TW202015743A - Non-invasive diagnostic imaging agent for heart disease - Google Patents

Abstract

The present invention provides compounds that accumulate at a high level in cardiac lesions and are suitable as a nuclear medicine tracer in PET imaging, enables in vivo detection of cardiac lesions by using said compounds, and provides a non-invasive diagnostic imaging agent for heart disease containing as an active ingredient a radiolabeled compound represented by formula (1) or a salt thereof. [In the formula, X1 represents a hydrogen atom or a halogen atom, X2 represents a fluorine atom or a nitrile group, and X3 represents a radioactive fluorine atom.].

Description

Non-invasive imaging diagnostics for heart disease

The present invention relates to a non-invasive imaging diagnostic agent for heart disease. 【technical background】

Chronic heart failure, although left ventricular remodeling such as ventricular hypertrophy or fibrosis of the heart is ongoing, there are also reports of the renin-angiotensin-aldosterone system (renin- The hyperfunction of the angiotensin-aldosterone system (RAAS) is associated with this process; the renin-angiotensin-aldosterone system is a regulatory mechanism for the circulatory system that regulates blood pressure in the body, but in recent years, there have also been reports It is pointed out that in addition to the renin-angiotensin-aldosterone system of the systemic circulatory system, there are data showing the presence of a localized renin-angiotensin-aldosterone system or aldosterone synthesis system in the heart.

For example, Non-Patent Document 1 describes that blood drawn by a cardiac catheterization test shows that aldosterone is synthesized in a human heart failure. secretion.

Also, in Non-Patent Document 2, the phenomenon of increased gene expression of CYP11B2 as an aldosterone synthase has been clearly examined by autopsy on the heart, and therefore, it is shown that this increase in gene expression of CYP11B2 is related For myocardial fibrosis or cardiac dysfunction.

In addition, various compounds that selectively inhibit CYP11B2 were developed, and by selectively inhibiting CYP11B2, attempts were made to treat cardiovascular diseases "Patent Documents 1 to 3, Non-Patent Documents 3 to 5".

Not only target cardiovascular diseases, but also describe adrenal lesions and primary aldosteronism (primary aldosteronism) imaging diagnosis is possible, as a goal, also developed a variety of compounds showing high selectivity for CYP11B2 "Patent Literature 4~11, Non-Patent Document 6".

A non-invasive method to detect the expression of CYP11B2 in the heart is disclosed in the International Publication 2017/213247 booklet. About the heart image in vivo, single photon emission computed tomography (SPECT) or positron computed tomography ( positron emission tomography (PET) tracers have been reported to show the possibility of performing nuclear medical examinations for myocardial remodeling such as fibrosis in heart patients.

【Patent Literature】

[Patent Document 1] Special Table No. 2013-512271 [Patent Document 2] Special Table No. 2011-520799 [Patent Document 3] Special Table No. 2014-526539 [Patent Literature 4] Special Table No. 2013-534911 [Patent Document 5] Special Table No. 2014-129315 [Patent Literature 6] Special Table No. 2015-093831 [Patent Document 7] Special Table No. 2015-093832 [Patent Literature 8] Special Table No. 2015-093833 [Patent Document 9] Special Table No. 2015-110563 [Patent Literature 10] Special Table No. 2015-193545 [Patent Literature 11] Special Table No. 2015-199205 Brochure [Patent Literature 12] Special Table No. 2017-213247 【Non-patent literature】

[Non-Patent Document 1] Mizuno, Y. et al., Circulation, Volume. 103, Page 72-7 (2001) [Non-Patent Document 2] Satoh, M. et al., Clinical Science, Volume. 102, pages 381-386 (2002) [Non-Patent Document 3] Grombein, C. M., European Journal of Medicinal Chemistry, Volume 89, Pages 597-605 (2015) [Non-Patent Document 4] Grombein, C. M., European Journal of Medicinal Chemistry, Volume 90, Pages 788-796 (2015) [Non-Patent Document 5] Martin, R. E. et al., Journal of Medicinal Chemistry, Volume 58, Page 8054-8065 (2015) [Non-Patent Document 6] Abe, T., Journal of Clinical Endocrinol Metabolism, Volume 101, Page 1008-1015 (2016)

Detecting the expression of CYP11B2 in the heart of patients with heart disease is considered to be possible to evaluate the progress of heart disease such as heart failure. In addition, considering that the small lesions of a few millimeters (mm) from the initial stage of heart disease gradually increase the lesion site, it is generally considered that the lesion is detected earlier, the time point of treatment intervention can be earlier, and may be prognostic Contribute to improvement.

One of the methods for detecting changes in the molecular level in vivo can be listed as follows: single photon emission computed tomography (SPECT) or positron emission tomography (PET) Nuclear medicine diagnosis.

The inventors have created a model rat of heart failure, confirmed that CYP11B2 is hyperactive at the site of heart disease, and then, after a nuclear medical examination using a radiolabeled compound with aldosterone synthetase binding capacity, it has been shown to be detectable in lesions CYP11B2 "Patent Literature 12" expressed at However, the expression level of CYP11B2 is not necessarily the smallest in heart disease, and it is still unclear whether the level can be detected by nuclear medicine examination of single photon emission computed tomography (SPECT) or positive tomography (PET). In addition, in order to evaluate the progress of small lesions over time, a more quantitative mode can be applied, and a tracer with a higher binding force to the target can be used. After the radioactive labeling compound is administered, the nucleus To the extent that a medical examination can detect it, tracers accumulate at the heart disease, creating the need to wait.

Here, since the radiation dose of the radiolabeled compound administered into the living body increases its exposure in proportion to the exposure time, each nuclear medical examination requires a relatively long waiting time. The exposure time is one Increased, the amount of exposure in the body also increased; judging from the relationship between the threshold dose of organ damage caused by radiation, it is possible to limit the number of times that can be checked. Testing and evaluation of the progress of the process over time is expected to develop a tracer of positive resolution tomography (PET) with better spatial resolution and quantification, and a shorter waiting time after administration.

Radioactive fluorine element "fluoro -18 ⁽¹⁸ F)" half-life of 110 minutes, is the positron tomography (PET) is widely used nuclide in clinical use. Although Patent Document 12 shows data of single photon emission computed tomography (SPECT) and positive electron tomography (PET) tracers (tracer), compared with single photon emission computed tomography tracers, positive electron tomography, especially fluorine The accumulation of -18 ( ¹⁸ F) tracer in the heart is weak, and in the positron tomography experiment, it is impossible to depict the heart disease. This matter has been obvious through the insight of the inventor.

The present invention has been made in view of the foregoing, and provides a compound that has high accumulation in a heart disease site and is suitable as a nuclear medicine examination tracking agent for PET scan. By using this compound, it can be used in The site of heart disease is detected in vivo.

《化學式中，X₁ 係表示氫原子或鹵素原子，X₂ 係表示氟原子或腈基（nitrile group），X₃ 係表示放射性氟原子。》According to the present invention, it contains a radiolabeled compound represented by the following chemical formula (1) or a salt thereof as an active ingredient to provide a non-invasive imaging diagnostic agent for heart disease.

In the chemical formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom. 》

According to the present invention, heart disease lesions can be detected non-invasively, and in particular, by positron tomography (PET) photography, it is possible to depict the heart disease changes.

The above-mentioned objects, as well as other objects, features and advantages, can be made clearer through the appropriate embodiments described below and the following drawings accompanying them.

The present invention is a non-invasive imaging diagnostic agent for heart disease that contains the radioactive fluorine-labeling compound represented by the aforementioned chemical formula (1) or a salt thereof as an active ingredient. According to the imaging diagnostic agent of the present invention, it is possible to trace the site of ongoing fibrosis.

In the present invention, the so-called "non-invasive imaging diagnostic agent" is used for nuclear medical examination, more specifically, it is used for positron emission tomography (PET) ) Things used.

In the present invention, the so-called "heart disease" includes ischemic heart disease and non-ischemic heart disease. If possible, it is caused by heart fibrosis An example of such diseases is heart failure. In the present invention, the "ischemic heart disease" is not limited as long as it is a heart disease caused by myocardial ischemia. For example, coronary heart disease angina ), myocardial infarction (myocardial infarction), acute coronary syndrome (acute coronary syndrome), ischemic heart failure (ischemic heart failure), etc. can be listed. In addition, in the present invention, the "non-ischemic heart disease" includes myocarditis, hypertensive heart disease, and dilated cardiomyopathy. , Hypertrophic cardiomyopathy, non-ischemic heart failure, etc.

In the present invention, from the viewpoint of improving the photographic nature of heart disease, in the chemical formula (1), when X ₁ is a hydrogen atom, X ₂ is a fluorine atom, which is preferable. In addition, from the same viewpoint, in the chemical formula (1), when X ₁ is a halogen atom, X ₂ is a fluorine atom or a nitrile group, which is preferable. In addition, from the same viewpoint, in the aforementioned chemical formula (1), when X ₁ is a fluorine atom, X ₂ is a fluorine atom or a nitrile group, which is preferable. In the aforementioned chemical formula (1), by using a radioactive fluorine atom as X ₃ , it can be applied to nuclear medicine examinations, and more specifically, it can be applied to the use of an imaging diagnostic agent for positron computed tomography (PET). In the present invention, since a narrow part of a heart disease is taken as a photographic object, it is ideal for use in positive resolution computed tomography with good spatial resolution and quantitativeness.

The ideal form of the compound related to the present invention may include three compounds represented by the following chemical formulas,

The radioactive compound or salt thereof related to the present invention represented by the aforementioned chemical formula (1) can be manufactured using, for example, the manufacturing method described in Patent Document 11 “International Publication No. 2015/199205”, specifically, using The compound represented by the following chemical formula (2) or a salt thereof can be produced through a radiofluorination reaction.

In the aforementioned chemical formula (2), X ₁ represents a hydrogen atom or a halogen atom; X ₂ represents a fluorine atom or a nitrile group; R ₁ represents a halogen atom, substituted or unsubstituted alkylsulfonyloxy Group (alkylsulfonyloxy group), or, substituted or unsubstituted arylsulfonyloxy (arylsulfonyloxy group).

In the aforementioned chemical formula (2), the ideal forms of X ₁ and X ₂ are the same as the description about the aforementioned chemical formula (1). In the aforementioned chemical formula (2), a substituted or unsubstituted alkylsulfonyloxy group (alkylsulfonyloxy group) is preferably an alkylsulfonyloxy group having 1 to 12 carbon atoms, and a substituted alkylsulfonyloxy group, The hydrogen atoms of the alkyl chain may be replaced with halogen atoms. Furthermore, in the present invention, the substituted or unsubstituted arylsulfonyloxy group is more preferably a substituted or unsubstituted benzenesulfonyloxy group, and more preferably a substituted benzenesulfonyloxy group Oxy. In the substituted arylsulfonyloxy group, the hydrogen atom of the aryl ring is replaced with an alkyl group having 1 to 12 carbon atoms or an nitro group, which is preferable. Examples of ideal specific examples of the substituted or unsubstituted alkylsulfonyloxy group and the substituted or unsubstituted arylsulfonyloxy group include: methanesulfonyloxy group, benzenesulfonyloxy group group), p-toluenesulfonyloxy group (p-toluenesulfonyloxy group), p-nitrobenzenesulfonyloxy (p-nitrobenzenesulfonyloxy group) or trifluoromethanesulfonyloxy (trifluoromethanesulfonyloxy group).

Hereinafter, an example of the method for producing the compound represented by the aforementioned chemical formula (1) will be described using the following graphical formula 1. Among the compounds represented by the aforementioned chemical formula (1), X ₃ is a compound with a hydroxy group as a starting material, and a chemical group “halogen” represented by R _{1 in} the aforementioned chemical formula (2) is introduced into the hydroxy group Atom, substituted or unsubstituted alkylsulfonyloxy group, or, substituted or unsubstituted arylsulfonyloxy group", the compound represented by the aforementioned chemical formula (2) is obtained as a label precursor (Labeling precursor) "Schematic Formula 1, Step a"; Secondly, a nucleophilic substitution reaction is performed on the chemical group represented by R ₁ using a radioactive halide ion to obtain the foregoing chemical formula (1) Represented radioactive compound "schematic formula 1, step b".

Here, the "radioactive halide ion" includes a radioactive fluoride ion "for example, [ ¹⁸ F]fluoride ion". In the compound represented by the precursor chemical formula (2), R _{1 is} preferably a chlorine atom, a bromine atom, an iodine atom, a substituted or unsubstituted alkylsulfonyloxy group, or, substituted or unsubstituted Arylsulfonyloxy group (arylsulfonyloxy group). In addition, the nucleophilic substitution reaction using radioactive fluoride ions is preferably carried out in the presence of a base such as an alkali metal carbonate.

For example, by using a radioactive fluoride ion to perform a radiofluorination reaction, a radioactive compound in which X ₃ in the compound represented by chemical formula (1) is a radioactive fluorine atom can be obtained. The radioactive fluorination reaction is ideally carried out in the presence of a base, and can also be carried out in 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8] Various phase transfer catalysts such as hexacarbon (4,7,13,16,21, 24-Hexaoxa-1,10-diaza bicyclo[8.8.8]hexacosane) "trade name: Kryptofix® 222" Under the existence.

When using the radioactive compound represented by the aforementioned chemical formula (1) or its salt as a medicine, after radioactive fluorination reaction, unreacted radioactive fluorine atoms and insoluble impurities are preferably filled by membrane filtration Columns of various packing agents, high performance liquid chromatography, etc., are refined.

In the present invention, the "salts" may be any substances that can be used as medicines. For example, they may be inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid , Glycolic acid, salicylic acid, pyranosidic acid "glucuronic acid, galacturonic acid, etc.", α-hydroxy acid ( α-hydroxy acids) "citric acid, tartaric acid, etc.", amino acids (aspartic acid, glutamic acid, etc.), aromatic acids (Aromatic acids) "benzoic acid, cinnamic acid, etc.", sulfonic acids "p-toluene sulfonic acid, ethanesulfonic acid, etc." Acids, salts formed.

The non-invasive imaging diagnostic agent of the present invention is a formulation containing the aforementioned radioactive fluorine element labeling compound or salt thereof in a form that is appropriately put into a living body. 【Example】

Hereinafter, embodiments will be disclosed to explain the present invention in more detail, but the present invention is not limited to this content.

In the examples, the molecular structure of each compound was identified by Proton nuclear magnetic resonance spectra ( ¹ H-NMR). Nuclear magnetic resonance spectroscopy (NMR) device, using AVANCEIII "made by Bruker Technology Co., Ltd. (Bruker)", resonance frequency using 500 MHz (megahertz; MHz), using tetramethylsilane (TMS) as an internal standard, setting tetramethyl Silane resonance is 0.00 parts per million (ppm). All chemical shifts are the parts per million (ppm) of the delta scale (delta), so for the microdivision of the signal, use the abbreviation "s: singlet" (Singlet), d: doublet (doublet), t: triplet (triplet), dd: double doublet (double doublet), dt: double triplet (double triplet), m: multiplet (multiplet), bs: Broad singlet, quin: quintet. In the following, the "room temperature" in the examples is 25°C. In the synthesis example of each compound, each step of compound synthesis is carried out repeatedly according to needs, and when used as an intermediate for other synthesis, etc., the required amount can be secured.

[Reference Example 1] Synthesis of Compound 100 The synthesis of compound 100 was carried out according to the scheme shown in FIG. 1 of International Publication No. 2015/199205.

[Reference Example 2] Synthesis of Compound ^[18 F] 100 in accordance with International Publication No. 2015/199205 illustrates the FIG formula (scheme) shown in FIG. 2, the compound ^[18 F] Synthesis of 100.

[Example 1] Synthesis of Compound 101 The compound 101 was synthesized according to the following formula 2 below.

N- (5- fluoro-2-nitrophenyl) -2-fluoro-ethylamine (N- (5-fluoro-2- nitrophenyl) -2- fluoroethylamine) Synthesis of "Compound 2" is 2,4- After fluoronitrobenzene (2,4-difluoronitrobenzene) "Compound 1""109.7 microliters (μL), 1.0 millimoles (mmol)" was dissolved in dichloromethane "3.0 ml (mL)", under argon Under argon gas environment, under ice cooling, add potassium carbonate (691.0 mg (mg), 5.0 millimoles (mmol)) and 2-fluoroethylamine (298.6 mg) , 3.0 millimoles", stirred at room temperature for 2 days. After the reaction was completed, after adding water at room temperature, it was extracted three times with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to colloidal chromatography ( Silica gel chromatography) "eluent: n-hexane/ethyl acetate=20/1→10/1" was purified to obtain N-(5-fluoro-2 -Nitrophenyl)-2-fluoroethylamine (N-(5-fluoro-2-nitrophenyl)-2-fluoroethylamine) "Compound 2""231.2 mg, 1.14 mmol". H NMR of compound 2 ⁽¹ H-NMR) "Solvent: deuterated chloroform (deuterated chloroform)": δ8.36 ( bs, 1H), 8.25 (dd, J = 9.5, 6.1Hz, 1H), 6.52 ( dd, J=11.3, 2.6Hz, 1H), 6.44-6.41 (m, 1H), 4.70 (dt, J=47, 5.0Hz, 2H), 3.62 (dq, J=25, 4.1Hz, 2H).

Synthesis of 3-fluoro-N-[2-fluoroethyl]-1,6-phenylenediamine (3-fluoro-N-[2-fluoroethyl]-1,6-phenylendiamine) "Compound 3" 5-fluoro-2-nitrophenyl)-2-fluoroethylamine (N-(5-fluoro-2-nitrophenyl)-2-fluoroethyl amine) "Compound 2""231.2 mg, 1.14 mmol" dissolved After ethyl acetate "4.0 milliliters (mL)", add tin(II) {tin( II ) chloride; tin( II ) chloride; stannous chloride) "867.4 mg, 4.57 millimoles" and water "82.3 micro Liters, 4.57 millimoles", heated to reflux for 8 hours under argon gas environment. After the reaction was completed, 4 mol (M) sodium hydroxide aqueous solution was added, and the deposited precipitate was filtered, and the resulting filtrate was extracted three times with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was subjected to colloidal chromatography (silica gel chromatography) "eluent: n-hexane (n -hexane)/ethyl acetate=5/1→2/1》for purification to obtain 3-fluoro-N-[2-fluoroethyl]-1,6-phenylenediamine (3-fluoro- N-[2-fluoroethyl]-1,6-phenylendiamine) "Compound 3""137.9 mg, 0.801 mmol". NMR spectrum of compound 3 hydrogen ⁽¹ H-NMR) "Solvent: deuterated chloroform (deuterated chloroform)": δ6.66-6.63 ( m, 1H), 6.39-6.35 (m, 2H), 4.67 (dt, J =47, 4.9Hz, 2H), 3.41 (dt, J=27, 4.8Hz, 1H), 3.18 (bs, 2H).

5-{ 6-fluoro-1-[2-fluoroethyl] benzimidazol-2-yl}pyridine-3-methanol (5-{6-fluoro-1-[2-fluoroethyl] benzimidazole-2-yl} pyridine-3-methanol) Synthesis of "Compound 4 " Dissolve 5-hydroxymethyl-3-pyridinecarboxaldehyde (109.9 mg, 0.801 mmol) in N,N'-dimethyl After N,N'-dimethylformamide "1 ml", under ice cooling, add 3-fluoro-N-[2-fluoroethyl]-1,6-phenylenediamine (3-fluoro- N-[2-fluoroethyl]-1,6-phenylendiamine) "Compound 3""137.9 mg, 0.801 mmol" dissolved in N,N'-dimethylformamide (N,N'-dimethylformamide) "2 Ml" and Oxone {registered trademark} potassium monopersulfate compound (Oxone (R) Monopersulfate Compound; Potassium peroxymonosulfate) "590.8 mg, 0.961 millimoles", stirred at room temperature under argon gas environment 2 hours and 30 minutes. After the reaction, under ice cooling, saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution were added, and extracted three times with ethyl acetate; the combined ethyl acetate layer was dried over anhydrous sodium sulfate and depressurized After concentration, the crude product obtained was subjected to colloidal chromatography (silica gel chromatography) "eluent: ethyl acetate/n-hexane/methanol=10/ 5/1" was refined to obtain 5-{6-fluoro-1-[2-fluoroethyl] benzimidazol-2-yl}pyridine-3-methanol (5-{6-fluoro-1-[2- fluoroethyl] benzimidazole-2-yl}pyridine-3-methanol) "Compound 4""148.7 mg, 0.514 mmol". Nuclear magnetic resonance hydrogen spectroscopy of compound 4 ( ¹ H-NMR) "Solvent: deuterated chloroform": δ 8.87 (d, J=2.1Hz, 1H), 8.76 (d, J=2.1Hz, 1H) , 8.13 (t, J=2.1Hz, 1H), 7.78 (dd, J=8.9, 4.9Hz, 1H), 7.15-7.09 (m, 2H), 4.86 (d, J=5.6Hz, 2H), 4.80 ( dt, J=47, 4.8Hz, 2H), 4.50 (dt, J=25, 4.8Hz, 2H).

6-fluoro-1- (2-fluoroethyl) -2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole (6-fluoro-1- (2 -fluoroethyl) -2-[5-(imidazol- 1 -ylmethyl) pyridin- 3 -yl] benzimidazole ) The synthesis of "Compound 101" will be 5-{6-fluoro-1-[2-fluoroethyl] benzimidazole-2- Yl}pyridine-3-methanol (5-{6-fluoro-1-[2-fluoroethyl] benzimidazole-2-yl}pyridine-3-methanol) "Compound 4""148.7 mg, 0.514 mmol" dissolved in tetrahydrofuran (tetrahydrofuran) "5 ml" in the future, triethyl amine (triethylamine) "214.3 l, 1.54 mmol"; and then, cooled to -20 deg.] C, added p - toluenesulfonic anhydride (p -toluenesulfonic anhydride) "335.5 Milligrams, 1.03 millimoles", under argon atmosphere, stirred at -20 ℃ for 4 hours. Next, was added triethylamine (triethylamine) "214.3 l, 1.54 mmol," and p - toluenesulfonic anhydride (p -toluenesulfonic anhydride) "335.5 mg, 1.03 mmol," in an argon atmosphere, Stir at -20°C for 3 hours. After the reaction, triethylamine "1.1 ml, 7.71 mmol" and imidazole "349.9 mg, 5.14 mmol" were added, and the mixture was stirred at room temperature overnight under an argon atmosphere. After the reaction, the gel fraction chromatography (silica gel chromatography) "eluent (eluent): chloroform (chloroform) / methanol (methaol) = 20/1" was purified, and the fraction obtained was concentrated under reduced pressure , Dissolve in ethyl acetate and wash with saturated aqueous sodium bicarbonate. Next, the washed ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to obtain 6-fluoro-1-(2-fluoroethyl)-2-[5-(imidazol-1-ylmethyl)pyridine-3 -Yl] benzimidazole (6-fluoro-1-(2-fluoroethyl)-2-[5-(imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole) "Compound 101""31.5 mg, 0.093 mmol ear". Nuclear magnetic resonance hydrogen spectroscopy ( ¹ H-NMR) of compound 101 "Solvent: deuterated chloroform": δ8.94 (d, J=2.0Hz, 1H), 8.64 (d, J=2.2Hz, 1H) , 7.87 (t, J=1.9Hz, 1H), 7.77 (dd, J=9.5,4.9Hz, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 7.13-7.09 (m, 2H), 6.96 (t, J=1.3Hz, 1H), 5.26 (s, 2H), 4.77 (dt, J=47,4.7Hz, 2H), 4.42 (dt, J=25,4.8Hz, 2H).

[Example 2] Synthesis of compound [ ¹⁸ F]101 The synthesis of compound [ ¹⁸ F]101 was carried out according to the following schematic formula 2.

2- (Laid - butyldiphenylsilyl silicon alkyloxy) ethylamine (2- (tert-butyldiphenylsilyloxy) ethylamine ) Synthesis of "Compound 6" 2-Amino-ethanol (2-aminoethanol) "Compound 5"" 2.2 ml, 40.0 mmol) dissolved in dichloromethane "100 ml", at room temperature, add tert-butyldiphenylsilyl chloride (15.6 ml, 60.0 mmol) Ear" and imidazole (5.44 g, 80.0 mmol), stirred at room temperature overnight under argon atmosphere. After the reaction was completed, under ice cooling, after adding water, it was extracted three times with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was layered on the colloid layer. Analysis (silica gel chromatography) "elution solution (eluent): ethyl acetate (ethyl acetate) → ethyl acetate/methanol = 10/1 → 5/1" for purification to obtain 2-(tert-butyldiphenyl Silyloxy) ethylamine (2-(tert-butyldiphenylsilyloxy)ethylamine) "Compound 6""12.2 grams, 40.7 millimoles". Nuclear magnetic resonance hydrogen spectroscopy ( ¹ H-NMR) of compound 6 "Solvent: deuterated chloroform": δ 7.67-7.65 (m, 4H), 7.44-7.36 (m, 6H), 3.70 (t, J =5.3HZ, 2H), 2.84 (t, J=5.3HZ, 2H), 2.79 (bs, 2H), 3.08 (bs, 2H), 1.07 (s, 9H).

N-( 5-fluoro-2-nitrophenyl)-2-(tert-butyldiphenylsilyloxy) ethylamine (N-(5-fluoro-2-nitrophenyl)-2-( tert-butyldiphenylsilyloxy) ethylamine) "Compound 7" Synthesis of 2,4-difluoronitrobenzene (2,4-difluoronitrobenzene) "Compound 1""66.9 microliters, 0.60 millimoles" dissolved in dichloromethane (dichloromethane ) After "2.0 ml", under argon atmosphere, under ice cooling, add potassium carbonate "420.5 mg, 3.04 mmol" and 2-(tert-butyldiphenylsilyloxy)ethylamine (2-(tert-butyldiphenylsilyloxy)ethylamine) "Compound 6""546.7 mg, 1.83 mmol", stirring at room temperature overnight. After the reaction was completed, at room temperature, after adding water, it was extracted three times with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was chromatographed on a colloidal layer. (Silica gel chromatography) "eluent: n-hexane/ethyl acetate = 20/1→10/1" was purified to obtain N-(5-fluoro-2-nitrophenyl)-2 -(Te-butyldiphenylsilyloxy) ethylamine (N-(5-fluoro-2-nitrophenyl)-2-(tert-butyldiphenylsilyloxy) ethylamine) "Compound 7""286.9 mg, 0.654 mmol Mohr. Nuclear magnetic resonance hydrogen spectroscopy ( ¹ H-NMR) of compound 7 "Solvent: deuterated chloroform": δ 8.51 (bs, 1H), 8.22 (dd, J=9.5, 6.2 Hz, 1H), 7.67- 7.65 (m, 4H), 7.43-7.36 (m, 6H), 6.43 (dd, J=11.5, 2.6Hz, 1H), 6.37-6.33 (m, 1H), 3.90 (t, J=5.4Hz, 2H) , 3.47 (q, J=5.4Hz, 2H), 1.07 (s, 9H).

3-fluoro -N- [2- (Laid - butyldiphenylsilyl silicon alkyloxy) ethyl] -1,6-phenylenediamine (3-fluoro-N- [2- (tert-butyldiphenylsilyloxy) ethyl ]-1,6-phenylenediamine) "Compound 8" Synthesis of N-(5-fluoro-2-nitrophenyl)-2-(tert-butyldiphenylsilyloxy) ethylamine ( N-(5-fluoro-2-nitrophenyl)-2-(tert-butyldiphenylsilyloxy) ethylamine) "Compound 7""286.9 mg, 0.654 millimoles" was dissolved in methanol "3.0 ml" and added under argon atmosphere 10% palladium on carbon (Pd/C) "11.2 mg"; Next, stir under hydrogen gas at room temperature overnight. After the reaction was completed, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to colloidal chromatography (silica gel chromatography) "eluent: positive- Hexane/ethyl acetate=20/1→5/1》 was purified to obtain 3-fluoro-N-[2-(tert-butyldiphenylsilyloxy)ethyl]-1,6- Phenylenediamine (3-fluoro-N-[2-(tert-butyldiphenylsilyloxy) ethyl]-1,6-phenylenediamine) "Compound 8""122.4 mg, 0.300 mmol". Nuclear magnetic resonance hydrogen spectroscopy of compound 8 ( ¹ H-NMR) "Solvent: deuterated chloroform": δ 7.67 (dd, J=6.0, 1.3Hz, 4H), 7.43-7.41 (m, 2H), 7.39-7.36 (m,4H), 6.62 (dd, J=8.3,5.7HZ, 1H), 6.34-6.28 (m, 2H), 4.16 (bs, 1H), 3.91 (t, J=5.4Hz, 2H) , 3.21 (q, J=5.2Hz, 2H), 3.08 (bs, 2H), 1.07 (s, 9H).

5- {6-fluoro-1- [2- (Laid - butyldiphenylsilyl silicon alkyloxy) ethyl] benzimidazol-2-yl} pyridine-3-methanol (5- {6-fl uoro -1-[2-( tert-butyldiphenylsilyloxy) ethyl] benzimidazole-2-yl} pyridine-3-methanol ) "Compound 9 " synthesis of 5-hydroxymethyl-3-pyridinecarboxaldehyde ) "40.8 mg, 0.298 mmol" dissolved in N,N'-dimethylformamide (N,N'-dimethylformamide) "0.5 ml", under ice cooling, add 3-fluoro-N-[ 2-(tert-butyldiphenylsilyloxy) ethyl]-1,6-phenylenediamine (3-fluoro-N-[2-(tert-butyldiphenylsilyloxy) ethyl]-1,6-phenylenediamine ) "Compound 8""122.4 mg, 0.300 millimoles" and Oxone {registered trademark} potassium monopersulfate compound (Oxone (R) Monopersulfate Compound; Potassium peroxymonosulfate) "221.3 mg, 0.360 millimoles", in argon Under an argon gas environment, stir at room temperature for 30 minutes. After the reaction was completed, under ice cooling, after adding saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution, it was extracted three times with ethyl acetate; the combined ethyl acetate layer was dried over anhydrous sodium sulfate and reduced Concentrate under pressure to obtain the crude product, in colloidal chromatography (silica gel chromatography) "elution solution (eluent): ethyl acetate (ethyl acetate) / n-hexane (n-hexane) / methanol = 10 /5/1" was refined to obtain 5-{6-fluoro-1-[2-(tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridine-3- Methanol (5-{6-fluoro-1-[2-(tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridine-3-methanol) "Compound 9""131.3 mg, 0.250 mmol". Nuclear magnetic resonance hydrogen spectroscopy of compound 9 ( ¹ H-NMR) "Solvent: deuterated chloroform": δ 8.96 (d, J=2.1Hz, 1H), 8.73 (d, J=2.1Hz, 1H) , 8.12 (t, J=2.1Hz, 1H), 7.77 (dd, J=8.8, 4.8Hz, 1H), 7.38-7.36 (m, 6H), 7.29-7.28 (m, 4H), 7.09-7.05 (m , 1H), 6.91 (dd, J=8.7,2.4Hz, 1H), 4.76 (d, J=5.8Hz, 2H), 4.40(t, J=5.7Hz, 2H), 3.94 (t, J=5.7Hz , 2H), 0.89 (s, 9H).

6-fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] -1- [2- (Laid - butyldiphenylsilyl silicon alkyloxy) ethyl] benzimidazole ( 6-fluoro-2-[5-(imidazole-1-ylmethyl) pyridine-3-yl]-1-[2- tert-butyldiphenylsilyloxy) ethyl] benzimidazole ) The synthesis of "Compound 10 " will be 5-{6-fluoro -1-[2-(tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridine-3-methanol (5-{6-fluoro-1-[2-( tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridine-3-methanol) "Compound 9""131.3 mg, 0.250 mmol" dissolved in dichloromethane "2.5 ml", under ice cooling, Add triethylamine (104.4 microliters, 0.750 millimoles) and p-toluenesulfonic anhydride (163.0 mg, 0.500 millimoles), under argon gas, in Stir at room temperature for 1 hour and 30 minutes. After the reaction was completed, water was added and extracted three times with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Imidazole (85.0 mg, 1.25 mmol) was dissolved in N,N'-dimethylformamide (0.2 mL) and cooled with ice. After adding triethylamine "174.1 microliters, 1.25 millimoles", the previously obtained crude product was dissolved in N,N'-dimethylformamide "0.8 ml" and added in an argon atmosphere at Stir at room temperature for 4 hours. After the reaction was completed, water was added and extracted three times with ethyl acetate; the combined ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was subjected to colloidal chromatography (silica gel chromatography). "Eluent: dichloromethane/methanol=30/1→20/1→10/1" was purified to obtain 6-fluoro-2-[5-(imidazol-1-ylmethyl ) Pyridin-3-yl]-1-[2-(tert-butyldiphenylsilyloxy) ethyl] benzimidazole (6-fluoro-2-[5-(imidazole-1-ylmethyl) pyridine-3-yl]-1-[2-tert-butyldiphenylsilyloxy) ethyl] benzimidazole) "Compound 10""128.1 mg, 0.222 mmol". Nuclear magnetic resonance hydrogen spectroscopy ( ¹ H-NMR) of compound 10 "Solvent: deuterated chloroform": δ 9.06 (d, J=2.2Hz, 1H), 8.55 (d, J=2.2Hz, 1H) , 7.92 (t, J=2.2Hz, 1H), 7.76 (dd, J=8.8, 4.8Hz, 1H), 7.55 (s, 1H), 7.40-7.35 (m, 6H), 7.29-7.27 (m, 4H ), 7.09-7.05 (m, 2H), 6.90-6.86 (m, 2H), 5.13 (s, 2H), 4.34 (t, J=5.5Hz, 2H), 3.94 (t, J=5.5Hz, 2H) , 0.89 (s, 9H).

2-{6- fluoro -2-[5-( imidazol- 1 -ylmethyl ) pyridin- 3 -yl ] benzimidazol- 1 -yl } ethanol ( 2-{ 6-fluoro-2-[5- ( imidazole-1-ylmethyl) pyridine-3-yl] benzimidazole-1-yl} ethanol ) "Compound 11 " synthesis of 6-fluoro-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl ]-1-[2-(tert-butyldiphenylsilyloxy) ethyl] benzimidazole (6-fluoro-2-[5-(imidazole-1-ylmethyl) pyridine-3-yl] -1-[2-tert-butyldiphenylsilyloxy) ethyl] benzimidazole) "Compound 10""128.1 mg, 0.222 millimoles" was dissolved in tetrahydrofuran "2.0 mL", and tetrabutylammonium fluoride ( tetrabutylammonium fluoride) "0.33 ml, tetrahydrofuran solution, about 1 mole concentration (M), 0.33 millimoles", stirred at room temperature for 1 hour and 30 minutes under an argon atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting crude product was subjected to colloidal chromatography (silica gel chromatography) "eluent: dichloromethane/methanol=20/1→10/1. → 5/1》 Refined to obtain 2-{6-fluoro-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl] benzimidazol-1-yl} ethanol (2-{6 -fluoro-2-[5-(imidazole-1-ylmethyl) pyridine-3-yl] benzimidazole-1-yl} ethanol) "Compound 11""25.8 mg, 0.0765 mmol". Nuclear magnetic resonance hydrogen spectroscopy ( ¹ H-NMR) of compound 11 "Solvent: deuterated chloroform": δ 9.07 (d, J=2.2Hz, 1H), 8.64 (d, J=2.2Hz, 1H) , 7.87 (t, J=2.2Hz, 1H), 7.73 (dd, J=8.9,4.8Hz, 1H), 7.62 (s, 1H), 7.15 (d, J=2.4Hz, 1H), 7.13 (s, 1H), 7.12 (dt, J=10.3,2.4Hz, 1H), 6.98 (t, J=1.3Hz, 1H), 5.27 (s, 2H), 4.21 (t, J=5.7Hz, 2H), 3.99 ( t, J=5.7Hz, 2H), 2.44(bs, 1H).

6- chloro -5- fluoro -2-[5-( imidazol- 1 -ylmethyl ) pyridin- 3 -yl ]-1-[2-( p-toluenesulfonyloxy) ethyl] benzimidazole (6 -chloro-5-fluoro-2-[5-imidazole-1-ylmethyl) pyridine-3-yl]-1-[2-( p-toluene sulfonyloxy benzimidazole) The synthesis of "Compound 12" will be 2-{6-fluoro -2-[5-(imidazol-1-ylmethyl)pyridin-3-yl] benzimidazol-1-yl} ethanol (2-{6-fluoro-2-[5-(imidazole-1-ylmethyl) pyridine-3-yl] benzimidazole-1-yl} ethanol) "Compound 11""20.0 mg, 0.0593 mmol" was dissolved in dichloromethane "1.0 ml", then p-toluenesulfonic anhydride (p-toluenesulfonic anhydride) "22.6 mg, 0.119 millimoles" and triethylamine "24.8 microliters, 0.176 millimoles", stirred for 3 hours at room temperature under an argon gas environment. After the reaction, it is purified by colloidal chromatography (silica gel chromatography) "eluent: chloroform/methanol=20/1→10/1", and the resulting fraction is concentrated under reduced pressure to make it Dissolved in ethyl acetate and washed with water. Next, the washed ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to obtain 6-chloro-5-fluoro-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl]-1- [2-(p-toluenesulfonyloxy) ethyl] benzimidazole (6-chloro-5-fluoro-2-[5-imidazole-1-ylmethyl) pyridine-3-yl]-1-[2-( p-toluene sulfonyloxy benzimidazole) "Compound 12""10.9 mg, 0.0229 mmol". Nuclear magnetic resonance hydrogen spectrum ( ¹ H-NMR) of compound 12 "Solvent: deuterated methanol": δ8.82 (d, J=2.1Hz, 1H), 8.70 (d, J=2.1Hz, 1H) , 8.02 (t, J=2.1Hz, 1H), 7.90 (s, 1H), 7.62 (dd, J=8.8, 4.7 Hz, 1H), 7.28 (dd, J=6.4, 1.8Hz, 3H), 7.21 ( dd, J=8.9,2.4Hz, 1H), 7.13-7.10 (m, 1H), 7.06 (t, J=2.3Hz, 3H), 5.46 (s, 2H), 4.49 (t, J=5.9Hz, 2H ), 4.25 (t, J=5.9Hz, 2H), 2.32 (s, 3H).

Synthesis of compound [ ¹⁸ F]101 The heavy oxygen water (oxygen-18 water; Heavy-oxygen water; H ₂ ¹⁸ O) containing [ ¹⁸ F]fluoride ion "radiation energy 2330 million baker, correction at the start of synthesis "Value", put in a Sep-Pak column (Sep-Pak column) "Trade Name: Sep-Pak [registered trademark] Light Cartridge Accell [registered trademark] Plus QMA Carbonate, manufactured by Waters Corporation, the filling amount of the filling agent is 130 mg." As an eluent, [ ¹⁸ F] fluoride ions are adsorbed and trapped. A potassium carbonate aqueous solution "42.4 micromoles/liter, 0.3 ml" and Kryptofix (222) "trade name, manufactured by Merck""14 mg, 37.2 micromolar" were used in the column The acetonitrile solution "0.7 ml" is used as the eluent to dissolve [ ¹⁸ F]fluoride ions. This liquid was heated to 110°C under an argon atmosphere to evaporate the water, and then added acetonitrile "0.5 ml Ï 2 times to make it azeotropic and dry; the 6-chloro-5-fluoro-2-[5- (Imidazol-1-ylmethyl)pyridin-3-yl]-1-[2-(p-toluenesulfonyloxy)ethyl] benzimidazole (6-chloro-5-fluoro-2-[5-imidazole -1-ylmethyl) pyridine-3-yl]-1-[2-( p-toluene sulfonyloxy benzimidazole) "Compound 12""5 mg, 0.0102 millimoles" of acetonitrile/dimethyl sulfoxide The mixed liquid "9:1""1.0ml" was added to the solid and heated at 100°C for 5 minutes. After the reaction was completed, water for injection "2.0 mL" was added, and high-performance liquid chromatography (HPLC) with the following conditions was used to convert 6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl )-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl] benzimidazole (6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5- imidazole-1 -ylmethyl) pyridine-3-yl] benzimidazole) "Compound [ ¹⁸ F]101" was taken out. <High-performance liquid chromatography conditions> Column: Develosil RP-Aqueous "trade name, manufactured by Nomura Chemical Co., size: 10Ï250 mm" Mobile phase: ammonium bicarbonate solution of 10 millimolar concentration (mM)/acetonitrile=70/ 30 Flow rate: 4.0 ml/min Detector: Ultraviolet and visible spectrophotometer (Detection wavelength: 254 nanometers (nm)) The liquid after adding 10 ml of water to this portion flows through Sep-Pak C18 The column "Trade Name: Sep-Pak [registered trademark] Light C18 Cartriges, manufactured by Waters, 130 mg of filling agent filling", 6-fluoro-1-(2-[ ¹⁸ F] fluorine Ethyl)-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl] benzimidazole (6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5- imidazole -1-ylmethyl) pyridine-3-yl] benzimidazole) "Compound [ ¹⁸ F]101" is adsorbed and trapped in the column. After the column was washed with 5 ml of water, ethanol was used as the eluent to make 6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5-(imidazol-1-ylmethyl ) Pyridin-3-yl] benzimidazole (6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5-imidazole-1-ylmethyl) pyridine-3-yl] benzimidazole) "compound [ ¹⁸ F]101》elutes to give 6-fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5-(imidazol-1-ylmethyl)pyridin-3-yl]benzimidazole (6 -fluoro-1-(2-[ ¹⁸ F]fluoroethyl)-2-[5- imidazole-1-ylmethyl) pyridine-3-yl] benzimidazole) "Compound [ ¹⁸ F]101" in ethanol. The radiant energy obtained was 707 million Baker "49 minutes after the start of the synthesis" just after the synthesis was completed. In addition, under the following conditions, thin layer chromatography (Thin layer chromatography; TLC) analysis was performed, and the purity of the radiochemistry was 98.3%. <Thin-layer chromatography analysis conditions> Thin-layer chromatography slide: DSilica Gel 60 F254 "trade name, manufactured by Merck" Dissolution agent: acetonitrile/water/diethylamine = 10/1/1 refractive index detection (Refractive index detector): Rita Star, manufactured by raytest company

[Example 3] Using an autoradiography in vitro of a rat model of ischemic heart disease, Wistar rat "male" underwent incision of the thoracic cavity under isoflurane anesthesia, After the left coronary artery was ligated for 30 minutes, it was refused (perfusion) and the chest cavity was sutured to make a rat model of ischemic heart disease. One week after the operation, after the aforementioned model rats were killed under isoflurane anesthesia, the heart was removed, and a 5 micron thin slice was attached to the slide glass and attached to the slide glass "Before use -80 Store at ℃. The slices were returned to room temperature from -80°C as pre-incubation, immersed in phosphate buffered salts (PBS) at 37°C for 5 minutes, and then in human plasma, At 37°C, immerse for 5 minutes. Next, as a reaction step, individual plasma containing compound [ ¹⁸ F]101 "Radiation energy concentration: about 40 kilobec/ml" or compound [ ¹⁸ F]100 "Radiation energy concentration: about 40 kilobec/ml" was prepared individually Hereinafter, referred to as "reaction solution", the pre-cultured sections are immersed in the reaction solution at 37°C for 10 minutes. Then, it was immersed in human plasma at 37°C for 2 minutes and exposed 5 times to wash the slices. The washed slices are fully dried. In addition, filter paper cut into a circular shape is added to the slide glass, immersed in a known amount of reaction solution, and dried to be used as a standard radiation source. The dried slices and standard radiation source are exposed to an imaging plate "BAS-SR2040, manufactured by Fuji Film", and obtained automatically using a Fluoro Image Analyzer (Typhoon FLA 7000 IP; manufactured by GE Healthcare). Radiography (autoradiography).

The result of compound [ ¹⁸ F]101 is shown in FIG. 1A, and the result of compound [ ¹⁸ F]100 is shown in FIG. 1B. As shown in FIG. 1A, the accumulation of compound [ ¹⁸ F]101 in the lesion area has been confirmed; in contrast, as shown in FIG. 1B, the accumulation of compound [ ¹⁸ F]100 in the lesion area is hardly seen.

其結果顯示於圖2《n=1》。圖2係圖1的自動放射顯影中，相對於標準放射線源的信號強度的缺血再灌流部位的信號強度，以柱狀圖表示的圖。如圖2所示，確認在病變區域的化合物[¹⁸ F]101的蓄積，而在病變區域的化合物[¹⁸ F]100的蓄積則幾乎看不見。In the autoradiography of compound [ ¹⁸ F]101 and compound [ ¹⁸ F]100, the region of interest (ROI) is obtained at the site of ischemia-reperfusion, as calculated by formula (1), relative to the standard For the correction value of the radiation source, find the radioactivity count (correction value) of each part and compare.

The results are shown in Figure 2 "n=1". FIG. 2 is a graph showing the signal intensity of the ischemia-reperfusion site with respect to the signal intensity of the standard radiation source in the autoradiography of FIG. 1 as a bar graph. As shown in FIG. 2, the accumulation of compound [ ¹⁸ F]101 in the lesion area was confirmed, but the accumulation of compound [ ¹⁸ F]100 in the lesion area was almost invisible.

[Example 4] Positive Computed Tomography (PET) experiment of Wistar rat "male" using ischemic heart disease model rats under the isoflurane anesthesia (isoflurane anesthesia) to open the chest cavity, the left Thirty minutes after coronary artery ligation, perfusion was performed, and the chest cavity was sutured to make an ischemic heart disease model rat. The aforementioned model rats were administered compound [ ¹⁸ F]101 "approximately 40 million bakers/animal" 1 week after the start of the operation, and 60 minutes after the administration, using the positive computer tomography equipment "exploreVISTA, manufactured by GEHC" For about 10 minutes. The results are shown in Figure 3A. In addition, the same experiment was conducted using a normal rat "control rat", and the results are shown in Fig. 3B. In addition, a model rat made in the same manner as described above was administered with compound [ ¹⁸ F]100 "about 40 million bakers/animal" one week after the start of the operation, starting immediately after the administration, to 60 after the administration Minutes, using the aforesaid positron tomography equipment to dynamically perform photography, the last frame of "10 minutes" image, that is, the image within 10 minutes starting 50 minutes after the injection, is shown in FIG. 3C. 3A~C, (a) is the short axis cross-sectional image (short axis cross-sectional image); (b) is the horizontal long axis cross-sectional image (horizontal long axis cross section image); (c) is the vertical long axis Vertical long axis cross section image. The triangular arrow indicates the ischemic part of the heart, the arrow indicates the heart part, and the pentagonal arrow indicates the liver. It is obvious from the comparison between FIGS. 3A and 3B that the compound [ ¹⁸ F]101 of the present invention accumulates in the lesion site “ischemic site” of the model rat, and the lesion site “ischemic site” can be depicted. In addition, from the comparison between FIG. 3A and FIG. 3C, the comparison of the compound [ ¹⁸ F]101 and the compound [ ¹⁸ F]100 of the present invention shows that the lesion site can be more depicted.

This patent application is based on Japanese Patent Application No. 2018-089920 filed on May 8, 2018, and claims priority, and the entire disclosure content is incorporated herein.

[Figure 1] Figures 1A and B separately show the results of autoradiography of compound [ ¹⁸ F]101 and compound [ ¹⁸ F]100 using ischemic heart disease model rat heart slices Figure. [Figure 2] Figure 2 shows a bar graph showing the signal intensity of the ischemia reperfusion site relative to the signal intensity of the standard source in the automatic radiographic imaging of Figure 1 Picture. [FIG 3] FIG. 3A based compound administered and ischemic heart disease model ^[18 F] 101 rats positron tomography (PET) imaging; positron FIG. 3B-based compound is administered to normal rats ^[18 F] 101 of Tomography (PET) image; Figure 3C is a positron tomography (PET) image of an ischemic heart disease model rat administered with compound [ ¹⁸ F]100. In the figure, (a) is a short axis cross section image, (b) is a horizontal long axis cross section image, and (c) is a vertical long axis cross section image. The triangular arrowhead "wedge symbol" indicates the ischemic part of the heart, the arrow indicates the heart part, and the pentagonal arrow indicates the liver.

Claims (9)

A non-invasive imaging diagnostic agent for heart disease is a non-invasive imaging diagnostic agent for heart disease containing a radiolabeled compound represented by the following chemical formula (1) or a salt thereof as an active ingredient.

In the chemical formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom. 》 The non-invasive imaging diagnostic agent as described in item 1 of the scope of patent application, wherein in the aforementioned chemical formula (1), X ₁ is a hydrogen atom. The non-invasive imaging diagnostic agent as described in item 2 of the patent application scope, wherein X ₂ in the aforementioned chemical formula (1) is a fluorine atom. The non-invasive imaging diagnostic agent as described in item 1 of the scope of patent application, wherein in the aforementioned chemical formula (1), X ₁ is a halogen atom. The non-invasive imaging diagnostic agent as described in any of items 1 to 4 of the patent application scope is applied to positron emission tomography (PET). The non-invasive imaging diagnostic agent as described in any one of items 1 to 5 of the patent application scope, wherein the aforementioned heart disease is an ischemic heart disease. The non-invasive imaging diagnostic agent as described in item 6 of the patent scope, wherein the aforementioned ischemic heart disease is coronary heart disease angina, myocardial infarction, acute coronary syndrome ) Or ischemic heart failure. The non-invasive imaging diagnostic agent according to any one of claims 1 to 5 of the patent application, wherein the aforementioned heart disease is an ischemic heart disease. The non-invasive imaging diagnostic agent as described in item 8 of the patent application scope, wherein the aforementioned non-ischemic heart disease is myocarditis, hypertensive heart disease, and dilated cardiomyopathy , Hypertrophic cardiomyopathy (hypertrophic cardiomyopathy) or non-ischemic heart failure (non-ischemic heart failure).

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