TW202600178A - Diagnostic agents for cardiac function - Google Patents

Abstract

This invention is a diagnostic agent for cardiac function, which contains a compound represented by general formula (1-0) as its 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 from ₁ to ₅ , _and ^Q1 represents F or _-OCH3 ].

Description

Diagnostic agents for cardiac function

This invention relates to a diagnostic agent for cardiac function.

Positron emission tomography (PET) is being used in various diagnostic procedures. As a probe suitable for PET, for example, patent 1 discloses a compound suitable for detecting mitochondrial complex-1. [Prior Art Literature Patent Literature]

Patent Document 1: International Publication No. 2014/30709

[Problem to be solved by the invention] To date, there have been no reports from the industry of using the compound disclosed in Patent Document 1 for the diagnosis of cardiac function.

Previously, early detection methods for abnormal heart function involved electrocardiograms (ECGs) or blood biochemistry tests. However, ECG diagnosis requires an abnormality to occur during the measurement, leading to numerous omissions. In recent years, continuous monitoring using devices such as Holter monitors has become increasingly common. While convenient, these devices must be worn for over 24 hours, and the burden on patients from prolonged monitoring should not be overlooked. In blood biochemistry tests, following myocardial cell damage such as in myocardial infarction, enzymes such as creatine kinase (CK) and aspartate transaminase (AST) are released into the bloodstream approximately 24 hours after the onset of the disease, thus requiring precise localization testing. Furthermore, even in cases originating from skeletal muscle, the activity of these enzymes sometimes shows the same changes as in myocardial infarction, indicating problems with indicators of myocardial function abnormalities.

Regarding imaging diagnostics related to the heart, ultrasound, CT (Computed Tomography), and MRI (Magnetic Resonance Imaging) are the mainstream methods. However, these are all methods for assessing the morphology and movement of the myocardium, as well as the physical quantity of blood output. These assessment methods are suitable for measuring the worsening of symptoms in the late stages of the disease, but not for early detection.

In cardiac examinations based on nuclear medicine, such as PET _, ruthenium ( ^82Rb )-ammonia ([ ^13N ]NH3)-water ([ ¹⁵ ] _H2O ) is sometimes used. However, it mainly measures changes in myocardial blood flow distribution caused by myocardial ischemia, rather than measuring the biochemical function of the myocardium that is directly related to the diagnosis of the disease or the judgment of the treatment effect. Myocardial function examinations using PET also include the measurement of myocardial oxygen consumption using [ ^11C ]acetate. However, the half-life of ^11C is relatively short, only 20 minutes. Therefore, only PET facilities equipped with cyclotrons can be used, and thus it is not yet widespread. As a PET probe targeting the heart, [ ^18F ]FDG (Fluorodeoxyglucose) is used to confirm the viability of myocardial cells after myocardial infarction, or to examine cardiac sarcoma by utilizing the property of [ ^18F ]FDG which is easily distributed in inflammation. The tissue accumulation of [ ^18F ]FDG is affected by the blood glucose concentration, so fasting is required for one night before the examination. In addition, diabetic patients with high blood glucose concentration are difficult to be the subjects of the examination.

In view of the above, the purpose of this invention is to provide a diagnostic agent for cardiac function, which can highly sensitively diagnose changes in cardiac function. [Technical means to solve the problem]

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.

[Chemistry 1] In the general formula (1-0), R represents -O( _CH2 ) _n- , -O( _CH2 ) _nOC2H4- , -CH2O( _CH2 ) _{n- or -CH2O} ( _CH2 ) _nOC2H4- , _n represents an integer from ₁ to ₅ , and ^Q1 represents F or _{-OCH3 .}

Compound (1-0) is known to be used to detect mitochondrial complex-I (hereinafter also referred to as "MC-I"). The diagnostic agent for cardiac function of this invention accumulates in the heart, resulting in an accumulation amount proportional to the MC-I activity of the heart, thus enabling its effective use in the diagnosis of cardiac function. Furthermore, as shown in the embodiments described later, even without observed changes in biochemical or morphological indicators, the diagnostic agent for cardiac function of this invention can diagnose cardiac function based on the detection of MC-I activity. Therefore, the diagnostic agent of this invention can diagnose changes in cardiac function with high sensitivity. Furthermore, this also allows for the early diagnosis of changes in heart function.

In the above diagnostic reagent, ^Q1 can be ^18F or ^-O11CH3 . _This allows the compound to release positrons. The positrons released from the compound immediately combine with electrons to release gamma rays (annihilation radiation). By measuring these gamma rays using a device employed in positron emission tomography (PET), the compound accumulated in the heart can be quantified and imaged over time. That is, it can also be used as a marker compound in PET.

Furthermore, this invention can also be regarded as a diagnostic method for cardiac function, which includes: administering the above-mentioned diagnostic agent to the subject; detecting the compound (1-0) accumulated in the heart; and performing quantitative analysis on the amount of compound (1-0) accumulated in the heart.

Furthermore, the present invention can also be regarded as a compound represented by general formula (1-0) for the diagnosis of cardiac function. In addition, the present invention can also be regarded as the use of a compound represented by general formula (1-0) for the manufacture of a diagnostic agent for cardiac function.

The diagnostic agent of this invention can diagnose changes in cardiac function with high sensitivity, and therefore can also be used to evaluate the side effects of drugs on the heart. That is, the diagnostic agent of this invention can also be regarded as an evaluator of the side effects of drugs on the heart.

This invention includes, for example, the following inventions. [1] A diagnostic agent for cardiac function, comprising a compound represented by general formula (1-0) as an active ingredient. [Chemical 2] [In general formula (1-0), R represents -O( _CH2 ) _n- , -O( _CH2 ) _nOC2H4- , _-CH2O ( _CH2 ) _{n- or -CH2O} ( _CH2 ) _nOC2H4- , n represents an integer from ₁ to ₅ , and ^Q1 represents F or _-OCH3 ][2] An evaluator of the side effects of a drug on the heart, which contains a compound represented by general formula (1-0) as _an active ingredient. [Chemistry 3] [In general formula (1-0), R represents -O( _CH2 ) _n- , -O( _CH2 ) _nOC2H4- , _-CH2O ( _CH2 ) _{n- or -CH2O} ( _CH2 ) _nOC2H4- , n represents an integer from ₁ to ₅ , and ^Q1 represents F or -OCH3][ ₃ ] As described in [1] or [2], the above-mentioned active ingredient is a compound represented by general formula (1-0'). _[ Chemistry 4] [In general formula (1-0'), R, n, and ^Q1 are synonyms with R, n, and ^Q1 in general formula (1-0)][4] The agent described in any of [1] to [3], wherein the above-mentioned active ingredient is a compound represented by general formula (1-0''). [Chemistry 5] [In general formula (1-0''), n and ^Q1 are synonymous with n and ^Q1 in general formula (1-0)][5] The preparation described in any of [1] to [4], wherein the above-mentioned active ingredient is a compound represented by the following formula (1). [Chemistry 6] [In formula (1), ^Q1 is synonymous with ^Q1 in general formula (1-0)][6] An agent as described in any of [1] to [5], wherein ^Q1 is ^18F or -O ¹¹ _CH3 . [7] A method for diagnosing cardiac function in a subject, comprising: administering an agent as described in any of [1] to [6] to the subject; detecting the aforementioned active ingredient accumulated in the heart; and performing a quantitative analysis of the amount of the aforementioned active ingredient accumulated in the heart. [8] An assessment method for evaluating the side effects of a drug on the heart, comprising: administering the drug to a subject; administering the drug as described in any of [1] to [6] to a subject who has been given the drug; detecting the accumulation of the active ingredient in the heart; and performing a quantitative analysis of the accumulation of the active ingredient in the heart. [9] The drug as described in any of [1] to [6] is used to diagnose cardiac function. [10] The drug as described in any of [1] to [6] is used to assess the side effects of a drug on the heart. [11] The use of an active ingredient or preparation as described in any of [1] to [6] for the manufacture of a diagnostic agent for cardiac function. [12] The use of an active ingredient or preparation as described in any of [1] to [6] for the manufacture of an evaluator for the cardiac side effects of a drug. [Effects of the Invention]

According to the present invention, a diagnostic agent for cardiac function that can highly sensitively diagnose changes in cardiac function can be provided.

The following describes in detail the embodiments of the present invention. However, the present invention is not limited to the following embodiments.

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

[Chemistry 7]

In compound (1-0), R is -O( _CH2 ) _n- , -O( _{CH2 ) nOC2H4- , -CH2O(CH2)n-, or -CH2O(CH2)nOC2H4-. R is preferably -O(CH2)n- or -O ( CH2 ) nOC2H4- , and more preferably -O ( CH2 ) n- .}

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.

In compound (1-0), ^Q1 is F or _-OCH3 , preferably ^18F or ^-O11CH3 _. Compound (1-0) with ^Q1 _being ^18F or ^-O11CH3 releases a positive electron, making it suitable as a labeling compound (PET probe) for PET assays. Furthermore, when ^Q1 is ^-O11CH3 , the half-life is shorter at 20 minutes, allowing for multiple measurements within one day for the same subject. When ^Q1 is ^18F , the half-life is longer than _{that of} ^-O11CH3 at 110 minutes, thus extending the measurement interval.

There are no particular restrictions on the bonding positions of -OCH _2- with the pyridine ring and R, but it is preferred that the bonding position of -OCH _2- with the pyridine ring is at position 5 of the pyridine ring and the bonding position of R is at position 2 of the pyridine ring. The compound represented by the general formula (1-0') shown below (hereinafter also referred to as "compound (1-0')") is the structure when the bonding position of -OCH _2- with the pyridine ring is at position 5 of the pyridine ring and the bonding position of R is at position 2 of the pyridine ring.

[Chemistry 8]

In general formula (1-0'), R, n and Q ¹ are synonyms with R, n and Q ¹ in general formula (1-0).

For better suitability for the diagnostic use of cardiac function, compound (1-0) is preferably a compound represented by the 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)").

[Chemistry 9]

In general formula (1-0''), n and Q ¹ are synonyms with n and Q ¹ in general formula (1-0).

[Chemistry 10]

In equation (1), ^Q1 is synonymous with ^Q1 in general equation (1-0).

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

As a precursor to compound (1-0), for example, the compound represented by the following general formula (2-0) (hereinafter also referred to as "compound (2-0)"). As a precursor to compound (1-0'), compound (1-0'') and compound (1), for example, the following compound is an example in which the bonding positions of R, and the -OCH _2- bonded to the pyridine ring and R in compound (2-0) are the same as those in compound (1-0'), compound (1-0'') and compound (1).

[Chemistry 11]

In general formula (2-0), R is synonymous with R in general formula (1-0). ^Q2 represents a substituent that can be desorbed (substituent for sulfonyloxy, halogen atom, or hydroxyl group, etc.).

As a substituted sulfonyl group, examples include toluenesulfonyl (-OTs), methanesulfonyl (-OMs), trifluoromethanesulfonyl (-OTf), and nitrobenzenesulfonyl (-ONs), with -OTs being preferred.

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

Precursors can be synthesized, for example, by the method described in International Publication No. 2014/30709.

Because MC-1 specifically accumulates in the heart, the accumulation of compound (1-0) varies in relation to the degree of cardiac function. That is, if cardiac function declines, the accumulation of compound (1-0) decreases, and if cardiac function is hyperactive, the accumulation of compound (1-0) increases. Therefore, the diagnostic agent of this embodiment, by measuring the accumulation of compound (1-0), can be effectively used for the diagnosis of cardiac function. Decreased cardiac function may be accompanied by 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 assessment of cardiac function.

Regarding the diagnostic agent of this embodiment, it is used to diagnose cardiac function, for example, as a method for screening individuals with declining cardiac function (e.g., in group health checkups), a method for evaluating the side effects of medication on the heart, and a method for long-term observation of cardiac function (e.g., observing the development of symptoms causing cardiac dysfunction, confirming treatment effectiveness, or predicting prognosis). Therefore, the diagnostic agent for cardiac function in this embodiment can also be regarded as an evaluator of the side effects of medication on the heart and an evaluator of the treatment effectiveness of symptoms causing cardiac dysfunction.

The determination of the accumulation of compound (1-0) is not limited to this. For example, it can be performed by binding compound (1-0) with fluorescent pigments, or by labeling it with single-photon nuclei ( ^123I , ^99mTc , etc.) or positron-emitting nuclei, and then detecting the label. Positron labeling can be performed, for example, by setting ^Q1 of compound (1-0) to -O ¹¹ CH ₃ or ¹⁸ F. In the case of positron labeling, the intracellular distribution of compound (1-0) can be quantified and visualized over time by measuring annihilation radiation using a device used in PET.

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 contain other components such as surfactants, preservatives, and stabilizers in addition to the buffering components.

The diagnostic method for cardiac function according to this embodiment includes: administering the diagnostic agent of this invention to a subject; detecting the compound (1-0) accumulated in the heart; and performing quantitative analysis on the amount of compound (1-0) accumulated in the heart.

The method for assessing the cardiac side effects of the drug in this embodiment includes the procedure of administering the drug to a subject. Except that the subject in the above diagnostic method is considered to have already been administered the drug, the procedure can be performed in the same manner as the above diagnostic method. The drug can be any drug.

Examples of subjects include, for example, humans, monkeys, mice and rats, but are not limited to these.

Once the compound (1-0) reaches the heart, there are no particular restrictions on the method of administering the diagnostic agent to the recipient; it is usually administered intravenously.

Regarding the dosage of the diagnostic agent, there are no particular restrictions as long as it is sufficient to detect the cardiac test compound (1-0). The dosage can be appropriately set according to the recipient and the method of detecting the compound (1-0). For example, when using a diagnostic agent containing a compound (1-0) with Q ¹ being ^18F or -O ¹¹ CH ₃ , and detecting the compound (1-0) using a device used in PET, the dosage of the diagnostic agent (hereinafter also referred to as the "radioactive dose") can be from 1 MBq/kg body weight to 1000 MBq/kg body weight. The specific radioactivity of the compound (1-0) can be from 10 to 10,000 GBq/μmol. Furthermore, the dose of radioactivity administered depends on the sensitivity of the PET camera used and the size of the individual. For rodents (mice and rats), 0.1–0.5 mL of physiological saline is administered to a dose of approximately 200–500 MBq/kg body weight. In the case of primates other than humans (monkeys), 0.5–2 mL of physiological saline is administered to a dose of 40–200 MBq/kg body weight. In the case of humans, 1–5 mL of physiological saline is administered to a dose of 2–10 MBq/kg body weight.

There are no particular limitations on the detection methods for compounds (1-0) that accumulate in the heart, and they can be performed according to known methods. For example, when using a diagnostic agent containing a compound (1-0) with Q ¹ being ^18F or -O ¹¹ CH ₃ , the compound (1-0) can be detected by PET. There are no particular limitations on the measurement methods in PET, and they can be performed according to known methods. Furthermore, for example, as a method for measurement using PET, dynamic measurement can be performed for 60 minutes immediately after the diagnostic agent is administered, or PET measurement can be performed for 10 to 20 minutes after administering the diagnostic agent and waiting 30 to 40 minutes to allow the compound (1-0) to accumulate sufficiently in the heart.

There are no particular limitations on the method for quantitative analysis of the accumulation of compounds (1-0) in the heart, and well-known methods can be used. For example, the following method can be used: First, the accumulation image of compounds (1-0) obtained by PET scan is superimposed with the morphological image of the heart obtained by CT measurement, etc., to identify the PET image of the heart. Second, a target area is set on the PET image of the heart, and the normalization is performed according to the individual's body weight and the amount of radioactivity administered. The resulting value is set as the accumulation amount of compounds (1-0) in the heart. Alternatively, images obtained by PET scan using a probe capable of detecting the heart can be used instead of the morphological image of the heart.

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

The baseline value can be appropriately set according to the diagnostic purpose. For example, when implementing this diagnostic method in a group health checkup, the baseline value can be a pre-determined normal range based on the distribution of the accumulation amounts of compounds (1-0) in multiple similar subjects. In this case, whether the cardiac function of a specific subject is normal can be diagnosed by whether the quantitative analysis value of the accumulation amount in that specific subject is within that normal range.

Furthermore, for example, when implementing the diagnostic method of this implementation method to observe the development of the symptoms, confirm the treatment effect, or predict the prognosis for subjects suffering from symptoms that cause cardiac dysfunction (e.g., diabetes, lipid metabolism disorders, myocardial infarction, cardiac sarcoma, etc.), the benchmark value may be the measurement result of the accumulation of compound (1-0) at a certain time point of the subject (e.g., when healthy, at the time of initial diagnosis, at the start of treatment, at the end of treatment, etc.).

Furthermore, for example, when using the diagnostic method of this implementation in assessing the cardiac side effects of a drug, the benchmark value can be the measured accumulation of compound (1-0) in the subject before administration of the drug. In this case, if the quantitative analysis value of the accumulation in the subject who has already taken the drug is less than the benchmark value, it can be determined that the drug has cardiac side effects. [Example]

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

[Experimental Example 1: Synthesis of PET Probe] The [ ^18F ]BCPP-BF represented by the following formula was synthesized by the method described in the non-patented literature (J. Labelled Comp. Radiopharm., 2013, Vol. 56, No. 11, pp. 553-561). The radiochemical purity of the obtained final product was above 99%, and the specific radioactivity was 43.8–103.9 GBq/μmol. [Chem. 12]

Furthermore, as a comparison, [ ^18F ]BMS-747158-02 (2-tributyl-4-chloro-5-[4-(2-fluoro-ethoxymethyl)benzyloxy]-2H-terad-3-one: hereinafter referred to as [ ^18F ]BMS) is prepared as a known PET probe for identifying mitochondrial Complex-1, ^{and 18F} -fluorodeoxyglucose ([ ^18F ]FDG) is known as a PET probe for the heart. The radiochemical purity of [ ^18F ]BMS is ≥99%, and its specific radioactivity is 36.3 to 76.1 GBq/μmol. The radiochemical purity of [ ^18F ]FDG is ≥99%.

[Experiment Example 2: Evaluation of Cardiac Function in Type 2 Diabetic Model Rats] (Type 2 Diabetic Model Rats) Male Zucker Lepr ^fa /Lepr ^fa rats (hereinafter, also referred to as "diabetic rats") exhibiting a condition similar to that of human adults with type 2 diabetes were purchased from Charles River Co., Ltd., Japan, and were subjected to PET measurements at 5 and 26 weeks of age. As a control, male Zucker Lepr ^fa /+ rats (hereinafter, also referred to as "normal rats") were purchased from Charles River Co., Ltd., Japan.

(PET Measurement) Rats were anesthetized with isoflurane and fixed in the frame of an animal PET camera (SHR-38000, manufactured by Hamamatsu Photonics Co., Ltd.). After 15 minutes of transmission measurement for absorption correction, approximately 20 MBq/0.5 mL of [ ^18F ]BCPP-BF was injected into the rat's caudal vein, followed by 60 minutes of emission measurement. A target area was set in the heart, and the accumulation of [ ^18F ]BCPP-BF in the target area was calculated. Then, the calculated accumulation was normalized according to the individual's body weight and the dose of radioactivity administered, and set as the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive accumulation (SUV)). As a control, the amount of [ ^18F ]FDG in the heart (radioactive accumulation (SUV)) was measured in the same manner, except that [ ^18F ]FDG was used instead of [ ^18F ]BCPP-BF.

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

(Results) Figure 1(A) is a chart showing the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive accumulation (SUV)). Figure 1(B) is a chart showing the accumulation of [ ^18F ]FDG in the heart (radioactive accumulation (SUV)). Figure 1(B) is the result obtained using 26-week-old rats. In Figure 1, " "" indicates that the difference between the data of normal rats and diabetic rats of the same age is statistically significant (p < 0.05).

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. Furthermore, 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).

As shown in Figure 1(A), cardiac dysfunction in diabetic rats was successfully detected by PET measurement using [ ^18F ]BCPP-BF, specifically a decline in mitochondrial function at 5 and 26 weeks of age. At 26 weeks of age, the serum glucose concentration was 135.3 ± 17.9 mg/dL in normal rats and 588.3 ± 29.9 mg/dL in diabetic rats, indicating a statistically significant high level of diabetes. On the other hand, at 5 weeks of age, the serum glucose concentration was 146.0 ± 13.8 mg/dL in normal rats and 171.4 ± 24.2 mg/dL in diabetic rats, showing a slightly higher tendency, but not a statistically significant difference. This indicates that PET measurements using [ ^18F ]BCPP-BF can detect diabetic cardiac dysfunction at a very early stage.

On the other hand, as shown in Figure 1(B), in PET measurements using [ ^18F ]FDG, no significant difference was detected relative to normal rats in 26-week-old diabetic rats that reached statistically significant high values for diabetic status.

Based on previous studies using the same rat model as in this experiment, no differences were found in morphological changes and fibrosis in the hearts of normal and diabetic rats that were removed and evaluated at 14 weeks of age (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 in the ATP production rates from oxygen metabolism and glucose between normal and diabetic rats (Am. J. Physiol. Heart Circ. Physiol., 2005, Vol. 288, H2102-H2110). Furthermore, no difference was found between normal rats and diabetic rats in terms of heart rate at 14 weeks of age as measured in vivo and in terms of creatine kinase (CK)-mediated ATP transfer rate (CK flux), a biochemical indicator of myocardial energy metabolism (Physiol. Rep., 2015, 3(1), e12248).

Based on these results, it can be seen that mitochondrial function can be evaluated by using PET measurements with [ ^18F ]BCPP-BF, thereby enabling the detection of cardiac function decline caused by diabetes at a very early stage that cannot be detected by biochemical or morphological indicators with extremely high sensitivity.

[Experiment Example 3: Evaluation of Cardiac Side Effects of Administration of the Drug (Acetaminophen)] Acetaminophen (hereinafter also referred to as "APAP"), a representative antipyretic analgesic widely used worldwide, was administered to normal rats to evaluate its effects on cardiac function (side effects).

(PET Measurement) 100 mg/kg or 300 mg/kg of APAP was administered intravenously via the tail vein of rats. As a control group, rats were administered the solvent intravenously only in the same manner. Twenty-four hours after administration of APAP or solvent, the rats were subjected to PET measurement. The procedure for PET measurement was the same as in Experiment 2. As a control, [ ^18F ]BMS was used instead of [ ^18F ]BCPP-BF, and the measurement was performed in the same manner.

(Results) Figure 2(A) is a chart showing the amount of [ ^18F ]BCPP-BF in the heart (radioactive accumulation (SUV)). Figure 2(B) is a chart showing the amount of [ ^18F ]BMS in the heart (radioactive accumulation (SUV)). In Figure 2, " "" indicates that the difference in data between the rats and the control group (rats given the solvent) was statistically significant (p < 0.05).

Reports indicate that excessive administration 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). Previous studies by the inventors have shown that these diseases can be detected at an early stage in PET measurements using rats with [ ^18F ]BCPP-BF (EJNMMI Res., 2016, Vol. 6, pp. 82, Japanese Patent No. 7005126).

On the other hand, the effects of excessive APAP intake on cardiac function have been overlooked, perhaps because of the excessive damage to liver or kidney function. As shown in Figure 2(A), it was found that intravenous administration of 100 mg/kg and 300 mg/kg APAP for 24 hours after administration via PET with BCPP-BF [ ^18F ] also had a significant effect on cardiac mitochondrial function.

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

According to previous 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 administration group. On the other hand, no effect was observed 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 orally administered a high dose of 1000 mg/kg APAP and excised 24 hours later, but no histological necrosis observed in the liver was seen in the myocardium (Yonsei Med.J., 2012, Vol. 53, pp. 172-180).

Based on these results, it can be seen that using PET measurements with [ ^18F ]BCPP-BF to assess mitochondrial function can provide highly sensitive detection of the effects (side effects) of medications (APAPs) on cardiac function.

[Experiment Example 4: Evaluation of Cardiac Side Effects of Doxorubicin Administration] Doxorubicin (hereinafter, also known as "DOX") is an anticancer agent that inhibits DNA synthesis and thus inhibits the increase of cancer cells, thereby shrinking tumors (Med. Res. Rev., 2014, Vol. 34, pp. 106-135). Although DOX is used to treat various cancers such as malignant lymphoma, lung cancer, digestive system cancer, breast cancer, bladder tumors, and osteosarcoma, it is known to have side effects such as shortness of breath, dyspnea, chest pain, leg swelling, tachycardia, myocardial damage, and heart failure. Therefore, it is contraindicated in patients with abnormal cardiac function or a history of such conditions. The industry is seeking biomarkers for detecting the cardiotoxicity of DOX at an early stage. In this study, DOX was administered to normal rats to assess its effects on cardiac function (side effects).

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

(Results) Figure 3 is a chart showing the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive accumulation (SUV)). In Figure 3, " "" indicates that the difference in data between rats in the control group (rats that were given the solvent) and rats in the same time group after administration was statistically significant (p < 0.05).

As shown in Figure 3, a significant decrease in mitochondrial function was detected in high-dose (20 mg/kg) rats 24 hours after DOX administration, measured by PET with [ ^18F ]BCPP-BF. A similar significant decrease in mitochondrial function was also detected in low-dose (5 mg/kg) rats 96 hours after DOX administration.

According to previous studies, no cardiac dysfunction was detected 24 hours after intravenous administration of 20 mg/kg DOX, based on CK-tachycardia protein I (TnI), a blood marker of myocardial abnormalities (12). Furthermore, even after intravenous administration of a high dose (40 mg/kg) of DOX, which is much higher than our usual dosage, no cardiac dysfunction was detected 24 hours later based on CK, TnI, lactate dehydrogenase (LDH), or fatty acid-binding protein 3 (FABP3) (PLoS ONE, 2012, Vol. 7, e38867). Furthermore, even after repeated intravenous administration of 3 mg/kg DOX for 3 weeks, no changes in cardiac function such as heart rate and cardiac output, nor changes in myocardial metabolism measured by the use of TnI, LDH, and hyperpolarized [ ^1-13C ]pyruvate and [ ^2-13C ]pyruvate could be detected (Commun. Biol., 2020, Vol. 3, pp. 692).

Based on these results, it can be seen that using PET measurements with [ ^18F ]BCPP-BF to assess mitochondrial function can provide highly sensitive detection of the effects (side effects) of drugs (DOX) on cardiac function.

Figure 1(A) is a chart showing the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive uptake value (SUV)). Figure 1(B) is a chart showing the accumulation of [ ^18F ]FDG in the heart (radioactive uptake value (SUV)). Figure 2(A) is a chart showing the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive uptake value (SUV)). Figure 2(B) is a chart showing the accumulation of [ ^18F ]BMS in the heart (radioactive uptake value (SUV)). Figure 3 is a chart showing the accumulation of [ ^18F ]BCPP-BF in the heart (radioactive uptake value (SUV)).

Claims (6)

A diagnostic agent for cardiac function, comprising a compound represented by general formula (1-0) as its active ingredient, [Chemistry 1] [In general formula (1-0), R represents -O( _CH2 ) _n- , -O( _CH2 )nOC2H4-, _-CH2O ( _CH2 ) _{n- or -CH2O} ( _{CH2 ) nOC2H4-} , n represents an integer from ₁ to ₅ , _and ^Q1 represents F or _-OCH3 ]. An evaluator of the cardiac side effects of a drug containing a compound represented by general formula (1-0) as its active ingredient, [Chemistry 2] [In general formula (1-0), R represents -O( _CH2 ) _n- , -O( _CH2 )nOC2H4-, _-CH2O ( _CH2 ) _{n- or -CH2O} ( _CH2 ) _{nOC2H4- ,} n represents an integer from ₁ to ₅ , _and ^Q1 represents F or _-OCH3 ]. For example, in the preparation of claim 1 or 2, the aforementioned active ingredient is a compound represented by general formula (1-0'), [Chemical 3] [In general formula (1-0'), R, n and ^Q1 are synonyms with R, n and ^Q1 in general formula (1-0).] For example, in the preparation of item 1 or 2, the aforementioned active ingredient is a compound represented by the general formula (1-0''), [Chemistry 4] [In general formula (1-0''), n and ^Q1 are synonyms with n and ^Q1 in general formula (1-0).] For the preparations requested in item 1 or 2, wherein the aforementioned active ingredient is a compound represented by formula (1) below, [Chemical 5] [In formula (1), ^Q1 is synonymous with ^Q1 in general formula (1-0).] If the agent is requested in item 1 or 2, where ^Q1 is ^18F or -O ¹¹ _CH3 .