Diagnostic agent for ovarian function

Abstract

To provide a new diagnostic agent for ovarian function capable of diagnosing the functional change of ovary.SOLUTION: A diagnostic agent for ovarian function comprising 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) nOC2H4 -, - CH2O (CH2) n -, or - CH2O (CH2) nOC2H4 -, n represents an integer of 1 to 5, and Q1 represents F or -. OCH3. ] SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a diagnostic agent for ovarian function. [Background technology]

[0002] Positron emission tomography (PET) has been 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. Furthermore, Patent Document 2 discloses the use of the compound described in Patent Document 1 for diagnosing liver and kidney function. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2014 / 30709 [Patent Document 2] Patent No. 7005126 Summary of the Invention [Problem to be solved by the invention]

[0004] The use of the compound disclosed in Patent Document 1 for diagnosing ovarian function has not been reported to date. The ovaries are reproductive organs unique to women, and their function declines with age, making them the organ most clearly affected by aging in the form of menopause. The timing of menopause has been shown to affect lifespan, and early detection of ovarian aging, i.e., a decline in ovarian function, is useful not only for reproductive problems such as infertility, but also for maintaining overall health.

[0005] Here, anti-Mullerian hormone (hereinafter also referred to as "AMH"), an index of ovarian function, is commonly used to evaluate ovarian function. AMH is a hormone produced by granulosa cells in the follicles of the ovaries, and measuring AMH in the blood makes it possible to qualitatively evaluate ovarian reserve (the number of follicles in the ovaries, which decreases with age). Meanwhile, ovarian function is composed of "number (ovarian reserve)" and "quality (essential ovarian functions; egg production and ovulation, etc.)," ​​but measuring AMH in the blood does not allow evaluation of the quality aspect of ovarian function.

[0006] One method for evaluating the intrinsic function of the ovaries is to evaluate fibrosis using ovarian tissue specimens. Ovarian fibrosis is known to correlate with the intrinsic function of the ovaries, and the more ovarian function declines, the more ovarian fibrosis increases. However, because fibrosis evaluation using ovarian tissue specimens is performed on surgically removed ovarian tissue and is highly invasive, it cannot be used to evaluate ovarian function in general clinical practice.

[0007] In view of the above circumstances, an object of the present invention is to provide a novel diagnostic agent for ovarian function that can diagnose changes in ovarian function. [Means for solving the problem]

[0008] The present invention relates to a diagnostic agent for ovarian function, which contains a compound represented by general formula (1-0) (hereinafter also referred to as "compound (1-0)") as an active ingredient.

[0009] [ka] In the general formula (1-0), R is —O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, n is an integer of 1 to 5, and Q 1 indicates F or -OCH3.

[0010] 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 ovarian function according to the present invention accumulates in the ovaries, and the amount of accumulation reflects the MC-I activity in the ovaries, and is therefore suitable for use in diagnosing ovarian function. Furthermore, as shown in the Examples below, the diagnostic agent for ovarian function according to the present invention can diagnose ovarian function based on the detection of MC-I activity even when no changes are observed in indicators such as blood AMH. Therefore, the diagnostic agent according to the present invention can also diagnose changes in ovarian function at an early stage.

[0011] The above diagnostic agent is Q 1 but 18 F or -O 11 The compound may be CH3. 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 a device used in positron emission tomography (PET), the compound accumulating in the ovaries can be imaged quantitatively and over time. In other words, the compound can also be used as a labeled compound for PET.

[0012] The diagnostic agent for ovarian function according to the present invention accumulates in the ovaries, and the amount of accumulation is proportional to the ovarian fibrosis, making it suitable for use in evaluating ovarian fibrosis. Ovarian fibrosis is known to correlate with essential ovarian functions (egg development and ovulation, etc.), and even when no change is observed in the blood AMH indicator, ovarian function can be evaluated from the perspective of quality based on ovarian fibrosis. Therefore, the diagnostic agent according to the present invention can also be considered an agent for evaluating ovarian fibrosis, and can also non-invasively diagnose changes in ovarian function from the perspective of quality.

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

[0014] The present invention can also be considered as a compound represented by general formula (1-0) for use in diagnosing ovarian function or evaluating ovarian fibrosis. The present invention can also be considered as use of a compound represented by general formula (1-0) in the manufacture of an agent for diagnosing ovarian function or an agent for evaluating ovarian fibrosis.

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

[0016] The present invention includes, for example, the following inventions. [1] A diagnostic agent for ovarian function, comprising a compound represented by general formula (1-0) as an active ingredient. [ka] [In the general formula (1-0), R is —O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, n is an integer of 1 to 5, and Q 1 represents F or -OCH3. [2] An agent for evaluating ovarian fibrosis, comprising a compound represented by general formula (1-0) as an active ingredient. [ka] [In the general formula (1-0), R is —O(CH2) n -, -O(CH2)n OC2H4-, -CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, n is an integer of 1 to 5, and Q 1 represents F or -OCH3. [3] An agent for evaluating the effects or side effects of a drug on the ovaries, which comprises a compound represented by general formula (1-0) as an active ingredient. [ka] [In the general formula (1-0), R is —O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n -or -CH2O(CH2) n OC2H4-, n is an integer of 1 to 5, and Q 1 represents F or -OCH3. [4] The agent according to any one of [1] to [3], wherein the active ingredient is a compound represented by general formula (1-0'). [ka] [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.] [5] The agent according to any one of [1] to [4], wherein the active ingredient is a compound represented by general formula (1-0″). [ka] [In the general formula (1-0″), n and Q 1 represents n and Q in general formula (1-0). 1 is equivalent to.] [6] The agent according to any one of [1] to [5], wherein the active ingredient is a compound represented by the following formula (1): [ka] [In formula (1), Q 1 is Q in general formula (1-0) 1 is equivalent to.] [7] Q 1 but 18 F or -O 11 The agent according to any one of [1] to [6], wherein the agent is CH3. [8] 1. A method for diagnosing ovarian function in a subject, comprising: A diagnostic method comprising the steps of: administering the agent according to any one of [1] to [7] to a subject; detecting the active ingredient accumulated in the ovaries; and quantitatively analyzing the amount of the active ingredient accumulated in the ovaries. [9] 1. A method for assessing ovarian fibrosis in a subject, comprising: An evaluation method comprising the steps of: administering the agent according to any one of [1] to [7] to a subject; detecting the active ingredient accumulated in the ovaries; and quantitatively analyzing the amount of the active ingredient accumulated in the ovaries.

[10] A method for evaluating an effect or side effect of a drug on an ovary, comprising: administering the agent to a subject; An evaluation method comprising the steps of: administering the agent according to any one of [1] to [7] to a subject who has received the agent; detecting the active ingredient accumulated in the ovaries; and quantitatively analyzing the amount of the active ingredient accumulated in the ovaries.

[11] The agent according to any one of [1] to [7], which is used for diagnosing ovarian function.

[12] The agent according to any one of [1] to [7], for use in evaluating ovarian fibrosis.

[13] The agent according to any one of [1] to [7], which is used to evaluate the effect or side effect of a drug on the ovaries.

[14] Use of the active ingredient or agent according to any one of [1] to [7] in the manufacture of a diagnostic agent for ovarian function.

[15] Use of the active ingredient or agent according to any one of [1] to [7] in the manufacture of an agent for evaluating ovarian fibrosis.

[16] Use of an active ingredient or agent according to any one of [1] to [7] in the manufacture of an agent for evaluating the action or side effect of a drug on the ovaries. [Effects of the Invention]

[0017] According to the present invention, a novel diagnostic agent for ovarian function that can diagnose changes in ovarian function can be provided. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a graph showing the amount of [ 18 F]BCPP-EF accumulated in the ovaries of aged rats (radioactivity accumulated value (SUV)). [Figure 2] 1 is a graph showing the effect of administration of the mitochondrial function improving drug mitoquinone (hereinafter also referred to as "MitoQ") on the accumulation of [18F]BCPP-EF (radioactivity accumulation dose (SUV)) in the ovaries of aged rats. [Figure 3] 1 is a graph showing the area of ​​ovarian fibrosis in young, aged, and MitoQ-treated aged rats. [Figure 4] 1 is a graph showing the correlation between the amount of [ 18 F]BCPP-EF accumulation (SUV) and the ovarian fibrosis area (%). [Figure 5] 1 is a graph showing plasma AMH concentrations in young, aged, and MitoQ-treated aged rats. DETAILED DESCRIPTION OF THE INVENTION

[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 ovarian 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] [ka]

[0022] In compound (1-0), R is -O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n -or -CH2O(CH2) n OC2H4-. R is -O(CH2) n - or -O(CH2) n Preferably it is OC2H4-, and -O(CH2) n - is more preferable.

[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 -OCH3, 18 F or -O 11 Preferably CH3. Q 1 but 18 F or -O 11 Compound (1-0) which is CH3 can emit positrons and is therefore suitable as a labeled compound (PET probe) for use in the PET method. 1 -O 11 In the case of CH3, 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 min and -O 11 Since it is longer than CH3, it is possible to extend the measurement time for each measurement.

[0025] The bonding position of -OCH2- bonded to the pyridazine ring and the bonding position of R on the pyridine ring are not particularly limited, but it is preferable that -OCH2- bonded to the pyridazine ring is bonded to the 5-position of the pyridine ring and that R is bonded to 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 a structural formula when -OCH2- bonded to the pyridazine ring is bonded to the 5-position of the pyridine ring and that R is bonded to the 2-position of the pyridine ring.

[0026] [ka]

[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 it is more suitable for use in diagnosing ovarian function.

[0029] [ka]

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

[0031] [ka]

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

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

[0034] An example of a corresponding precursor of 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 compound (1-0'), compound (1-0"), and compound (1) is a compound in which R, the bonding position of -OCH2- bonded to the pyridazine ring in the pyridine ring, and the bonding position of R in compound (2-0) are the same as those in compound (1-0'), compound (1-0"), and compound (1).

[0035] [ka]

[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] Compound (1-0) accumulates in the ovaries in an MC-1-specific manner, and the amount of accumulation changes in correlation with the level of ovarian function. That is, when ovarian function declines, the amount of accumulation of compound (1-0) increases, and when ovarian function increases, the amount of accumulation of compound (1-0) decreases. Therefore, the diagnostic agent according to this embodiment is suitably used for diagnosing ovarian function through measuring the amount of accumulation of compound (1-0). Decrease in ovarian function may be associated with, for example, ovarian disease, disorder, dysfunction, etc. Diagnosis of ovarian function can also be referred to as evaluation of ovarian function.

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

[0042] Furthermore, the accumulation amount of compound (1-0) changes in correlation with ovarian fibrosis. That is, as ovarian fibrosis increases, the accumulation amount of compound (1-0) increases, and as ovarian fibrosis decreases, the accumulation amount of compound (1-0) decreases. Therefore, the diagnostic agent according to this embodiment is suitable for use in evaluating ovarian fibrosis through measurement of the accumulation amount of compound (1-0).

[0043] The amount of accumulation of compound (1-0) can be measured by, but not limited to, binding a fluorescent dye or the like to 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-containing nuclide to prepare a labeled compound, and then detecting the label. 1 -O 11 CH3 or 18F. When positron-labeled, the biodistribution of compound (1-0) can be quantitatively and time-dependently imaged by measuring the annihilation radiation using a device used in PET.

[0044] 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.

[0045] The method for diagnosing ovarian 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 ovary, and quantitatively analyzing the amount of compound (1-0) accumulated in the ovary.

[0046] The method for evaluating ovarian fibrosis 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 ovary, and quantitatively analyzing the amount of compound (1-0) accumulated in the ovary.

[0047] The method for evaluating the effect or side effect of a drug on the ovaries 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.

[0048] Examples of subjects include, but are not limited to, humans, monkeys, mice, and rats.

[0049] The method for administering the diagnostic agent to a subject is not particularly limited as long as compound (1-0) reaches the ovary, but is usually administered intravenously.

[0050] The dose of the diagnostic agent is not particularly limited as long as it is sufficient to detect compound (1-0) in the ovaries, and may be appropriately determined depending on the subject to which it is administered and the method for detecting compound (1-0). For example,1 but 18 F or -O 11 When a diagnostic agent containing compound (1-0), which is CH3, is used to detect compound (1-0) using a device used in PET, 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. For rodents (mice and rats), the administered radioactivity is approximately 200 to 500 MBq / kg body weight administered in 0.1 to 0.5 mL of saline solution. For non-human primates (monkeys), the administered radioactivity is 40 to 200 MBq / kg body weight administered in 0.5 to 2 mL of saline solution. For humans, the administered radioactivity is 2 to 10 MBq / kg body weight administered in 1 to 5 mL of saline solution.

[0051] The method for detecting compound (1-0) accumulated in the ovary is not particularly limited, and can be carried out according to a known method. For example, 1 but 18 F or -O 11 When a diagnostic agent containing compound (1-0) which is CH3 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 be performed by dynamic measurement for 60 minutes immediately after administration of the diagnostic agent, or by waiting 30 to 40 minutes after administration of the diagnostic agent to allow sufficient accumulation of compound (1-0) in the ovaries, followed by PET measurement for 10 to 20 minutes.

[0052] The method for quantitatively analyzing the accumulation of compound (1-0) in the ovaries 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 PET is superimposed on a morphological image of the ovaries obtained by CT measurement or the like to identify the PET image of the ovaries. Next, a region of interest is set on the PET image of the ovaries, 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 ovaries. Alternatively, an image obtained by PET using a probe capable of detecting the ovaries may be used instead of the morphological image of the ovaries.

[0053] The diagnostic method and the method for evaluating ovarian fibrosis 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 ovarian function.

[0054] The reference value may be appropriately set 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 ovarian function of a specific subject is normal or not can be diagnosed depending on whether the quantitative analysis value of the accumulation amount in the specific subject falls within the normal range.

[0055] Furthermore, for example, when the diagnostic method or the method for evaluating ovarian fibrosis according to the present embodiment is performed on a subject suffering from a condition that causes ovarian dysfunction 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.).

[0056] Furthermore, for example, when the diagnostic method according to this embodiment is carried out to evaluate the effect or side effect of a drug on the ovaries, 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 changes from the reference value, it can be determined that the drug has an effect or side effect on the ovaries. [Example]

[0057] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples.

[0058] Test Example 1: Synthesis of PET probe Represented by the following formula: 18 [F]BCPP-EF was synthesized according to the method described in the Examples of WO 2014 / 030709. The radiochemical purity of the final product obtained was 99% or more, and the specific activity was 54.2 GBq / μmol. [ka]

[0059] Test Example 2: Evaluation of ovarian function in Wistar rats (Wistar rats) Female Wistar rats were purchased from Japan SLC, and 3-month-old female Wistar rats (hereinafter also referred to as "young rats") and 13-month-old female Wistar rats (hereinafter also referred to as "old rats") were subjected to PET measurements to measure the ovarian [ 18 The amount of F]BCPP-EF accumulated was measured.

[0060] (PET measurement) The rats were anesthetized with isoflurane and fixed in the gantry of an animal PET camera (SHR-38000, Hamamatsu Photonics Co., Ltd.). After 15 minutes of transmission measurement for attenuation correction, approximately 5 MBq / 0.5 mL of [ 18After administration of [F]BCPP-EF, emission measurements were performed for 60 minutes. A region of interest was set in the ovary, and [F]BCPP-EF was measured. 18 The amount of F]BCPP-EF accumulated was then calculated. The calculated amount of accumulation was then normalized by the body weight and the amount of radioactivity administered for each individual, and the amount of [F]BCPP-EF accumulated in the ovaries was calculated. 18 The amount of accumulated F]BCPP-EF (radioactivity accumulated unit value (SUV)) was measured.

[0061] (result) Figure 1 shows the results of the transfection of each rat ovary. 18 1 is a graph showing the accumulation of [F]BCPP-EF (radioactivity accumulation (SUV)). As shown in FIG. 1, the accumulation of [F]BCPP-EF in the ovaries of aged rats was significantly higher than that in the ovaries of young rats. 18 The accumulation of [F]BCPP-EF in the ovaries was significantly increased (young rats: 0.96±0.09, aged rats: 1.27±0.22). These results suggest that in aged rats with reduced ovarian function, [F]BCPP-EF accumulation in the ovaries was significantly increased (young rats: 0.96±0.09, aged rats: 1.27±0.22). 18 It was shown that the accumulation of [F]BCPP-EF increased.

[0062] Test Example 3: Evaluation of ovarian function following administration of mitochondrial function improving drug (MitoQ) It has been reported that ovarian function can be restored by MitoQ, a drug that improves mitochondrial function (Sci Adv. 2022 Jun 17;8(24)).

[0063] (PET measurement) Aged rats were orally administered 5 mg / kg of MitoQ for one week. As a control, the elderly rats were orally administered only the solvent (distilled water) for one week. After administration of MitoQ or the solvent, the rats were subjected to PET measurements to determine the effect of MitoQ on the ovaries. 18 The accumulation of [F]BCPP-EF was measured. 18 The procedure for measuring the amount of accumulated [F]BCPP-EF was the same as in Test Example 2.

[0064] (result) Figure 2 shows the results of the [ 182 is a graph showing the accumulation of [F]BCPP-EF (radioactivity accumulation (SUV)). As shown in Figure 2, SUV in the ovaries was significantly reduced in MitoQ-administered aged rats (hereinafter also referred to as "MitoQ-administered aged rats") (vehicle administration: 1.27 ± 0.22, MitoQ administration: 0.87 ± 0.13). The use of an ovarian function improving drug reduces [ 18 It was shown that the accumulation of [F]BCPP-EF was similar to that in young fish.

[0065] Test Example 4: 18 F]Evaluation of the correlation between BCPP-EF accumulation and ovarian fibrosis As in Test Example 3, young rats, aged rats, and MitoQ-administered aged rats were prepared, and Picro Sirius Red-stained tissue specimens were prepared from the ovaries of each rat, and ovarian fibrosis was evaluated by image processing.

[0066] (Method for assessing ovarian fibrosis) Image data of the Picro Sirius Red-stained ovarian specimen was designated image data 1, and image areas corresponding to follicles were excluded from image data 1 to obtain image data 2. Image data 2 was then divided into RGB data, and the green image was subtracted from the red image and binarized to obtain image data 3. Image data 2 and 3 were used to calculate the ratio of the fibrotic area (number of pixels obtained by binarization) to the total area (total number of pixels) of the region of interest, and the fibrotic area of ​​the ovary for each rat was determined.

[0067] (result) Figure 3 is a graph showing the fibrotic area of ​​each rat ovary. Figure 4 shows the area of ​​fibrosis in each rat ovary obtained from Figures 1, 2, and 3. 18 Fig. 3 shows the correlation between the accumulation level (SUV) of [F]BCPP-EF and the ovarian fibrosis area (%). As shown in Fig. 3, ovarian fibrosis was significantly increased in aged rats compared to young rats, and was suppressed by MitoQ, a drug that improves mitochondrial function (Fig. 3; ovarian fibrosis area (%); young rats: 17.1±5.6, aged rats: 34.6±4.0, MitoQ-treated aged rats: 16.9±2.6). In addition, [18 When the correlation between the accumulation level (SUV) of [F]BCPP-EF and the fibrotic area (%) of the ovaries was examined, a clear correlation was confirmed as shown in Figure 4 ([ 18 Correlation between the accumulation level (SUV) of [F]BCPP-EF and the ovarian fibrosis area (%): R = 0.74). 18 It was shown that changes in the accumulation of [F]BCPP-EF correlated with ovarian fibrosis.

[0068] [Reference example: Evaluation of ovarian function by measuring plasma AMH concentration] Plasma AMH concentrations were measured and compared in young rats, aged rats, and MitoQ-treated aged rats.

[0069] (Measurement of plasma AMH concentration) Young rats, aged rats, and MitoQ-administered aged rats were prepared in the same manner as in Test Examples 2 to 4, and blood was collected from each rat. The collected blood was centrifuged to obtain plasma. The AMH concentration in the plasma of each rat was measured by ELISA using an anti-AMH antibody (using a rat AMH-ELISA kit manufactured by Elabscience).

[0070] (result) Figure 5 is a graph showing the plasma AMH concentration of each rat. As shown in Figure 5, when the plasma AMH concentrations of young rats, aged rats, and MitoQ-administered aged rats were compared, no significant differences were observed in any of the groups (young rats: 3.36 ± 0.39, aged rats: 3.03 ± 0.19, MitoQ-administered aged rats: 3.23 ± 0.19). 18 F]BCPP-EF has been shown to be able to evaluate ovarian function prior to AMH concentration, a conventional index for non-invasive evaluation of the ovaries. Furthermore, AMH only evaluates the number of reserve follicles remaining in the ovaries, whereas [F]BCPP-EF can evaluate the amount of [F]BCPP-EF to the ovaries. 18 The accumulation of [F]BCPP-EF correlated with ovarian fibrosis, which is an indicator of the ovarian's essential function of growing and releasing follicles, demonstrating that it is possible to non-invasively evaluate the essential function of the ovary.

Claims

1. A diagnostic agent for ovarian function, comprising a compound represented by general formula (1-0) as an active ingredient. 【Chemistry 1】 [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 ovarian fibrosis, comprising a compound represented by general formula (1-0) as an active ingredient. 【Chemistry 2】 [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. An agent for evaluating the action or side effect of a drug on the ovaries, which comprises a compound represented by general formula (1-0) as an active ingredient. 【Transformation 3】 [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.]

4. The agent according to any one of claims 1 to 3, wherein the active ingredient is a compound represented by general formula (1-0'): 【Chemistry 4】 [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.]

5. The agent according to any one of claims 1 to 3, wherein the active ingredient is a compound represented by general formula (1-0''). 【Transformation 5】 [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.]

6. The agent according to any one of claims 1 to 3, wherein the active ingredient is a compound represented by the following formula (1): 【Transformation 6】 [In formula (1), Q １ represents Q in general formula (1-0). １ is equivalent to the above.]

7. Q １ but １８ F or -O １１ CH ３ The agent according to any one of claims 1 to 3,

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