Diagnostic agent for cardiac function

Abstract

This diagnostic agent for cardiac function contains a compound represented by general formula (1-0) as an active ingredient. [In general formula (1-0), R represents -O(CH2)n-, -O(CH2)nOC2H4-, -CH2O(CH2)n-, or -CH2O(CH2)nOC2H4-, n represents an integer of 1-5, and Q1 represents F or -OCH3.]

Description

Diagnostic agent for cardiac function

[0001] The present invention relates to a diagnostic agent for cardiac function.

[0002] Positron emission tomography (PET) is applied to various diagnoses. For example, Patent Document 1 discloses a compound suitable for detecting mitochondrial complex-1 as a probe that can be used in PET.

[0003] International Publication No. 2014 / 30709

[0004] The use of the compounds disclosed in WO 02 / 04799 has not previously been reported for diagnostic purposes of cardiac function.

[0005] Traditionally, early detection of cardiac dysfunction has relied on electrocardiogram (ECG) measurements and blood biochemistry tests. However, ECG diagnosis requires that ECG abnormalities occur during the measurement period, leading to frequent oversight. In recent years, continuous monitoring using devices such as Holter monitors has become increasingly common. While convenient, these devices must be worn for at least 24 hours, placing a significant burden on patients during prolonged testing. Blood biochemistry tests require pinpoint detection because enzymes such as creatine kinase (CK) and aspartate aminotransferase (AST) are released into the blood in response to myocardial cell destruction, such as myocardial infarction, for approximately 24 hours after the onset of the disease. Furthermore, these enzyme activities can also show similar changes in skeletal muscle-related conditions as those associated with myocardial infarction, making them challenging to use as indicators of myocardial dysfunction.

[0006] The mainstream imaging diagnostics for the heart are ultrasound, CT, and MRI, but all of these are methods for evaluating the shape and movement of the myocardium, as well as the physical quantity of ejected blood. Therefore, although they are suitable for measuring symptoms in the later stages of the disease when they have progressed, they are not suitable evaluation methods for early detection.

[0007] Nuclear medicine tests such as PET scans of the heart use rubidium ( ８２ Rb) ammonia ([ １３ N]NH ３ )·water([ １５ ]H ２However, these mainly measure changes in myocardial blood flow distribution due to myocardial ischemia, and do not measure the biochemical functions of the myocardium that are directly linked to the diagnosis of pathology or the evaluation of treatment effectiveness. １１ C] Acetate to measure myocardial oxygen consumption, １１ Because the half-life of C is only 20 minutes, it can only be used in PET facilities equipped with a cyclotron, and is not widely used. １８ F]FDG is easily distributed in the confirmation of cardiomyocyte viability after myocardial infarction and inflammation [ １８ F]FDG is used to test for cardiac sarcoidosis, but １８ Since the tissue accumulation of [F]FDG depends on the blood glucose concentration, an overnight fasting period is required before the test, and diabetic patients with high blood glucose levels are difficult to test.

[0008] In view of the above circumstances, an object of the present invention is to provide a diagnostic agent for cardiac function that can diagnose changes in cardiac function with high sensitivity.

[0009] The present invention relates to a diagnostic agent for cardiac function, which contains a compound represented by general formula (1-0) (hereinafter also referred to as "compound (1-0)") as an active ingredient.

[0010] In the general formula (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -, n is an integer of 1 to 5, Q １ is F or -OCH ３ Shows.

[0011] It is known that compound (1-0) can be used to detect mitochondrial complex-I (hereinafter, also referred to as "MC-I"). The diagnostic agent for cardiac function according to the present invention accumulates in the heart, and the amount of accumulation is proportional to the cardiac MC-I activity, and therefore is suitable for use in diagnosing cardiac function. Furthermore, as shown in the examples described below, the diagnostic agent for cardiac function according to the present invention can diagnose cardiac function based on the detection of MC-I activity even in a state in which no changes in biochemical indicators, morphological indicators, etc. are observed. Therefore, the diagnostic agent according to the present invention can diagnose changes in cardiac function with high sensitivity. Furthermore, as a result, changes in cardiac function can also be diagnosed at an early stage.

[0012] The diagnostic agent is Q １ but １８ F or -O １１ CH ３ This allows the compound to emit positrons. The positrons emitted from the compound immediately combine with electrons to emit gamma rays (annihilation radiation). By measuring these gamma rays with an apparatus used in positron emission tomography (PET), the compound accumulating in the heart can be imaged quantitatively and over time. That is, the compound can also be used as a labeled compound for PET.

[0013] The present invention can also be considered as a method for diagnosing cardiac function, comprising the steps of administering the diagnostic agent to a subject, detecting compound (1-0) accumulated in the heart, and quantitatively analyzing the amount of compound (1-0) accumulated in the heart.

[0014] The present invention can also be understood as a compound represented by general formula (1-0) for use in diagnosing cardiac function. The present invention can also be understood as use of a compound represented by general formula (1-0) in the manufacture of a diagnostic agent for cardiac function.

[0015] The diagnostic agent according to the present invention can diagnose changes in cardiac function with high sensitivity, and therefore can also be used to evaluate side effects of drugs on the heart. That is, the diagnostic agent according to the present invention can also be considered as an agent for evaluating side effects of drugs on the heart.

[0016] The present invention includes, for example, the following inventions: [1] A diagnostic agent for cardiac function, which contains a compound represented by general formula (1-0) as an active ingredient. [In the general formula (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -, n is an integer of 1 to 5, Q １ is F or -OCH ３ [2] An agent for evaluating side effects of drugs on the heart, comprising a compound represented by general formula (1-0) as an active ingredient. [In the general formula (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -, n is an integer of 1 to 5, Q １ is F or -OCH ３ [3] The agent according to [1] or [2], wherein the active ingredient is a compound represented by general formula (1-0'). [In the general formula (1-0′), R, n and Q １ represents R, n and Q in general formula (1-0). １ [4] The agent according to any one of [1] to [3], wherein the active ingredient is a compound represented by general formula (1-0″). [In the general formula (1-0″), n and Q １ represents n and Q in general formula (1-0). １[5] The agent according to any one of [1] to [4], wherein the active ingredient is a compound represented by the following formula (1): [In formula (1), Q １ represents Q in general formula (1-0). １ It is the same as [6] Q １ but １８ F or -O １１ CH ３ The agent according to any one of [1] to [5], which is:

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[10] The agent according to any one of [1] to [5], which is:

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[12] Use of the active ingredient or agent according to any one of [1] to [6] in the manufacture of an agent for evaluating side effects of drugs on the heart.

[0017] According to the present invention, it is possible to provide a diagnostic agent for cardiac function that can diagnose changes in cardiac function with high sensitivity.

[0018] (A) [to the heart] １８ (B) Graph showing the accumulation of [F]BCPP-BF (radioactivity accumulation (SUV)). １８ (A) Graph showing the accumulation of [F]FDG (radioactivity accumulation (SUV)). １８ (B) Graph showing the accumulation of [F]BCPP-BF (radioactivity accumulation (SUV)). １８ 1 is a graph showing the accumulation amount (radioactivity accumulation amount (SUV)) of [F]BMS to the heart.１８ 1 is a graph showing the accumulation amount (accumulated radioactivity (SUV)) of [F]BCPP-BF.

[0019] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0020] The diagnostic agent for cardiac function according to this embodiment (hereinafter also simply referred to as "diagnostic agent") contains a compound represented by general formula (1-0) as an active ingredient. In this specification, unless otherwise specified, all isotopes of each atom are included.

[0021]

[0022] In compound (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -. R is -O(CH ２ ) ｎ - or -O(CH ２ ) ｎ O.C. ２ H ４ - is preferred, and -O(CH ２ ) ｎ It is more preferable that it is -.

[0023] In the compound (1-0), n is an integer of 1 to 5, preferably an integer of 2 to 5, more preferably an integer of 3 to 5, and even more preferably 4.

[0024] In compound (1-0), Q １ is F or -OCH ３ and １８ F or -O １１ CH ３ It is preferable that: １ but １８ F or -O１１ CH ３ The compound (1-0) represented by the formula: can emit positrons and is therefore suitable as a labeled compound (PET probe) for use in the PET method. １ Ga-O １１ CH ３ In this case, the half-life is as short as 20 minutes, making it possible to measure multiple times a day on the same subject. １ but １８ If F, the half-life is 110 minutes and -O １１ CH ３ Since the time is longer than the time required for measurement, it is possible to extend the time required for one measurement.

[0025] In the pyridine ring, —OCH bonded to the pyridazine ring ２ The bonding position of - and the bonding position of R are not particularly limited, but -OCH ２ It is preferable that the bonding position of - is the 5-position of the pyridine ring and the bonding position of R is the 2-position of the pyridine ring. The compound represented by the following general formula (1-0') (hereinafter also referred to as "compound (1-0')") has -OCH ２ This is a structural formula when the bonding position of - is the 5-position of the pyridine ring and the bonding position of R is the 2-position of the pyridine ring.

[0026]

[0027] In the general formula (1-0′), R, n and Q １ represents R, n and Q in general formula (1-0). １ is synonymous with.

[0028] Compound (1-0) is preferably a compound represented by general formula (1-0″) (hereinafter also referred to as “compound (1-0″)”), and more preferably a compound represented by formula (1) (hereinafter also referred to as “compound (1)”), because such compound is more suitable for diagnostic applications of cardiac function.

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[0030] In the general formula (1-0″), n and Q １ represents n and Q in general formula (1-0). １is synonymous with.

[0031]

[0032] In formula (1), Q １ represents Q in general formula (1-0). １ is synonymous with.

[0033] The compound (1-0) can be synthesized, for example, from a corresponding precursor. The same applies to the compound (1-0'), the compound (1-0'') and the compound (1).

[0034] An example of a corresponding precursor of the compound (1-0) is a compound represented by the following general formula (2-0) (hereinafter also referred to as "compound (2-0)"). An example of a corresponding precursor of the compound (1-0'), the compound (1-0"), and the compound (1) is —OCH ２ Examples of the compound include compounds in which the bonding position of - and the bonding position of R are the same as those of the compound (1-0'), the compound (1-0'') and the compound (1).

[0035]

[0036] In the general formula (2-0), R has the same meaning as R in the general formula (1-0). ２ represents a removable substituent (such as a substituted sulfonyloxy group, a halogen atom, or a hydroxyl group).

[0037] Examples of the substituted sulfonyloxy group include a tosyloxy group (-OTs), a methanesulfonyloxy group (-OMs), a trifluoromethanesulfonyloxy group (-OTf), and a nitrobenzenesulfonyloxy group (-ONs), with -OTs being preferred.

[0038] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

[0039] The precursor can be synthesized, for example, by the method described in WO 2014 / 30709.

[0040] Since compound (1-0) accumulates specifically in the heart, the amount of accumulation changes in correlation with the degree of cardiac function. That is, when cardiac function declines, the amount of accumulation of compound (1-0) decreases, and when cardiac function increases, the amount of accumulation of compound (1-0) increases. Therefore, the diagnostic agent according to this embodiment is suitably used for diagnosing cardiac function through measurement of the amount of accumulation of compound (1-0). Decrease in cardiac function may be associated with, for example, a disease, disorder, dysfunction, etc. of the heart (e.g., myocardium, cardiovascular). Diagnosis of cardiac function can also be referred to as evaluation of cardiac function.

[0041] The diagnostic agent according to this embodiment can be used, through the diagnosis of cardiac function, for example, in a method for screening subjects with reduced cardiac function (e.g., mass health checkups), a method for evaluating side effects of drugs on the heart, and a method for observing cardiac function over time (e.g., monitoring the progress of symptoms that cause cardiac dysfunction, confirming the effectiveness of treatment, or predicting prognosis). Therefore, the diagnostic agent for cardiac function according to this embodiment can also be regarded as, for example, an agent for evaluating side effects of drugs on the heart, or an agent for evaluating the effectiveness of treatment for symptoms that cause cardiac dysfunction.

[0042] The amount of accumulation of the compound (1-0) can be measured by, but not limited to, binding a fluorescent dye or the like to the compound (1-0) or by using a single photon nuclide ( １２３ I, ９９ｍ The positron labeling can be carried out by labeling the compound with a nuclides such as Tc or a positron nuclide to prepare a labeled compound, and then detecting the label. １ W-O １１ CH ３ or １８ In the case of positron labeling, the annihilation radiation can be measured using an apparatus used in the PET method, thereby enabling quantitative imaging of the distribution of compound (1-0) in the body over time.

[0043] The diagnostic agent according to this embodiment can be produced, for example, by dissolving compound (1-0) in any buffer solution. In this case, the diagnostic agent according to this embodiment is provided as a solution, which may contain other components such as a surfactant, a preservative, a stabilizer, etc. in addition to the buffer components.

[0044] The method for diagnosing cardiac function according to this embodiment includes the steps of administering the diagnostic agent according to the present invention to a subject, detecting compound (1-0) accumulated in the heart, and quantitatively analyzing the amount of compound (1-0) accumulated in the heart.

[0045] The method for evaluating the side effects of a drug on the heart according to this embodiment includes a step of administering a drug to a subject, and can be carried out in the same manner as the above-described diagnostic method, except that the subject in the above-described diagnostic method is a subject to which a drug has been administered. The drug may be any drug.

[0046] Examples of subjects include, but are not limited to, humans, monkeys, mice, and rats.

[0047] The method of administering the diagnostic agent to a subject is not particularly limited as long as compound (1-0) reaches the heart, but is usually administered intravenously.

[0048] The dose of the diagnostic agent is not particularly limited as long as it is sufficient to detect compound (1-0) in the heart, and may be appropriately determined depending on the subject to be administered and the method for detecting compound (1-0). For example, １ but １８ F or -O １１ CH ３When a diagnostic agent containing compound (1-0) is used to detect compound (1-0) using an apparatus used in a PET method, the dose of the diagnostic agent (hereinafter also referred to as the "administered radioactivity") may be 1 MBq / kg body weight to 1,000 MBq / kg body weight. The specific radioactivity of compound (1-0) may be 10 to 10,000 GBq / μmol. The administered radioactivity of the diagnostic agent depends on the sensitivity of the PET camera used and the volume of the subject, but in rodents (mice, rats), approximately 200 to 500 MBq / kg body weight is administered in 0.1 to 0.5 mL of physiological saline solution. In the case of non-human primates (monkeys), 40 to 200 MBq / kg body weight is administered in 0.5 to 2 mL of physiological saline, and in the case of humans, 2 to 10 MBq / kg body weight is administered in 1 to 5 mL of physiological saline solution.

[0049] The method for detecting compound (1-0) accumulated in the heart is not particularly limited, and can be carried out according to a known method. For example, １ but １８ F or -O １１ CH ３ When a diagnostic agent containing compound (1-0) is used, compound (1-0) can be detected by PET. The measurement method in PET is not particularly limited and can be carried out in accordance with known methods. For example, measurement by PET may involve dynamic measurement for 60 minutes starting immediately after administration of the diagnostic agent, or PET measurement may be carried out for 10 to 20 minutes after administration of the diagnostic agent, after waiting 30 to 40 minutes to allow compound (1-0) to sufficiently accumulate in the heart.

[0050] The method for quantitatively analyzing the accumulation amount of compound (1-0) in the heart is not particularly limited and can be carried out in accordance with known methods. For example, the following method can be mentioned. First, an accumulation image of compound (1-0) obtained by the PET method is superimposed on a morphological image of the heart obtained by CT measurement or the like, and the PET image of the heart is identified. Next, a region of interest is set on the PET image of the heart, and the value normalized by the body weight of the subject individual and the administered radioactivity is used as the accumulation amount of compound (1-0) in the heart. Furthermore, instead of the morphological image of the heart, an image obtained by the PET method using a probe capable of detecting the heart may be used.

[0051] The diagnostic method according to this embodiment may further include a step of comparing the quantitatively analyzed accumulation amount of compound (1-0) with a reference value to diagnose cardiac function.

[0052] The reference value may be set appropriately depending on the purpose of diagnosis. For example, when the diagnostic method according to this embodiment is carried out in a group health checkup, the reference value may be a normal range determined in advance from the distribution of the accumulation amount of compound (1-0) in a plurality of subjects of the same type. In this case, whether the cardiac function of a specific subject is normal can be diagnosed depending on whether the quantitative analysis value of the accumulation amount in the specific subject falls within the normal range.

[0053] Furthermore, for example, when the diagnostic method according to the present embodiment is carried out in a subject suffering from a condition that causes cardiac dysfunction (e.g., diabetes, dyslipidemia, myocardial infarction, cardiac sarcoidosis, etc.) for the purpose of monitoring the progress of the condition, confirming the therapeutic effect, predicting the prognosis, or the like, the reference value may be a measurement result of the amount of accumulation of compound (1-0) in the subject at a certain time point (e.g., when healthy, at the time of initial diagnosis, at the start of treatment, at the end of treatment, etc.).

[0054] Furthermore, for example, when the diagnostic method according to this embodiment is carried out to evaluate the side effects of a drug on the heart, the reference value may be the measurement result of the accumulation amount of compound (1-0) in a subject to be administered the drug before taking the drug. In this case, if the quantitative analysis value of the accumulation amount in a subject who has taken the drug is smaller than the reference value, it can be determined that the drug has a side effect on the heart.

[0055] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples.

[0056] [Test Example 1: Synthesis of PET probe] １８ [F]BCPP-BF was synthesized by the method described in a non-patent document (J. Labelled Comp. Radiopharm., 2013, Vol. 56, No. 11, pp. 553-561). The radiochemical purity of the final product obtained was 99% or higher, and the specific radioactivity was 43.8-103.9 GBq / μmol.

[0057] As a control, a PET probe known to recognize mitochondrial Complex-1 [ １８ F] BMS-747158-02 (2-tert-butyl-4-chloro-5-[4-(2-fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one: hereinafter, [ １８ F]BMS), known as a cardiac PET probe. １８ F-fluorodeoxyglucose ([ １８ [F]FDG) was prepared. １８ The radiochemical purity of [F]BMS was 99% or more, and the specific radioactivity was 36.3 to 76.1 GBq / μmol. １８ The radiochemical purity of [F]FDG was greater than 99%.

[0058] Test Example 2: Evaluation of cardiac function in type 2 diabetes model rats (Type 2 diabetes model rats) Male Zucker Leprosy rats, which develop a condition similar to type 2 diabetes in adults, were used. ｆａ / Lepr ｆａ Rats (hereinafter also referred to as "diabetic rats") were purchased from Charles River Japan, Inc. and subjected to PET measurements at 5 and 26 weeks of age. ｆａ / + rats (hereinafter also referred to as "normal rats") were purchased from Charles River Japan, Inc. and used.

[0059] (PET Measurement) Rats were anesthetized with isoflurane and fixed in the gantry of an animal PET camera (SHR-38000, manufactured by Hamamatsu Photonics Co., Ltd.). After 15 minutes of transmission measurement for attenuation correction, approximately 20 MBq / 0.5 mL of [ １８ F]BCPP-BF was administered and emission measurements were performed for 60 minutes. １８ The amount of accumulated [F]BCPP-BF was then calculated. The calculated amount of accumulated [F]BCPP-BF was then normalized by the body weight and the amount of administered radioactivity of each individual, and the amount of accumulated [F]BCPP-BF in the heart was calculated. １８The amount of accumulated radioactivity (SUV) of [F]BCPP-BF was used as a control. １８ F]BCPP-BF instead of [ １８ The same procedure was performed to induce [F]FDG in the heart. １８ The amount of accumulated radioactivity (SUV) was measured.

[0060] (Measurement of blood glucose concentration) Immediately after PET measurement, blood was collected from the rats and the blood glucose concentration was measured using an automatic biochemical analyzer (7180 manufactured by Hitachi High-Technologies Corporation).

[0061] (Results) Figure 1(A) shows the effect of [ １８ 1(B) is a graph showing the accumulation of [F]BCPP-BF (radioactivity accumulation (SUV)). １８ 1(B) shows the results of measurements in 26-week-old rats. In FIG. 1, a "★" indicates that the difference between the data from normal rats and diabetic rats of the same age was statistically significant (p<0.05).

[0062] If diabetes develops and blood sugar levels remain high for a long time, blood vessels become damaged, making patients more susceptible to complications such as heart disease, kidney disease, blindness, and leg amputation. It has also been reported that if diabetic patients experience attacks such as myocardial infarction or angina, they are at higher risk of heart failure and subsequent death (Circulation R., 2020, Vol. 126, pp. 1501-1525).

[0063] As shown in FIG. 1(A), １８PET measurements using [F]BCPP-BF were able to detect cardiac dysfunction in diabetic rats at 5 and 26 weeks of age as a decline in mitochondrial function. At 26 weeks of age, blood glucose levels were 135.3±17.9 mg / dL in normal rats and 588.3±29.9 mg / dL in diabetic rats, indicating that the diabetic rats had reached a diabetic state with statistically significant elevated levels. Meanwhile, blood glucose levels at 5 weeks of age were 146.0±13.8 mg / dL in normal rats and 171.4±24.2 mg / dL in diabetic rats, tending to be slightly higher, but not statistically significantly different. This suggests that [ １８ These results indicate that PET measurements using [F]BCPP-BF can detect abnormalities in cardiac function due to diabetes at an extremely early stage.

[0064] On the other hand, as shown in FIG. １８ PET measurements using [F]FDG showed no significant difference compared to normal rats, even in 26-week-old diabetic rats that had reached a diabetic state showing statistically significant high values.

[0065] According to a previous study using the same rat model as in this test example, no differences were found in the morphological changes and fibrosis of hearts isolated and evaluated from 14-week-old normal and diabetic rats (Am. J. Physiol. Heart Circ. Physiol., 2007, Vol. 293, H292-H298), and no differences were found between normal and diabetic rats in the oxygen metabolism and ATP production rate from glucose evaluated in hearts isolated at 12 weeks of age (Am. J. Physiol. Heart Circ. Physiol., 2005, Vol. 288, H2102-H2110). Furthermore, no differences were observed between normal and diabetic rats in the heart rate measured in vivo at 14 weeks of age or in the metabolic rate of ATP transfer via creatine kinase (CK) (CK flux), a biochemical indicator of myocardial energy metabolism (Physiol. Rep., 2015, 3(1), e12248).

[0066] From these results, １８It has been found that evaluation of mitochondrial function by PET measurement using [F]BCPP-BF can detect diabetes-induced cardiac decline with high sensitivity and at an extremely early stage that cannot be detected by biochemical or morphological indicators.

[0067] Test Example 3: Evaluation of adverse cardiac effects associated with drug (acetaminophen) administration Acetaminophen (hereinafter also referred to as "APAP"), a representative antipyretic analgesic widely used around the world, was administered to normal rats to evaluate its effects (adverse effects) on cardiac function.

[0068] (PET Measurement) APAP was intravenously administered at 100 mg / kg or 300 mg / kg to rats via the tail vein. As a control, rats were prepared to which only the solvent was intravenously administered in the same manner. 24 hours after administration of APAP or the solvent, the rats were subjected to PET measurement. The PET measurement procedure was the same as in Test Example 2. In addition, as a control, [ １８ F]BCPP-BF instead of [ １８ Measurements were similarly carried out using [F]BMS.

[0069] (Results) Figure 2(A) shows the effect of [ １８ 2(B) is a graph showing the accumulation of [F]BCPP-BF (radioactivity accumulation (SUV)). １８ 2 is a graph showing the accumulation of [F]BMS (radioactivity accumulation (SUV)). In FIG. 2, "★" indicates that the difference from the data of control rats (rats administered with the vehicle) was statistically significant (p<0.05).

[0070] It has been reported that excessive administration of APAP causes acute liver dysfunction (Semin. Liver Dis., 2008, Vol. 28, pp. 142-152) and acute kidney dysfunction (J. Am. Soc. Nephrol., 1995, Vol. 6, pp. 48-53). １８ It has been shown that PET measurements using [F]BCPP-BF in rats can detect these disorders early (EJNMMI Res., 2016, Vol. 6, pp. 82, Japanese Patent Publication No. 7005126).

[0071] On the other hand, perhaps because the damage caused by excessive intake of APAP to liver and kidney function is so severe, its effect on cardiac function has been overlooked. １８ PET measurements using [F]BCPP-BF revealed that 24 hours after intravenous administration of 100 mg / kg and 300 mg / kg APAP, cardiac mitochondrial function was also significantly affected.

[0072] On the other hand, as shown in FIG. １８ PET measurements using [F]BMS failed to detect any significant differences in cardiac mitochondrial function 24 hours after APAP administration under the same conditions.

[0073] Previous studies have shown that intravenous administration of 125 mg / kg APAP caused a transient, significant increase in blood pressure two minutes after administration, but no significant difference was observed between the control and vehicle-treated group after three minutes. However, no significant effect on heart rate was observed (J. Cardiovasc. Pharmacol. Therapeut., 2003, Vol. 8, pp. 277-284). Increased expression of inflammation-related genes was observed in the hearts of rats isolated 24 hours after oral administration of a high dose of 1000 mg / kg APAP. However, the histological necrotic changes observed in the liver were not observed in the myocardium (Yonsei Med. J., 2012, Vol. 53, pp. 172-180).

[0074] From these results, １８ It has been found that the effects (side effects) of the drug (APAP) on cardiac function can be detected with extremely high sensitivity by evaluating mitochondrial function through PET measurements using [F]BCPP-BF.

[0075] Test Example 4: Evaluation of Cardiac Side Effects Associated with Drug (Doxorubicin) Administration Doxorubicin (hereinafter also referred to as "DOX") is an anticancer drug that inhibits DNA synthesis, suppresses cancer cell proliferation, and reduces tumor size (Med. Res. Rev., 2014, Vol. 34, pp. 106-135). While DOX is used to treat various cancers, including malignant lymphoma, lung cancer, gastrointestinal cancer, breast cancer, bladder tumors, and osteosarcoma, it is known to have side effects such as myocardial damage and heart failure, including shortness of breath, difficulty breathing, chest pain, leg swelling, and tachycardia. Therefore, it is contraindicated for patients with or a history of cardiac dysfunction. Therefore, a biomarker for early detection of DOX cardiotoxicity is needed. In this test example, DOX was administered to normal rats, and its effects on cardiac function (side effects) were evaluated.

[0076] (PET Measurement) 5 mg / kg or 20 mg / kg of DOX was intravenously administered to rats via the tail vein. As a control, rats were similarly intravenously administered with the solvent alone. The rats were subjected to PET measurement 0.5 hours, 24 hours, and 96 hours after administration of DOX or the solvent. The PET measurement procedure was the same as in Test Example 2.

[0077] (Results) Figure 3 shows the effect of [ １８ 3 is a graph showing the accumulated amount of [F]BCPP-BF (accumulated radioactivity (SUV)). In FIG. 3, "★" indicates that the difference from the data of control rats (rats administered with the vehicle) at the same time after administration was statistically significant (p<0.05).

[0078] As shown in Fig. 3, １８ PET measurements using [F]BCPP-BF demonstrated significant mitochondrial dysfunction in rats receiving a high dose (20 mg / kg) of DOX starting at 24 hours after administration, and also in rats receiving a low dose (5 mg / kg) of DOX starting at 96 hours after administration.

[0079] Previous studies have shown that 24 hours after intravenous administration of 20 mg / kg DOX, CK and troponin I (TnI), blood markers of myocardial dysfunction, failed to detect cardiac dysfunction (12). Furthermore, even after intravenous administration of a much higher dose (40 mg / kg) of DOX than ours, CK, TnI, lactate dehydrogenase (LDH), and fatty acid-binding protein 3 (FABP3) failed to detect cardiac dysfunction (PLoS ONE, 2012, Vol. 7, e38867). Furthermore, even after repeated weekly intravenous administration of 3 mg / kg DOX for 3 weeks, cardiac function (e.g., heart rate, cardiac output), TnI, LDH, and hyperpolarized [1- １３ C] pyruvic acid [2- １３ No changes in myocardial metabolism measured using [C]pyruvate could be detected (Commun. Biol., 2020, Vol. 3, pp. 692).

[0080] From these results, １８ It has been found that the effects (side effects) of the drug (DOX) on cardiac function can be detected with extremely high sensitivity by evaluating mitochondrial function through PET measurements using [F]BCPP-BF.

Claims

1. A diagnostic agent for cardiac function, which contains a compound represented by general formula (1-0) as an active ingredient. [In the general formula (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -, n is an integer of 1 to 5, Q １ is F or -OCH ３ indicates.] 2. An agent for evaluating side effects of drugs on the heart, which contains a compound represented by general formula (1-0) as an active ingredient. [In the general formula (1-0), R is —O(CH ２ ) ｎ -, -O(CH ２ ) ｎ O.C. ２ H ４ -, -CH ２ O (CH ２ ) ｎ - or -CH ２ O (CH ２ ) ｎ O.C. ２ H ４ -, n is an integer of 1 to 5, Q １ is F or -OCH ３ indicates.] 3. The agent according to claim 1 or 2, wherein the active ingredient is a compound represented by general formula (1-0'). [In the general formula (1-0′), R, n and Q １ represents R, n and Q in general formula (1-0). １ is equivalent to the above.] 4. The agent according to claim 1 or 2, wherein the active ingredient is a compound represented by general formula (1-0''). [In the general formula (1-0″), n and Q １ represents n and Q in general formula (1-0). １ is equivalent to the above.] 5. The agent according to claim 1 or 2, wherein the active ingredient is a compound represented by the following formula (1): [In formula (1), Q １ represents Q in general formula (1-0). １ is equivalent to the above.] 6. Q １ but １８ F or -O １１ CH ３ The agent according to claim 1 or 2,

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