synthesized above is reacted with 2-amino-5-methoxypyridine synthesized by a known method (for example, the method described in FIG. 1, Steps 1 to 3). 2- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine is synthesized (FIG. 1, step 5). This step can be performed, for example, in the following manner.

First, 2-bromo-4′-hydroxyacetophenone and 2-amino-5-methoxypyridine are dissolved in an inert solvent such as acetonitrile and reacted at reflux temperature for 2 to 6 hours. Hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine hydrobromide is formed, resulting in a white precipitate. As a solvent at this time, in addition to acetonitrile, a solvent usually used in the same reaction such as methanol or acetone can be used. The reaction temperature may be any temperature at which it can be refluxed. For example, when acetonitrile is used as a solvent, the reaction temperature can be 105 ° C. It should be noted that the amount of the solvent used is sufficient if it is sufficient for the reaction. However, if it is too much, it is impossible to obtain a precipitate of the reaction product, so care must be taken. For example, when the reaction is performed using 2-bromo-4'-hydroxyacetophenone corresponding to 10 mmol, about 40 to 80 mL of solvent may be used.

Next, the reaction solution is filtered and the precipitate is filtered off, and then the white precipitate is suspended in a methanol / water mixture (1: 1), and a saturated aqueous sodium hydrogen carbonate solution is excessively added to the precipitate. When added in such a manner, 2- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine is liberated and precipitation occurs. By filtering this newly generated precipitate, 2- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine, which is the target product of this step, can be obtained (FIG. 1). Step 5). The amount of the methanol / water mixture is not particularly limited as long as it is a sufficient amount for the reaction. However, if the amount is too large, the precipitation of the product is hindered. For example, if 2-bromo-4'-hydroxyacetophenone equivalent to 10 mmol is used, a methanol / water mixture of about 40 to 100 mL may be used. Further, the amount of sodium hydrogen carbonate is not particularly limited as long as it is excessively large with respect to the precipitate as a reaction substrate. For example, when the reaction is performed under the above conditions, about 50 mL of saturated hydrogen carbonate. An aqueous sodium solution may be added to the reaction solution.

Next, the synthesized 2- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine was sufficiently dried and then dissolved in N, N-dimethylformamide, and potassium carbonate and propargyl bromide were added. Added. After stirring this mixture at room temperature for about one day, the reaction solution was poured into water and extracted with chloroform, and the chloroform layer was concentrated and chromatogram purification was carried out to give 6-methoxy-2- [4 ′-(2 “-Propynyloxy) phenyl] imidazo [1,2-a] pyridine is obtained (FIG. 1, step 6). The amount of potassium carbonate may be any amount that can neutralize the hydrobromic acid generated during the reaction. The amount of propargyl bromide, which is typically an auxiliary material, may be used in an amount equal to or larger than that of the reaction substrate, and is typically an excess amount relative to the reaction substrate. 4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine may be used in a molar ratio of about 1.5 times.

The obtained 6-methoxy-2- [4 ′-(2 ″ -propynyloxy) phenyl] imidazo [1,2-a] pyridine was dissolved in toluene, cooled to about 5 ° C., tributyltin hydroxide and the amount of catalyst. Dichlorobistriphenylphosphine palladium was added to the reaction solution, and the reaction solution was stirred and reacted while cooling to 5 ° C., and then the temperature of the reaction solution was increased to room temperature. The target product (E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine can be obtained ( Fig. 1, Step 7) At this time, the amount of tributyltin hydroxide may be an amount that satisfies the condition of being excessive with respect to the reaction substrate, and specifically, 6-methoxy-2- [ 4 - (2 "- propynyloxy) phenyl] imidazo [1,2-a] may be in 1.5 times in the molar ratio relative to pyridine.

A compound in which the functional group binding site in the imidazopyridine ring is a carbon other than the 6-position carbon corresponds to the target compound instead of 2-amino-5-methoxypyridine used in Step 5 of FIG. It can be obtained by using various compounds. For example, when synthesizing a compound in which a methoxy substituent is bonded to the carbon at the 8-position of the imidazopyridine ring, in step 5 of FIG. 1, instead of 2-amino-5-methoxypyridine, 2-amino-3-methoxy is synthesized. Pyridine may be used.

(Method for synthesizing radioactive halogen-labeled compounds)
Next, taking a radioiodine labeled compound as an example, a method for producing a radiohalogen-labeled compound according to another aspect of the present invention will be described.

The radioiodine labeled compound was synthesized by dissolving the labeled precursor compound synthesized as described above in an inert organic solvent, and adding a [ ^123I ] sodium iodide solution obtained by a known method to this. The reaction can be performed by adding an acid and an oxidizing agent. As the inert organic solvent for dissolving the labeling precursor compound, various solvents that are not reactive with the labeling precursor and [ ¹²³ I] sodium iodide can be used, and preferably methanol is used. Can do.

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

(Method for preparing and using diagnostic agent according to the present invention)
The diagnostic agent according to the present invention is blended with water or physiological saline adjusted to an appropriate pH or Ringer's solution, if necessary, in the same manner as other generally known radioactive diagnostic agents. It can be prepared as a liquid. In this case, the concentration of the present compound needs to be not more than the concentration at which the stability of the blended present compound is obtained. The dose of the compound is not particularly limited as long as it is a concentration sufficient to image the distribution of the administered drug. For example, in the case of iodine--123 ⁽¹²³ I) labeled compounds, per adult 50~600MBq about weight 60 kg, it can be used administered intravenously or locally. Distribution of administered agents can be imaged by known methods, in the case of example SPECT apparatus in the case of iodine -123 ⁽¹²³ I) labeled compounds, oxalic containing ^{-76 (76} Br) labeled compounds PET It can be imaged using the device.

EXAMPLES Hereinafter, although an Example, a comparative example, and a reference example are described and this invention is demonstrated further in detail, this invention is not limited to these content.

Example 1 Synthesis of (E) -2- [4 '-(3 "-Tributylstannyl-2" -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine

100.0 g (corresponding to 0.575 mol) of 2-bromo-3-hydroxypyridine was dissolved in 310 mL of dimethyl sulfoxide, and 575 mL (corresponding to 0.575 mol) of a 1 mol / L sodium methoxide-methanol solution was added thereto. Was heated to 90 ° C. and methanol was distilled off. After cooling the reaction solution to 10 ° C. or lower, 93.9 g (corresponding to 0.662 mol) of methyl iodide was added, and the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted twice with chloroform. The combined chloroform layers were washed with 1 mol / L sodium hydroxide, then washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-bromo-3-methoxypyridine 65. 0.4 g (corresponding to 0.348 mol) was obtained (FIG. 1, step 1).

Concentrated sulfuric acid (262 mL) was cooled to −2 ° C., 90% nitric acid (262 mL) was carefully added thereto, and then 2-bromo-3-methoxypyridine (65.3 g, equivalent to 0.347 mmol) was carefully added. The reaction mixture was stirred in an ice bath for 10 minutes, then stirred at room temperature for 30 minutes, further heated to 55 ° C. and stirred for 1.5 hours. The reaction solution was cooled to room temperature and then poured into ice in small portions to form a precipitate. The precipitate was collected by filtration and washed with water. This was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 55.7 g (corresponding to 0.239 mol) of 2-bromo-3-methoxy-6-nitropyridine (FIG. 1, step 2).

25.6 g (corresponding to 0.239 mol) of 2-bromo-3-methoxy-6-nitropyridine was dissolved in 1700 mL of ethanol, 37.3 g of 10% palladium carbon (50% wet) was added under an argon stream, and then 1 water of hydrazine was added. 283 mL of Japanese product was added dropwise. The reaction mixture was heated to reflux for 70 minutes, the reaction solution was cooled to room temperature, palladium carbon was filtered, the filtrate was washed with ethanol, and the washing solution was combined with the filtrate. The solution was concentrated under reduced pressure, 1300 mL of water and 130 mL of concentrated aqueous ammonia were added, and the mixture was extracted 8 times with chloroform. The combined chloroform layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product was distilled under reduced pressure to obtain 26.2 g (corresponding to 0.211 mol) of 2-amino-5-methoxypyridine ( FIG. 1, step 3).

50 mL of ethyl acetate was added to and suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and 8.18 g (corresponding to 60.0 mmol) of 4'-hydroxyacetophenone was dissolved in a mixed solution of 50 mL of ethyl acetate and 50 mL of chloroform. The solution was added and heated to reflux. After 5 hours, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and decolorized by adding activated carbon, and then the solution was filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1), recrystallized from ethyl acetate-petroleum ether, and 2-bromo-4′-hydroxyacetophenone. 7.25 g (corresponding to 33.7 mmol) was obtained (FIG. 1, step 4).

2-Bromo-4′-hydroxyacetophenone 1.08 g (corresponding to 5.0 mmol) and 2-amino-5-methoxypyridine 0.63 g (corresponding to 5.1 mmol) were dissolved in 30 mL of acetonitrile, and 4 in an oil bath at 105 ° C. Heated to reflux for hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitate was filtered off, washed with acetonitrile, and dried under reduced pressure. The obtained crude crystals were suspended in a mixed solution of 20 mL of water and 20 mL of methanol, about 10 mL of a saturated sodium bicarbonate solution was added thereto, and the mixture was shaken for 5 minutes using an ultrasonic cleaner. The precipitate was filtered off from the resulting mixture, washed well with water, and dried under reduced pressure to give 1.00 g of 4- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine (4 (Corresponding to .17 mmol) (FIG. 1, step 5).

To a solution of 2- (4′-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine 389 mg (equivalent to 1.62 mmol) in N, N-dimethylformamide 15 mL, potassium carbonate 337 mg (equivalent to 2.43 mmol) and Propargyl bromide 0.15 mL (equivalent to 2.00 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layers were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by flash silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1 → 2/3) to give 6-methoxy-2- [4 ′-(2 ″ -propynyloxy). ) Phenyl] imidazo [1,2-a] pyridine (393 mg, corresponding to 1.41 mmol) was obtained (FIG. 1, step 6).

After dissolving 100 mg (corresponding to 0.359 mmol) of 6-methoxy-2- [4 ′-(2 ″ -propynyloxy) phenyl] imidazo [1,2-a] pyridine in 2.0 mL of toluene and cooling to 5 ° C. To this, 0.15 mL (corresponding to 0.54 mmol) of tributyltin hydride and 5.0 mg (catalytic amount) of dichlorobistriphenylphosphine palladium were added, and the mixture was stirred for 20 minutes. The resulting crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give (E) -2- [4 ′-(3 ″ -tributylstannyl- 27.8-propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (87.8 mg, corresponding to 0.154 mmol) was obtained (FIG. 7).

NMR measurement results (internal standard substance) of the obtained (E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine : Tetramethylsilane) was as follows.

NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)
¹ H-NMR (solvent: deuterated chloroform, resonance frequency: 500 MHz): d 7.83 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.64 (
s, 1H), 7.50 (d, J = 9.6 Hz, 2H), 6.99-6.94 (m, 2H), 6.12-5.86 (m,
1H), 5.43-5.30 (m, 2H), 4.73-4.66 (m, 2H), 3.83 (s, 3H), 1.58-1.45 (m,
6H), 1.34-1.27 (m, 6H), 1.03-0.86 (m, 15H).

Reference Example 1 Synthesis of (E) -2- [4 ′-(3 ″ -iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (non-radioactive iodine)

76.4 mg of (E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine obtained in Example 1 (Equivalent to 0.134 mmol) was dissolved in 1.0 mL of dichloromethane, cooled to 0 ° C., 17.0 mg (equivalent to 0.134 mmol) of iodine was added, and the mixture was stirred for 5 minutes. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium thiosulfate solution were added, and extraction was performed 3 times with dichloromethane. The combined dichloromethane layer was washed with water and saturated brine, 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), and (E) -2- [4 ′-(3 ″ -iodo-2 ″ -propenyl). 4.7 mg (corresponding to 0.0116 mmol) of (oxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was obtained (FIG. 2, step 1).

NMR measurement results of the obtained (E) -2- [4 ′-(3 ″ -iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (internal standard substance: tetra Methylsilane) was as follows.

NMR apparatus used: JNM-ECP-500 (manufactured by JEOL Ltd.)
¹ H-NMR (solvent: deuterated chloroform, resonance frequency: 500 MHz): d 7.85 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.65 (
s, 1H), 7.51 (d, J = 9.6 Hz, 1H), 6.97-6.94 (m, 3H), 6.81-6.76 (m,
1H), 4.50 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H).

Example 2 Synthesis of (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine

(E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine in methanol / dimethyl sulfoxide = 9/1 mixed solution To 50 μL (concentration: 1 mg / mL), 1 μL / L hydrochloric acid 75 μL, 1 mmol / mL sodium iodide 10 μL, 254 MBq [ ¹²³ I] sodium iodide 50 μL, 10% (W / V) hydrogen peroxide 10 μL were added. The mixture was allowed to stand at 50 ° C. for 10 minutes, and then subjected to HPLC under the following conditions. E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl ] -6-methoxyimidazo [1,2-a] pyridine fraction was collected.

HPLC conditions:
Column: Phenomenex Luna C18 (trade name, manufactured by Phenomenex, size: 4.6 × 150 mm)
Mobile phase: water containing 0.1% trifluoroacetic acid / acetonitrile containing 0.1% trifluoroacetic acid = 80/20 → 0/100 (17 minutes, linear gradient)
Flow rate: 1.0 mL / min Detector: Ultraviolet-visible absorptiometer (detection wavelength: 282 nm) and radiation detector (Raytest STEFFI type)

A solution obtained by adding 10 mL of water to the fraction was passed through a reverse phase column (trade name: Sep-Pak (registered trademark) Light C18 Cartridges, manufactured by Waters, 130 mg of filler, E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was adsorbed and collected on the column. The column was washed with 1 mL of water, and then 1 mL of diethyl ether was passed therethrough to pass through (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxy. Imidazo [1,2-a] pyridine was eluted. The amount of radioactivity obtained was 120.0 MBq immediately after synthesis. Moreover, when the TLC analysis by the following conditions was conducted, the radiochemical purity was 98%.

TLC analysis conditions:
TLC plate: Silica Gel 60 F ₂₅₄ (product name, manufactured by Merck)
Developing phase: chloroform / methanol / triethylamine = 100/1/2
Detector: Bioimaging analyzer (Type: BAS-2500, manufactured by Fuji Photo Film Co., Ltd.)

Reference Example 2 Synthesis of [ ¹²³ I] -IMPY

[ ¹²³ I] -IMPY was synthesized according to the following steps for use in comparative examples in the measurement of logP _{octanol and} the like.

Literature (Zhi-Ping Zhuang
et al., J. Med. Chem, 2003, 46, p.237-243) according to the method described in 6-tributylstannyl-2- [4 ′-(N, N-dimethylamino) phenyl] imidazo [1 , 2-a] pyridine was synthesized and dissolved in methanol (concentration: 1 mg / mL). To 53 μL of the solution, 75 μL of 1 mol / L hydrochloric acid, 224 to 253 MBq of [ ¹²³ I] sodium iodide 60 to 70 μL, 1 mmol / L
Sodium iodide solution 10 μL, 10% (W / V) hydrogen peroxide 15 μL was added. The mixture was allowed to stand at 50 ° C. for 10 minutes, and then subjected to HPLC under the same conditions as in Example 2 to fractionate the [ ¹²³ I] -IMPY fraction.

A solution obtained by adding 10 mL of water to the fraction was added to a reverse phase column (trade name: Sep-Pak (registered trademark) Light).
C8 Cartridges, manufactured by Waters, packing amount of filler: 145 mg), and [ ¹²³ I] -IMPY was adsorbed and collected on the column. The column was washed with 1 mL of water, and then 1 mL of diethyl ether was passed through to elute [ ¹²³ I] -IMPY. The amount of radioactivity obtained was 41 to 57 MBq immediately after synthesis. Moreover, when the TLC analysis was conducted on the conditions similar to Example 2, the radiochemical purity was 93%.

(Example 3, Comparative Example 1) Measurement of partition coefficient using octanol extraction method

A partition coefficient (hereinafter referred to as _logPoctanol ) using an octanol extraction method, which is generally known as an indicator of the blood-brain barrier (hereinafter referred to as BBB) permeability of the compound, was measured.

(Method)
(E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine in diethyl ether (Example 3) And [ ¹²³ I] -IMPY in diethyl ether (Comparative Example 1) were each diluted with 10 mg / mL ascorbic acid-containing physiological saline to adjust the radioactivity concentration to 20 to 30 MBq / mL. 10 μL of each of these solutions was added to 2 mL of octanol, and 2 mL of 10 mmol / L phosphate buffer (pH 7.4) was further added and stirred for 30 seconds. Each mixed solution was centrifuged (2000 rotations / minute × 60 minutes) with a low-speed centrifuge (model: CTD4, manufactured by Hitachi Koki Co., Ltd.), and 1 mL each of an octanol layer and an aqueous layer was collected. The radioactivity count of each layer was measured with an autowell gamma system (type: ARC-301B, manufactured by Aloka). The logP _octanol value was calculated from the formula (1) using the obtained radioactivity count.

(result)
The results are shown in Table 1. As shown in this table, the log P of (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine. The value of _octanol was 2.6. For compounds that can permeate the BBB, the logP _octanol value is known to be between 1 and 3 (Douglas D. Dischino
et al., J. Nucl. Med., (1983), 24, p. 1030-1038). From the above results, (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is similar to IMPY. It was suggested that it has BBB permeability.

(Example 4, Comparative Example 2) Measurement of migration into brain and clearance

(E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was used to give male Wistar rats ( The time course of radioactivity accumulation in the brain at 7 weeks of age was measured.

(Method)
(E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was added to 10 mg / mL ascorbic acid-containing physiological A 0.05 mL solution (radioactive concentration 40 MBq / mL) dissolved in a saline solution was prepared and administered to male Wister rats (7 weeks old) from the tail vein under thiopental anesthesia. Blood was collected from the abdominal aorta at 2 minutes, 5 minutes, 30 minutes, and 60 minutes after administration, the brain was collected, the brain mass was measured, and the radioactivity of the brain was measured with a single channel analyzer (detector model number: SP-20). , Applied Koken Kogyo Co., Ltd.) (hereinafter referred to as A in this example). Further, the remaining whole body radioactivity was measured in the same manner (hereinafter referred to as B in this example). Using these measurement results, the amount of radioactivity accumulated per unit weight (% ID / g) in the brain at each dissection time point was calculated from the following formula (2) (Example 4).
Separately, a solution (radioactivity concentration 30 MBq / mL) in which [ ¹²³ I] -IMPY was dissolved in a physiological saline containing 10 mg / mL ascorbic acid was prepared, and the same operation as described above was performed. The amount of radioactivity accumulated per unit weight (% ID / g) was calculated (Comparative Example 2).
In each of Example 4 and Comparative Example 2, the experiment was performed using three animals at each time point.

(result)
The results are shown in Table 2. As shown in Table 2, (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is At the 2 minute point after administration, as with ¹²³ I-IMPY, high radioactivity accumulation was observed at the 2 minute point after administration, and then showed a tendency to disappear rapidly over 60 minutes. From this result, (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is ¹²³ I— Like IMPY, it was suggested to have high brain migration and rapid clearance from the brain.

Example 5 Cerebral amyloid by (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine Confirmation of drawing

In order to evaluate whether the compound according to the present invention can depict amyloid in the brain, the following experiment was conducted.

(Method)
(1) Aβ _1-42 (Wako Pure Chemical Industries) was dissolved in a phosphate buffer (pH 7.4) and shaken at 37 ° C. for 72 hours, and 1 mg / mL aggregated Aβ suspension (hereinafter, this example) To obtain an amyloid suspension).

(2) Under thiopental anesthesia, 2.5 μL (corresponding to 25 μg) of the amyloid suspension was injected into one side of the amygdala of a male Wistar rat (7 weeks old), and as a control, phosphate buffered physiology was applied to the opposite side of the amygdala. 2.5 μL of saline (pH 7.4) was injected. Rats one day after injection of amyloid suspension and phosphate buffered saline (pH 7.4) were used as specimens.

(3) (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was added to 10 mg / mL ascorbine A solution (radioactivity concentration 40 MBq / mL) dissolved in an acid-containing physiological saline was prepared and used as a sample solution. This sample solution was administered to the rats through the tail vein under thiopental anesthesia (dose: 0.5 mL, dosed radioactivity: equivalent to 12-15 MBq).

(4) The brain was extracted 60 minutes after administration, and a 10 μm thick brain section was prepared using a microtome (format: CM3050S, manufactured by LEICA). The brain section was exposed on an imaging plate for 20 hours, and then image analysis was performed using a bioimaging analyzer (form: BAS-2500, manufactured by Fuji Photo Film Co., Ltd.).

(5) After completion of the above image analysis using a bioimaging analyzer, pathological staining with thioflavin T was performed and a fluorescence microscope (Nikon Corporation, model: TE2000-U type, excitation wavelength: 400 to 440 nm, detection wavelength: 470 nm) ) Was used to confirm that amyloid was deposited on the section (FIG. 3b).

(result)
FIG. 3 shows an image of autoradiogram and thioflavin T staining in a brain section of a rat injected with amyloid brain. As shown in this figure, clear radioactivity accumulation was observed in the amygdaloid nucleus on the side injected with the amyloid suspension. Moreover, it was confirmed from the result of thioflavin T staining at the radioactive accumulation site that amyloid was present at the site. On the other hand, no significant radioactivity accumulation was confirmed in the amygdaloid nucleus on the side injected with physiological saline compared with other sites.
From this result, (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is amyloid in the brain. It was suggested that it has the ability to accumulate in the brain and has the ability to depict amyloid in the brain.

Example 6 Synthesis of (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine

(E) -2- [4 ′-(3 ″ -tributylstannyl-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine in methanol / dimethyl sulfoxide = 9/1 mixed solution To 50 μL (concentration: 1 mg / mL), 1 μL / L hydrochloric acid 75 μL, 1 mmol / mL sodium iodide 10 μL, 24 MBq of [ ¹²⁵ I] sodium iodide 10 μL, 10% (W / V) hydrogen peroxide 10 μL were added. The mixture was allowed to stand at 50 ° C. for 10 minutes, and then subjected to HPLC under the following conditions (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) The phenyl] -6-methoxyimidazo [1,2-a] pyridine fraction was fractionated.

HPLC conditions:
Column: Phenomenex Luna C18 (trade name, manufactured by Phenomenex, size: 4.6 × 150 mm)
Mobile phase: 0.1% trifluoroacetic acid / acetonitrile containing 0.1% trifluoroacetic acid = 80/20 → 0/100 (17 minutes, linear gradient)
Flow rate: 1.0 mL / min Detector: Ultraviolet-visible absorptiometer (detection wavelength: 282 nm) and radiation detector (Raytest STEFFI type)

A liquid obtained by adding 10 mL of water to the fraction was passed through a reverse phase column (trade name: Sep-Pak (registered trademark) Light C18 Cartridges, manufactured by Waters, 130 mg of filler) (E) -2. -[4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was adsorbed and collected on the column. The column was washed with 1 mL of water, and then 1 mL of ethanol was passed through to give (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo. [1,2-a] pyridine was eluted. The amount of radioactivity obtained was 16.0 MBq immediately after synthesis. Moreover, when the TLC analysis was performed on the following conditions, the radiochemical purity was 92%.

TLC analysis conditions:
TLC plate: TLC plate: Silica Gel 60 F254 (product name, manufactured by Merck)
Developing phase: chloroform / methanol / triethylamine = 100/1/2
Detector: Bioimaging analyzer (Type: BAS-2500, manufactured by Fuji Photo Film Co., Ltd.)

(Example 7) Measurement of amyloid binding

The amyloid affinity of the compound of the present invention was evaluated by the following in vitro binding test.

(1) Aβ1-42 (Wako Pure Chemical Industries) was dissolved in a phosphate buffer (pH 7.4) and shaken at 37 ° C. for 72 hours to agglomerate 1 mg / mL of Aβ (hereinafter referred to in this example) And amyloid) suspension (hereinafter referred to as amyloid suspension in this example).

(2) Regarding the above amyloid suspension, literature (Naiki, H. et al., Laboratory
Investigation.74, p.374-383 (1996))) Qualitative experiment by fluorimetry using Thioflavin T (Fluka) was performed, and the aggregated Aβ obtained in (1) is amyloid (Measurement conditions: excitation wavelength 446 nm, fluorescence wavelength 490 nm).

(3) (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2] synthesized by the method of Example 6 above -A] An ethanol solution of pyridine (radioactivity concentration 16 MBq / mL) was prepared, and this was diluted with a phosphate buffer (pH 7.4) containing 1% bovine serum albumin to obtain (E) -2- [4 A solution corresponding to 2 nmol / L as a total amount of '-(3 ″ -iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was prepared.
(4) In each well of a 96-well microplate, 50 μL of the solution prepared in (3) above (final concentration 400 pM) and the amyloid suspension are dissolved in 1% bovine serum albumin-containing phosphate buffer (pH 7.4). After adding 50 μL of the solution (the amyloid concentration is adjusted according to the amyloid concentration in the sample solution), 150 μL of the same buffer solution is added, and the final concentration of amyloid is 25, 62.5, 250, 625, 1000 nmol / A solution of L was prepared.

(5) The microplate was shaken at 22 ° C. for 3 hours at a constant speed (400 revolutions / minute), and then the mixed solution in each well was filtered through a glass fiber filter (Millipore, Multiscreen ™ -FC). (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine and free (E) bound to 2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine was isolated.

(6) The glass fiber filter obtained by filtering the mixed solution was washed with a phosphate buffer containing 1% bovine serum albumin (0.5 mL × 5 times), and then the radioactivity of the glass fiber filter was determined by the autowell gamma system (Aloka). ARC-301B).

(7) From the measurement result of (6), (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] The relationship between the amount of pyridine bound to amyloid and the amount of amyloid added was evaluated. For non-specific binding, in (4) above, (E) -2- [4 ′-(3 ″ -iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (non- (RI-labeled compound) was determined using a sample to which 5 μmol / L (final concentration) was added (Example 7).

FIG. 4 shows the relationship between the amyloid concentration in the sample solution and the radioactivity count on the glass fiber filter measured in (6) above. The radioactivity on the glass fiber filter increased in proportion to the amyloid concentration (added amount) (Example 7). Under the conditions in this experiment, amyloid and the compound bound thereto are retained in the glass fiber. Therefore, it can be said that the radioactivity count on the glass fiber reflects the amount of compound bound to amyloid. Radioactivity counts on glass fiber filters in (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine The value of (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxy was increased as the amyloid concentration increased. It was suggested that imidazo [1,2-a] pyridine is a compound having a property of binding to amyloid.
From the above results, (E) -2- [4 ′-(3 ″-[ ¹²⁵ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is amyloid-binding. It was suggested to have

The compounds and detection reagents according to the present invention can be used in the field of diagnostic medicine.

Synthesis scheme of (E) -2- [4 '-(3 "-tributylstannyl-2" -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (E) -2- [4 '-(3 "-Iodo-2" -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (non-radioactive iodo) synthetic scheme (A) In a brain section after administration of (E) -2- [4 ′-(3 ″-[ ¹²³ I] iodo-2 ″ -propenyloxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine. Autoradiogram and (b) Fluorescent microscopic image of thioflavin T-stained sample (enlarged display of amyloid suspension administration site). Relationship between amyloid concentration and radioactivity in sample solution

Claims (3)

Following formula (1):
(In the formula, R ¹ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group;
R ² is a radioactive halogen selected from the group consisting of ⁷⁶ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I;
m is an integer of 1 to 4) or a salt thereof. Following formula (2):
(Wherein R ³ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group;
R ⁴ is a group selected from the group consisting of a non-radioactive halogen substituent, a trialkylstannyl substituent having 1 to 4 carbon atoms in the alkyl chain, and a triphenylstannyl substituent;
m is an integer of 1 to 4) or a salt thereof. Following formula (1):
(In the formula, R ¹ is a group selected from the group consisting of an alkyl substituent having 1 to 4 carbon atoms, an alkoxy substituent having 1 to 4 carbon atoms, and a hydroxyl group;
R ² is a radioactive halogen selected from the group consisting of ⁷⁶ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I;
m is an integer of 1 to 4). A reagent for detecting amyloid deposited in a living tissue comprising a compound represented by the formula: