Diagnostic agent for cardiac function

Abstract

The present application relates to a diagnostic agent for cardiac function, which contains a compound represented by general formula (1-0) as an effective ingredient. [In general formula (1-0), R represents -O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n - or -CH2O(CH2) n OC2H4-, n represents an integer of 1 to 5, and Q 1 represents F or -OCH3].

Description

Technical Field

[0001] This invention relates to a diagnostic agent for cardiac function. Background Technology

[0002] Positron emission tomography (PET) is being used in various diagnostic procedures. For example, Patent Document 1 discloses a compound suitable for detecting mitochondrial Complex-1, which can be used as a probe in PET.

[0003] Existing technical documents

[0004] Patent documents

[0005] Patent Document 1: International Publication No. 2014 / 30709 Summary of the Invention

[0006] The technical problem that the invention aims to solve

[0007] There have been no reports of the compounds disclosed in Patent Document 1 being used for diagnostic purposes of cardiac function.

[0008] Previously, early detection of cardiac dysfunction relied on electrocardiograms (ECG) or blood biochemistry tests. However, ECG diagnosis requires abnormal cardiac activity to occur during the measurement period, leading to significant omissions. In recent years, continuous monitoring using devices like Holter monitors has become more common. While convenient, the need for continuous monitoring for over 24 hours places a considerable burden on patients. In blood biochemistry tests, enzymes such as creatine kinase (CK) and aspartate aminotransferase (AST) are released into the bloodstream within approximately 24 hours of the onset of symptoms due to myocardial cell damage, requiring precise localization. Furthermore, even in symptoms originating from skeletal muscle, these enzyme activities sometimes exhibit similar changes to those seen in myocardial infarction, raising concerns about their effectiveness as indicators of myocardial dysfunction.

[0009] Regarding imaging diagnosis related to the heart, ultrasound, CT, and MRI are the mainstream methods. However, these are all methods for evaluating the morphology and movement of the myocardium and the physical quantity of blood output. Therefore, although they are suitable for measuring the symptom development in the late stage of the disease, they are not suitable for evaluation methods for early detection.

[0010] In cardiac examinations based on nuclear medicine, such as PET scans, rubidium (BN) is sometimes used. 82 Rb)-ammonia([ 13 N]NH3)-water([ 15]H2O), but mainly measures changes in myocardial blood flow distribution caused by myocardial ischemia, rather than measuring myocardial biochemical functions directly related to disease diagnosis or treatment effectiveness. PET myocardial function testing also has its uses. 11 C] Measurement of myocardial oxygen consumption by acetate, etc., but 11 C has a short half-life of only 20 minutes, therefore it can only be used in PET facilities equipped with cyclotrons, and thus is not yet widely available. As a PET probe targeting the heart, [ 18 F]FDG is used to confirm the viability of cardiomyocytes after myocardial infarction, or to utilize [F]FDG which is easily distributed in inflammation. 18 The properties of FDG are used for the examination of cardiac sarcoidosis. 18 The tissue aggregation of FDG is affected by the blood glucose concentration. Therefore, fasting for one night is required before the test. In addition, diabetic patients with high blood glucose concentration are unlikely to be candidates for the test.

[0011] In view of the above, the object of the present invention is to provide a cardiac function diagnostic agent that can diagnose changes in cardiac function with good sensitivity.

[0012] Technical means for solving technical problems

[0013] This 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.

[0014] In the general formula (1-0), R represents -O(CH2). n -、-O(CH2) n OC2H4-、-CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, where n represents an integer from 1 to 5, and Q 1 It represents F or -OCH3.

[0015] Compounds (1-0) are known to be used to detect mitochondrial complex-I (hereinafter also referred to as "MC-I"). The cardiac function diagnostic agent of the present invention accumulates in the heart, further becoming an aggregate proportional to the MC-I activity of the heart, thus making it suitable for diagnostic purposes of cardiac function. Furthermore, as shown in the examples described later, even without observing changes in biochemical or morphological indicators, the cardiac function diagnostic agent of the present invention can diagnose cardiac function based on the detection of MC-I activity. Therefore, the diagnostic agent of the present invention can diagnose changes in cardiac function with good sensitivity. In addition, it is also possible to diagnose changes in cardiac function at an early stage.

[0016] Of the diagnostic agents mentioned above, Q 1 It can also be 18 F or -O 11 CH3. Thus, the above compound can release positrons. The positrons released from the above compound immediately combine with electrons to release gamma rays (annihilation radiation). By measuring these gamma rays using the apparatus used in positron emission tomography (PET), the above compound accumulated in the heart can be quantified and imaged over time. That is, it can also be used as a labeling compound in PET.

[0017] Alternatively, the present invention can also be regarded as a diagnostic method for cardiac function, which includes: a step of administering the above-mentioned diagnostic agent to a subject; a step of detecting the compound (1-0) accumulated in the heart; and a step of quantitatively analyzing the amount of compound (1-0) accumulated in the heart.

[0018] Furthermore, the present invention can also be considered as the use of the compound represented by general formula (1-0) for the diagnosis of cardiac function. Additionally, the present invention can also be considered as the use of the compound represented by general formula (1-0) in the manufacture of diagnostic agents for cardiac function.

[0019] The diagnostic reagent of the present invention can diagnose changes in cardiac function with good sensitivity, and therefore can also be used to evaluate the side effects of drugs on the heart. That is, the diagnostic reagent of the present invention can also be regarded as an evaluator of the side effects of drugs on the heart.

[0020] This invention includes, for example, the following inventions.

[0021] [1] A diagnostic agent for cardiac function, which contains a compound represented by the general formula (1-0) as an active ingredient. In general formula (1-0), R represents -O(CH2). n -、-O(CH2) n OC2H4-、-CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, where n represents an integer from 1 to 5, and Q 1 This indicates F or -OCH3.

[0022] [2] An evaluation agent for the cardiac side effects of a drug, which 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) n OC2H4-, where n represents an integer from 1 to 5, and Q 1 This indicates F or -OCH3.

[0023] [3] As described in [1] or [2], wherein the active ingredient is a compound represented by the general formula (1-0'). In general formula (1-0'), R, n, and Q 1 With respect to R, n, and Q in general formula (1-0) 1 Same meaning.

[0024] [4] An agent as described in any of [1] to [3], wherein the active ingredient is a compound represented by the general formula (1-0''). In the general formula (1-0''), n and Q 1 With respect to n and Q in general formula (1-0) 1 Same meaning.

[0025] [5] An agent as described in any of [1] to [4], wherein the active ingredient is a compound represented by the following formula (1). In equation (1), Q 1 Q in general formula (1-0) 1 Same meaning.

[0026] [6] The agent described in any of [1] to [5], wherein Q 1 for 18 F or -O 11 CH3.

[0027] [7] A method for diagnosing cardiac function in an individual, comprising: A process of administering the agent described in any one of [1] to a subject; a process of detecting the active ingredient accumulated in the heart; and a process of quantitatively analyzing the amount of the active ingredient accumulated in the heart.

[0028] [8] An evaluation method for evaluating the side effects of a drug on the heart, comprising: The process of administering the drug to a subject; A process of administering the drug to a subject to which the agent has been administered according to any of [1] to [6]; a process of detecting the active ingredient accumulated in the heart; and a process of quantitatively analyzing the amount of the active ingredient accumulated in the heart.

[0029] [9] The agent described in any of [1] to [6] for the diagnosis of cardiac function.

[0030]

[10] The agent described in any of [1] to [6] used to evaluate the cardiac side effects of the agent.

[0031]

[11] Use of any of the active ingredients or agents described in [1] to [6] in the manufacture of diagnostic agents for cardiac function.

[0032]

[12] Use of any of the active ingredients or agents described in [1] to [6] in the manufacture of an evaluation agent for the cardiac side effects of a pharmaceutical agent.

[0033] The effects of the invention

[0034] According to the present invention, a diagnostic agent for cardiac function that can sensitively diagnose changes in cardiac function can be provided. Attached Figure Description

[0035] Figure 1 (A) represents [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Figure 1 (B) means [ 18 A graph of the amount of F]FDG accumulated in the heart (radioactive accumulation (SUV)).

[0036] Figure 2 (A) represents [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Figure 2 (B) means [ 18 F]BMS graph of the amount of radioactive accumulation (SUV) in the heart.

[0037] Figure 3 It means [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Detailed Implementation

[0038] The following describes in detail the methods of implementing the present invention. However, the present invention is not limited to the following embodiments.

[0039] The diagnostic agent for cardiac function in this embodiment (hereinafter also simply referred to as the "diagnostic agent") contains a compound represented by general formula (1-0) as its active ingredient. Furthermore, unless otherwise specified, each atom in this specification includes all isotopes.

[0040] In compound (1-0), R is -O(CH2). n -、-O(CH2) n OC2H4-、-CH2O(CH2) n -or -CH2O(CH2) n OC2H4-. R is preferably -O(CH2). n -or -O(CH2) n OC2H4-, more preferably -O(CH2) n -

[0041] In compound (1-0), n is an integer from 1 to 5, preferably an integer from 2 to 5, more preferably an integer from 3 to 5, and even more preferably 4.

[0042] In compound (1-0), Q 1 It is F or -OCH3, preferably. 18 F or -O 11 CH3. Q 1 for 18 F or -O 11 Compounds of CH3 (1-0) can release positrons, making them suitable as labeling compounds (PET probes) for PET methods. Additionally, in Q... 1 -O 11 In the case of CH3, the half-life is short, at 20 minutes; therefore, multiple measurements can be taken within one day for the same subject. In Q... 1 for 18 In the case of F, the half-life is greater than that of -O. 11 The CH3 time is 110 minutes, therefore, the measurement time can be extended by one time.

[0043] There are no particular restrictions on the bonding positions of -OCH2- with the pyridazine ring and R, but preferably the -OCH2- with the pyridazine ring is at position 5 of the pyridazine ring and R is at position 2 of the pyridazine ring. The compound represented by the general formula (1-0') shown below (hereinafter also referred to as "compound (1-0')") is the structural formula when the -OCH2- with the pyridazine ring is at position 5 of the pyridazine ring and R is at position 2 of the pyridazine ring.

[0044] In the general formula (1-0'), R, n and Q 1 With respect to R, n, and Q in general formula (1-0) 1 Same meaning.

[0045] For diagnostic purposes more suitable for cardiac function, 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)").

[0046] In the general formula (1-0''), n and Q 1 With respect to n and Q in general formula (1-0) 1 Same meaning.

[0047] In equation (1), Q 1 Q in general formula (1-0) 1 Same meaning.

[0048] Compound (1-0) can be synthesized, for example, from its corresponding precursor. The same applies to compounds (1-0'), (1-0''), and (1).

[0049] As precursors to compound (1-0), for example, compounds represented by the following general formula (2-0) (hereinafter also referred to as "compound (2-0)"). As precursors to compounds (1-0'), (1-0'') and (1), for example, compounds in which the bonding positions of R, and -OCH2- bonded to the pyridazine ring in the pyridine ring, and the bonding positions of R are the same as those in compounds (1-0'), (1-0'') and (1).

[0050] In general formula (2-0), R has the same meaning as R in general formula (1-0). Q 2 This indicates a substituent that can be removed (such as a sulfonyloxy group, halogen atom, or hydroxyl group).

[0051] As alternative sulfonyloxy groups, examples include p-toluenesulfonyloxy (-OTs), methanesulfonyloxy (-OMs), trifluoromethanesulfonyloxy (-OTf), and nitrobenzenesulfonyloxy (-ONs), with -OTs being preferred.

[0052] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

[0053] The precursor can be synthesized, for example, by the method described in International Publication No. 2014 / 30709.

[0054] Because MC-1 specifically accumulates in the heart, the amount of compound (1-0) accumulated changes in relation to the degree of cardiac function. That is, if cardiac function declines, the amount of compound (1-0) accumulated decreases, and if cardiac function is hyperactive, the amount of compound (1-0) accumulated increases. Therefore, the diagnostic agent of this embodiment, by measuring the amount of compound (1-0) accumulated, can be applied to the diagnosis of cardiac function. Decreased cardiac function may be accompanied by, for example, diseases, injuries, or dysfunctions of the heart (e.g., myocardium, cardiovascular system). Furthermore, the diagnosis of cardiac function can also be referred to as the evaluation of cardiac function.

[0055] Regarding the diagnostic agent of this embodiment, it can be used to diagnose cardiac function, for example, in methods for screening individuals with decreased cardiac function (e.g., group health checkups), in methods for evaluating the side effects of drugs on the heart, and in methods for observing cardiac function over time (e.g., observing the development of symptoms causing cardiac dysfunction, confirming treatment effectiveness, or predicting prognosis). Therefore, the diagnostic agent for cardiac function of this embodiment can also be considered, for example, as an evaluator of the side effects of drugs on the heart and an evaluator of the treatment effect of symptoms causing cardiac dysfunction.

[0056] The determination of the aggregation amount of compound (1-0) is not limited to this; for example, it can be achieved by binding compound (1-0) with fluorescent dyes, or by using single-photon nuclides (…). 123 I, 99m Labeled compounds are created by labeling compounds with positron-emitting electrons (such as Tc) or positron-emitting nuclides, and the labeling is performed by detecting the label. Positron labeling, for example, can be achieved by labeling the Q of a compound (1-0). 1 Set to -O 11 CH3 or 18 F is used. With positron labeling, the in vivo distribution of compound (1-0) can be quantified and time-lapsed imaged by measuring annihilation radiation using the apparatus used in PET.

[0057] The diagnostic reagent of this embodiment can be manufactured, for example, by dissolving compound (1-0) in any buffer solution. In this case, the diagnostic reagent of this embodiment is provided in solution form and may also contain other components such as surfactants, preservatives, and stabilizers in addition to the buffer component.

[0058] The diagnostic method for cardiac function according to this embodiment includes: a step of administering the diagnostic agent of the present invention to a subject; a step of detecting compounds (1-0) accumulated in the heart; and a step of quantitatively analyzing the amount of compounds (1-0) accumulated in the heart.

[0059] The method for evaluating the cardiac side effects of the drug in this embodiment includes a step of administering the drug to a subject. Except that the subject in the above-described diagnostic method is defined as a subject who has already been given the drug, it can be implemented in the same manner as the above-described diagnostic method. The drug can be any drug.

[0060] As objects, examples could include people, monkeys, mice, and rats, but are not limited to these.

[0061] There are no particular restrictions on the method of administering the diagnostic agent to the subject, provided that the compound (1-0) reaches the heart; intravenous administration is usually preferred.

[0062] Regarding the dosage of diagnostic reagents, there are no particular restrictions as long as the dosage is sufficient for detecting compound (1-0) in the heart. The dosage can be appropriately set according to the target population and the method for detecting compound (1-0). For example, when using reagents containing Q... 1 for 18 F or -O 11 When using a diagnostic reagent for compound (1-0) of CH3 and detecting compound (1-0) using a device employed in PET scanning, the dosage of the diagnostic reagent (hereinafter also referred to as "dosage radioactivity") can range from 1 MBq / kg body weight to 1000 MBq / kg body weight. The specific radioactivity of compound (1-0) can range from 10 to 10,000 GBq / μmol. Furthermore, the dosage radioactivity of the diagnostic reagent depends on the sensitivity of the PET camera used and the size of the individual. For rodents (mice, rats), approximately 200 to 500 MBq / kg body weight is administered in the form of 0.1 to 0.5 mL of physiological saline solution. In the case of primates other than humans (monkeys), 40 to 200 MBq / kg body weight is administered in 0.5 to 2 mL of physiological saline solution, and in the case of humans, 2 to 10 MBq / kg body weight is administered in 1 to 5 mL of physiological saline solution.

[0063] There are no particular limitations on the method for detecting compounds (1-0) that accumulate in the heart; they can be performed according to well-known methods. For example, using methods containing Q... 1 for 18 F or -O 11 In the case of a diagnostic reagent for compound (1-0) of CH3, compound (1-0) can be detected by PET. There are no particular limitations on the measurement method in PET, and it can be performed according to known methods. Alternatively, as a method for measurement using PET, dynamic measurement can be performed for 60 minutes immediately after administration of the diagnostic reagent, or PET measurement can be performed for 10-20 minutes after waiting 30-40 minutes after administration of the diagnostic reagent to allow compound (1-0) to accumulate sufficiently in the heart.

[0064] There are no particular limitations on the method for quantitatively analyzing the accumulation amount of compound (1-0) in the heart, and it can be performed according to known methods. For example, the following method can be used. First, an image of the accumulation of compound (1-0) obtained by PET is overlaid with a morphological image of the heart obtained by CT measurement or the like to identify the PET image of the heart. Next, a region of interest is defined on the PET image of the heart, and the image is normalized according to the weight of the individual and the radioactivity of the administered drug. The resulting value is taken as the accumulation amount of compound (1-0) in the heart. Alternatively, an image obtained by PET using a probe that can detect the heart can be used instead of a morphological image of the heart.

[0065] The diagnostic method of this embodiment may further include: a step of diagnosing cardiac function by comparing the aggregate amount of the quantitatively analyzed compound (1-0) with a reference value.

[0066] The baseline value can be appropriately set according to the diagnostic purpose. For example, when implementing the diagnostic method of this embodiment in a group health check, the baseline value can be a normal range predetermined based on the distribution of the aggregation amount of compounds (1-0) in multiple similar subjects. In this case, whether the cardiac function of a specific subject is normal can be diagnosed based on whether the quantitative analysis value of the aggregation amount in that specific subject falls within this normal range.

[0067] Additionally, for example, in subjects suffering from symptoms that cause cardiac dysfunction (e.g., diabetes, lipid metabolism disorders, myocardial infarction, cardiac sarcoidosis, etc.), when implementing the diagnostic method of this embodiment to observe the development of the symptoms, confirm the treatment effect, or predict the prognosis, the benchmark value can be the measurement result of the amount of compound (1-0) aggregated at a certain moment in the subject's life (e.g., when healthy, at the time of initial diagnosis, at the start of treatment, at the end of treatment, etc.).

[0068] Furthermore, for example, when implementing the diagnostic method of this embodiment in evaluating the cardiac side effects of the drug, the baseline value can be the measurement result of the amount of compound (1-0) aggregated in the subject before taking the drug. In this case, if the quantitative analysis value of the amount of aggregated compound (1-0) in the subject who has taken the drug is less than the baseline value, it can be determined that the drug has cardiac side effects.

[0069] Example

[0070] The present invention will now be described in more detail with reference to embodiments. However, the present invention is not limited thereto.

[0071] [Experimental Example 1: Synthesis of PET Probe]

[0072] The following formula represents [ 18F]BCPP-BF was synthesized using the method described in non-patent literature (J. Labelled Comp. Radiopharm., 2013, Vol. 56, No. 11, pp. 553-561). The final product obtained had a radiochemical purity of over 99% and a specific radioactivity of 43.8–103.9 GBq / μmol.

[0073] Additionally, as a control, a PET probe known for identifying mitochondria, Complex-1, was prepared. 18 F]BMS-747158-02(2-tert-butyl-4-chloro-5-[4-(2-fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazine-3-one: Hereinafter referred to as [ 18 F]BMS), known as a PET probe targeting the heart. 18 F-fluorodeoxyglucose ([ 18 F]FDG). [ 18 The radiochemical purity of F]BMS is above 99%, and its radioactivity is 36.3–76.1 GBq / μmol. 18 The radiochemical purity of F]FDG is over 99%.

[0074] [Experiment 2: Evaluation of cardiac function in a type 2 diabetic rat model]

[0075] (Type 2 diabetes model rats)

[0076] Purchased from Charles River Japan, Inc. a male Zucker Lepr exhibiting symptoms similar to those of type 2 diabetes in adults. fa / Lepr fa Rats (hereinafter also referred to as "diabetic rats") were used for PET measurements at 5 weeks and 26 weeks of age. As a control, male Zucker Lepr rats were purchased from Charles River Japan, Inc. fa / + rats (hereinafter also referred to as "normal rats") were used.

[0077] (PET Measurement)

[0078] Rats were anesthetized with isoflurane and fixed in the support of an animal PET camera (SHR-38000, manufactured by Hamamatsu Photonics Co., Ltd.). After 15 minutes of transmittance measurement for absorption correction, approximately 20 MBq / 0.5 mL of [[] was administered via the rat's tail vein. 18 F]BCPP-BF was administered, and emission measurements were performed for 60 minutes. The area of ​​interest was set at the heart, and [...]. 18The accumulation amount of BCPP-BF in the region of interest. Next, the calculated accumulation amount was normalized according to the individual's body weight and the administered radioactivity, denoted as [F]. 18 [F] BCPP-BF accumulation in the heart (radioactive accumulation (SUV)). As a control, in addition to using [ 18 F]FDG to replace [ 18 In addition to F]BCPP-BF, it was determined in the same manner. 18 The amount of F]FDG accumulated in the heart (radioactive accumulation (SUV)).

[0079] (Determination of blood glucose concentration)

[0080] Blood was collected from rats immediately after PET measurement to determine blood glucose concentration. Blood glucose concentration was determined using an automated biochemical analyzer (Hitachi High-Tech Corporation 7180).

[0081] (result)

[0082] Figure 1 (A) represents [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Figure 1 (B) means [ 18 A graph of the amount of F]FDG accumulated in the heart (radioactive accumulation (SUV)). Figure 1 (B) is the result obtained using 26-week-old rats. Figure 1 middle," "This indicates that the difference between the data of normal rats and diabetic rats of the same age was statistically significant (p < 0.05).

[0083] According to reports, if a person has diabetes and their blood sugar levels remain high, their blood vessels will be damaged, making them more susceptible to complications such as heart disease, kidney disease, blindness, and amputation. In addition, if a diabetic patient experiences a myocardial infarction or angina, the risk of heart failure and subsequent death increases (Circulation R., 2020, Vol. 126, pp. 1501-1525).

[0084] like Figure 1 As shown in (A), by using [ 18PET measurements using [F]BCPP-BF detected cardiac dysfunction in diabetic rats at 5 and 26 weeks of age in the form of decreased mitochondrial function. Regarding serum glucose concentration at 26 weeks of age, normal rats had a concentration of 135.3 ± 17.9 mg / dL, while diabetic rats had a concentration of 588.3 ± 29.9 mg / dL, indicating a statistically significantly elevated diabetic state. On the other hand, regarding serum glucose concentration at 5 weeks of age, normal rats had a concentration of 146.0 ± 13.8 mg / dL, while diabetic rats had a concentration of 171.4 ± 24.2 mg / dL, showing a slightly higher tendency, but not a statistically significant difference. This suggests that by using [F]BCPP-BF, [the following analysis was performed]. 18 PET measurements of F]BCPP-BF can detect diabetic cardiac dysfunction at a very early stage.

[0085] On the other hand, such as Figure 1 As shown in (B), [[] was used 18 In PET measurements of F]FDG, no significant difference was detected relative to normal rats in 26-week-old diabetic rats that reached a statistically significant high value for diabetes.

[0086] Based on prior studies using the same rat model as in this study, no differences were found in the morphological changes and fibrosis of the hearts removed and evaluated from 14-week-old normal and diabetic rats (Am. J. Physiol. Heart Circ. Physiol., 2007, Vol. 293, H292-H298). In the evaluation of hearts removed at 12 weeks of age, no differences were found between normal and diabetic rats in terms of ATP production from oxygen metabolism and glucose (Am. J. Physiol. Heart Circ. Physiol., 2005, Vol. 288, H2102-H2110). Furthermore, no differences were found between normal and diabetic rats in heart rate at 14 weeks of age as measured in vivo, or in the metabolic rate of ATP transfer via creatine kinase (CK) flux, a biochemical indicator of myocardial energy metabolism (Physiol. Rep., 2015, 3(1), e12248).

[0087] Based on these results, it can be concluded that by utilizing [ 18 PET measurements of F]BCPP-BF can be used to evaluate mitochondrial function, and can detect the decline in cardiac function caused by diabetes at a very early stage when biochemical and morphological indicators cannot be detected, with excellent sensitivity.

[0088] [Experimental Example 3: Evaluation of Cardiac Side Effects from Concomitant Drug Administration (Acetaminophen)]

[0089] The effects on cardiac function (side effects) of acetaminophen (hereinafter also referred to as "APAP"), a representative antipyretic analgesic widely used in the world, were evaluated in normal rats.

[0090] (PET Measurement)

[0091] APAP was administered intravenously at a dose of 100 mg / kg or 300 mg / kg via the tail vein of rats. As a control, rats were administered the solvent intravenously only in the same manner. Twenty-four hours after administration of APAP or the solvent, the rats were subjected to PET measurements. The procedure for PET measurements was the same as in Experiment 2. Additionally, as a control, […]. 18 F]BMS to replace [ 18 F]BCPP-BF was determined in the same manner.

[0092] (result)

[0093] Figure 2 (A) represents [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Figure 2 (B) means [ 18 F]BMS graph of the amount of radioactive accumulation (SUV) in the heart. Figure 2 middle," "" indicates that the difference in data between the rats and the control rats (rats given the solvent) was statistically significant (p < 0.05).

[0094] Reports indicate that overdose of APAP can cause acute liver dysfunction (Semin. Liver Dis., 2008, Vol. 28, pp. 142-152) or acute kidney dysfunction (J. Am. Soc. Nephrol., 1995, Vol. 6, pp. 48-53). Prior studies by the inventors have shown that when using […] 18 These impairments were detected at an early stage in PET measurements of rats with F]BCPP-BF (EJNMMI Res., 2016, Vol. 6, pp. 82, Japanese Patent No. 7005126).

[0095] On the other hand, the impact of excessive APAP intake on cardiac function has been largely overlooked, perhaps because it may cause excessive damage to liver or kidney function. Figure 2 As shown in (A), it was found that: by using [ 18PET measurements of F]BCPP-BF showed that intravenous administration of 100 mg / kg and 300 mg / kg APAP 24 hours later also had a significant effect on cardiac mitochondrial function.

[0096] On the other hand, such as Figure 2 As shown in (B), when using [ 18 In PET measurements by F]BMS, no significant difference was detected in cardiac mitochondrial function 24 hours after APAP administration under the same conditions.

[0097] According to prior studies, intravenous administration of 125 mg / kg APAP resulted in a transient and significant increase in blood pressure after 2 minutes, but after 3 minutes, no significant difference was observed compared to the solvent-administered group. On the other hand, no effect was found on heart rate (J. Cardiovasc. Pharmacol. Therapeut., 2003, Vol. 8, pp. 277-284). Increased expression of inflammation-related genes was confirmed in the hearts of rats that were orally administered a high dose of 1000 mg / kg APAP and removed 24 hours later, but no histological necrosis observed in the liver was found in the myocardium (Yonsei Med. J., 2012, Vol. 53, pp. 172-180).

[0098] Based on these results, it can be concluded that by utilizing [ 18 PET measurements of F]BCPP-BF are used to evaluate mitochondrial function and can detect the effects (side effects) of drugs (APAP) on cardiac function with extremely high sensitivity.

[0099] [Example 4: Evaluation of cardiac side effects from comorbidity (doxorubicin) administration]

[0100] Doxorubicin (hereinafter, also known as "DOX") is an anticancer agent that inhibits DNA synthesis and thus suppresses the growth of cancer cells, thereby shrinking tumors (Med. Res. Rev., 2014, Vol. 34, pp. 106-135). Although 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 shortness of breath, dyspnea, chest pain, leg edema, and tachycardia, which can lead to myocardial damage and heart failure. Therefore, it is contraindicated in patients with abnormal cardiac function or a history of such conditions. This study sought biomarkers to detect the cardiotoxicity of DOX in its early stages. In this experimental case, DOX was administered to normal rats to evaluate its effects on cardiac function (side effects).

[0101] (PET Measurement)

[0102] DOX was administered intravenously at a dose of 5 mg / kg or 20 mg / kg via the tail vein of rats. As a control, rats were administered the solution intravenously only in the same manner. Rats were subjected to PET measurements 0.5 hours, 24 hours, and 96 hours after DOX or solution administration. The PET measurement procedure was the same as in Experiment 2.

[0103] (result)

[0104] Figure 3 It means [ 18 A graph showing the amount of BCPP-BF accumulated in the heart (radioactive accumulation (SUV)). Figure 3 middle," "This indicates that the differences in data between rats that were administered the solvent and control rats at the same time after administration were statistically significant (p < 0.05).

[0105] like Figure 3 As shown, by using [ 18 PET measurements of F]BCPP-BF showed a significant decrease in mitochondrial function in high-dose (20 mg / kg) rats 24 hours after DOX administration. Additionally, a significant decrease in mitochondrial function was also detected in low-dose (5 mg / kg) rats 96 hours after DOX administration.

[0106] According to prior studies, 24 hours after intravenous administration of 20 mg / kg DOX, no abnormalities in cardiac function were detected by CK-troponin I (TnI), a blood marker of myocardial abnormalities (12). Furthermore, even after intravenous administration of a much higher dose (40 mg / kg) of DOX 24 hours prior, no abnormalities in cardiac function were detected by CK, TnI, lactate dehydrogenase (LDH), or fatty acid-binding protein 3 (FABP3) (PLoS ONE, 2012, Vol. 7, e38867). Moreover, even after repeated intravenous administration of 3 mg / kg DOX weekly for 3 weeks, no changes in cardiac function such as heart rate or cardiac output, or changes in TnI, LDH, or further hyperpolarization were detected [1-]. 13 [C]Pyruvic acid, [2- 13 [C] Changes in myocardial metabolism as measured by pyruvate (Commun.Biol., 2020, Vol. 3, pp. 692).

[0107] Based on these results, it can be concluded that by utilizing [ 18PET measurements of F]BCPP-BF are used to evaluate mitochondrial function and can detect the effects (side effects) of drugs (DOX) on cardiac function with extremely high sensitivity.

Claims

1. A diagnostic agent for cardiac function, wherein, It contains compounds represented by the general formula (1-0) as active ingredients. In the general formula (1-0), R represents -O(CH2). n -、-O(CH2) n OC2H4-、-CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, where n represents an integer from 1 to 5, and Q 1 It represents F or -OCH3.

2. An evaluation agent for the cardiac side effects of a drug, wherein, It contains compounds represented by the general formula (1-0) as active ingredients. In the general formula (1-0), R represents -O(CH2). n -、-O(CH2) n OC2H4-、-CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, where n represents an integer from 1 to 5, and Q 1 It represents F or -OCH3.

3. The agent as described in claim 1 or 2, wherein, The active ingredient is a compound represented by the general formula (1-0'). In the general formula (1-0'), R, n and Q 1 With respect to R, n, and Q in general formula (1-0) 1 Same meaning.

4. The agent as described in claim 1 or 2, wherein, The active ingredient is a compound represented by the general formula (1-0''). In the general formula (1-0''), n and Q 1 With respect to n and Q in general formula (1-0) 1 Same meaning.

5. The agent as described in claim 1 or 2, wherein, The active ingredient is a compound represented by the following formula (1). In equation (1), Q 1 Q in general formula (1-0) 1 Same meaning.

6. The agent as described in claim 1 or 2, wherein, Q 1 for 18 F or -O 11 CH3.

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