Pancreatic function diagnostic agent

Abstract

To provide a diagnostic agent for a pancreatic function that enable early diagnosis of change in a pancreatic function.SOLUTION: A diagnostic agent for a pancreatic function contains a compound represented by general formula (1-0) as an active ingredient. [In general formula (1-0), R represents -O(CH2)n-, -O(CH2)nOC2H4-, -CH2O(CH2)n-, or -CH2O(CH2)nOC2H4-; n represents an integer of 1-5; and Q1 represents F or -OCH3.]SELECTED DRAWING: None

Description

[Technical field]

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

[0002] The pancreas has an exocrine function that secretes digestive fluids (pancreatic juices) that contain amylase, which breaks down carbohydrates, trypsin, which breaks down proteins, and lipase, which breaks down fats, and an endocrine function that secretes hormones such as insulin and glucagon, which are necessary for sugar metabolism. Therefore, when the pancreas malfunctions, the body is unable to produce or absorb the energy it needs to survive from food, leading to a decline in the function of various organs due to a lack of nutritional supply to cells. Even now, when early detection and early treatment of cancer have become widespread, pancreatic cancer is often detected late, and the 5-year survival rate is still less than 10%, making it one of the most difficult cancers to treat.

[0003] Conventionally, for example, imaging diagnosis using X-ray CT and MRI, as well as diagnosis using an ultrasonic endoscope, have been used to diagnose pancreatic diseases such as acute pancreatitis, chronic pancreatitis, and early pancreatic cancer (e.g., Non-Patent Documents 1 and 2). On the other hand, Non-Patent Document 3 reports that in type II diabetes patients, the use of a PET probe ([ 18 It has been disclosed that the uptake of F[FDG] is increased. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Journal of the Japanese Society of Abdominal Emergency Medicine, 2008, Vol. 28, pp. 561-571 [Non-Patent Document 2] Journal of the Pancreas,2009,10,280-283 [Non-Patent Document 3] PLoS ONE, 2019, Vol. 14, e0213202 Summary of the Invention [Problem to be solved by the invention]

[0005] Conventional image diagnosis using X-ray CT or MRI utilizes information based on structural changes in organs, such as atrophy or calcification of the pancreas, and is therefore unable to detect changes in biological function prior to structural changes. This is also true for diagnosis using an ultrasound endoscope. Moreover, diagnosis using an ultrasound endoscope is a more invasive examination method. In addition, the method disclosed in Non-Patent Document 3 is [ 18 This involves a PET scan using [F]FDG as a probe, and can only evaluate increased accumulation that reflects inflammation in organs.

[0006] Therefore, an object of the present invention is to provide a diagnostic agent for pancreatic function that can diagnose changes in pancreatic function at an early stage. [Means for solving the problem]

[0007] The present invention relates to a diagnostic agent for pancreatic function, which comprises a compound represented by general formula (1-0) (hereinafter also referred to as "compound (1-0)") as an active ingredient.

[0008] [ka] 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 from 1 to 5, Q 1 F or -OCH 3 Shows.

[0009] 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 pancreatic function according to the present invention accumulates in the pancreas and accumulates in an amount proportional to the MC-I activity of the pancreas, and is therefore suitable for use in diagnosing pancreatic function. As shown in the examples below, the decrease in MC-I activity in the pancreas occurs prior to the deterioration of biochemical indicators (e.g., an increase in blood glucose concentration). Therefore, the diagnostic agent according to the present invention can diagnose changes in pancreatic function at an early stage.

[0010] The above diagnostic agent is Q 1 but 18 F or -O 11 CH 3 This allows the compound to emit positrons. The positrons emitted from the compound immediately combine with electrons to emit gamma rays (annihilation radiation). By measuring these gamma rays with an apparatus used in positron emission tomography (PET), the compound accumulating in the pancreas can be imaged quantitatively and over time. In other words, the compound can also be used as a labeling compound for the PET method.

[0011] The present invention can also be considered as a method for diagnosing pancreatic function, comprising the steps of administering the diagnostic agent to a subject, detecting compound (1-0) accumulated in the pancreas, and quantitatively analyzing the amount of compound (1-0) accumulated in the pancreas.

[0012] The present invention can further be understood as a compound represented by general formula (1-0) for use in diagnosing pancreatic function. The present invention can also be understood as use of a compound represented by general formula (1-0) in the manufacture of a diagnostic agent for pancreatic function. Effect of the Invention

[0013] According to the present invention, it is possible to provide a diagnostic agent for pancreatic function that can diagnose changes in pancreatic function at an early stage. [Brief description of the drawings]

[0014] [Figure 1] 1 is a graph plotting the amount of radioactivity accumulated (SUV) measured by the autopsy method versus the amount of radioactivity accumulated (SUV) measured by the PET measurement method, with regard to the accumulation of [18F]BCPP-BF in the pancreas. [Diagram 2] 2(A) shows the pancreatic uptake (SUV) of [18F]BCPP-BF, (B) the pancreatic weight, and (C) the blood glucose concentration in lean and fatty rats of each week of age. [Diagram 3] 1 is a graph showing the relationship between the uptake (SUV) of [18F]BCPP-BF into the pancreas and the blood glucose concentration or blood neutral fat concentration. [Figure 4] (A) Graph showing the number of insulin-positive cells per unit area in the pancreas of 5-week-old and 16-week-old rats. (B) Graph showing the relationship between the uptake (SUV) of [18F]BCPP-BF in the pancreas of 16-week-old rats (Lean and Fatty rats) and the number of insulin-positive cells per unit area. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Hereinafter, an embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0016] The diagnostic agent for pancreatic function according to this embodiment contains a compound represented by general formula (1-0) as an active ingredient.

[0017] [ka]

[0018] In compound (1-0), R is -O(CH 2 ) n -, -O(CH 2 ) n O.C. 2 H 4 -, -CH 2 O(CH 2 )n -or-CH 2 O(CH 2 ) n O.C. 2 H 4 -. R is -O(CH 2 ) n - or -O(CH 2 ) n O.C. 2 H 4 - is preferred, -O(CH 2 ) n - is more preferable.

[0019] 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.

[0020] In compound (1-0), Q 1 F or -OCH 3 and 18 F or -O 11 CH 3 It is preferable that 1 but 18 F or -O 11 CH 3 Compound (1-0) having the formula Q is capable of emitting positrons and is therefore suitable as a labeled compound (PET probe) for use in the PET method. 1 -O 11 CH 3 In this case, the half-life is short at 20 minutes, making it possible to perform multiple measurements on the same subject in one day. 1 but 18 F has a half-life of 110 minutes and -O 11 CH 3 This makes it possible to extend the time for each measurement.

[0021] In the pyridine ring, -OCH is bonded to the pyridazine ring. 2 The bonding position of - and the bonding position of R are not particularly limited, but -OCH 2It is preferable that the bonding position of - is the 5-position of the pyridine ring, and the bonding position of R is the 2-position of the pyridine ring. The compound represented by the following general formula (1-0') (hereinafter also referred to as "compound (1-0')") has -OCH bonded to the pyridazine ring. 2 This is the structural formula when - is bonded to the 5-position of the pyridine ring and R is bonded to the 2-position of the pyridine ring.

[0022] [ka]

[0023] In the general formula (1-0'), R, n and Q 1 R, n and Q in general formula (1-0) 1 is synonymous with.

[0024] 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)”), since this is more suitable for diagnostic purposes of pancreatic function.

[0025] [ka]

[0026] In the general formula (1-0″), n and Q 1 represents n and Q in general formula (1-0). 1 is synonymous with.

[0027] [ka]

[0028] In formula (1), Q 1 Q in the general formula (1-0) 1 is synonymous with.

[0029] Compound (1-0) can be synthesized, for example, from a corresponding precursor. The same applies to compounds (1-0'), (1-0'') and (1).

[0030] An example of a corresponding precursor of the compound (1-0) is a compound represented by the following general formula (2-0) (hereinafter, also referred to as "compound (2-0)"). An example of a corresponding precursor of the compound (1-0'), the compound (1-0'') and the compound (1) is the compound (2-0) in which R and -OCH bonded to the pyridazine ring in the pyridine ring are bonded to the pyridazine ring. 2 Compounds in which the bonding position of - and the bonding position of R are the same as those in compound (1-0'), compound (1-0'') and compound (1) are included.

[0031] [ka]

[0032] 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).

[0033] 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.

[0034] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

[0035] The precursor can be synthesized, for example, by the method described in WO 2014 / 30709.

[0036] Compound (1-0) accumulates in the pancreas specifically in an MC-1 manner, and the amount of accumulation changes in correlation with the level of pancreatic function. That is, when pancreatic function is decreased, the amount of accumulation of compound (1-0) decreases, and when pancreatic function is enhanced, the amount of accumulation of compound (1-0) increases. Therefore, the diagnostic agent according to this embodiment is suitably used for diagnosing pancreatic function through measurement of the amount of accumulation of compound (1-0).

[0037] The amount of accumulation of compound (1-0) can be measured, but is not limited to this, by 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 nucleus such as Tc or a positron nuclide to obtain a labeled compound, and then detecting the label. 1 -O 11 CH 3 or 18 F. When positron-labeled, the annihilation radiation can be measured with an apparatus used in PET to quantitatively image the distribution of compound (1-0) in the body over time.

[0038] 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, and may contain other components such as a surfactant, a preservative, a stabilizer, etc. in addition to the buffer components.

[0039] The method for diagnosing pancreatic 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 pancreas, and quantitatively analyzing the amount of compound (1-0) accumulated in the pancreas.

[0040] Subjects include, but are not limited to, for example, humans, monkeys, mice, and rats.

[0041] The method for administering the diagnostic agent to a subject is not particularly limited as long as compound (1-0) reaches the pancreas, but is usually administered intravenously.

[0042] The dose of the diagnostic agent is not particularly limited as long as it is sufficient to detect compound (1-0) in the pancreas, 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 CH 3 When a diagnostic agent containing compound (1-0) is used to detect compound (1-0) with an apparatus used in the PET method, the dose of the diagnostic agent (hereinafter also referred to as "administered radioactivity") may be 1 MBq / kg body weight to 1000 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 individual, but for rodents (mice, rats), approximately 200 to 500 MBq / kg body weight is administered as 0.1 to 0.5 mL of physiological saline solution. For non-human primates (monkeys), 40 to 200 MBq / kg body weight is administered in 0.5 to 2 mL of physiological saline, and for humans, 2 to 10 MBq / kg body weight is administered as 1 to 5 mL of physiological saline solution.

[0043] The method for detecting the compound (1-0) accumulated in the pancreas is not particularly limited, and can be carried out according to a known method. For example, 1 but 18 F or -O 11 CH 3 When a diagnostic agent containing compound (1-0) is used, compound (1-0) can be detected by PET. The measurement method in PET is not particularly limited and can be carried out in accordance with a known method. For example, the measurement method by PET may be dynamic measurement for 60 minutes immediately after administration of the diagnostic agent, or PET measurement for 10 to 20 minutes may be performed after waiting 30 to 40 minutes after administration of the diagnostic agent to allow compound (1-0) to accumulate sufficiently in the pancreas.

[0044] The method for quantitatively analyzing the accumulation amount of compound (1-0) in the pancreas is not particularly limited, and can be carried out according to a known method. For example, the following method can be mentioned. First, an accumulation image of compound (1-0) obtained by the PET method is superimposed on a morphological image of the pancreas obtained by CT measurement or the like to identify the PET image of the pancreas. Next, a region of interest is set on the PET image of the pancreas, and the value normalized by the weight of the subject individual and the administered radioactivity amount is set as the accumulation amount of compound (1-0) in the pancreas. In addition, instead of the morphological image of the pancreas, an image obtained by the PET method using a probe capable of detecting the pancreas may be used.

[0045] The diagnostic method according to this embodiment may further include a step of comparing the quantitatively analyzed accumulation amount of compound (1-0) with a reference value to diagnose pancreatic function.

[0046] The reference value may be appropriately set depending on the purpose of diagnosis. For example, when the diagnostic method according to the present 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 kind. In this case, whether the pancreatic 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.

[0047] Furthermore, for example, when the diagnostic method according to the present embodiment is carried out in a subject suffering from a condition that causes pancreatic dysfunction (e.g., diabetes, dyslipidemia, chronic pancreatitis, acute pancreatitis, pancreatic cancer, etc.) for the purpose of observing 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 accumulation amount of compound (1-0) in the subject at a certain point in time (e.g., when healthy, at the time of initial diagnosis, at the start of treatment, at the end of treatment, etc.). EXAMPLES

[0048] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these.

[0049] [Test Example 1: Synthesis of PET probe] Represented by the following formula: 18 [F]BCPP-BF was synthesized by the method described in a non-patent document (J. Labelled Comp. Radiopharm., 2013, Vol. 56, No. 11, pp. 553-561). The radiochemical purity of the final product obtained was 100.0%, and the specific radioactivity was 74.5 GBq / μmol. [ka]

[0050] In addition, to identify the location of the pancreas, a probe (D-[ 11 C]MT) was prepared. D-[ 11 C]MT was synthesized by the method described in Example 1 of WO 2005 / 115971. The radiochemical purity of the final product obtained was 100.0%, and the specific activity was 56.4 GBq / μmol.

[0051] [Test Example 2: Evaluation of pancreatic function in type II diabetes model rats] (Type II diabetes model rats) Male Zucker Leprfa / Leprfa rats (hereinafter also referred to as "Fatty rats"), which develop a pathology similar to adult human type II diabetes, and male Zucker Leprfa / + rats (hereinafter also referred to as "Lean rats") as controls, were purchased from Charles River Japan, Inc., and subjected to PET measurements at the ages of 5, 8, 16, and 26 weeks, respectively.

[0052] (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 absorption correction, approximately 20 MBq / 0.5 mL of D-[ 11 After administration of [C]MT, emission measurements were performed for 60 minutes.18 F]BCPP-BF was administered and emission measurements were performed for 60 minutes. After the PET measurements, D-[ 11 A region of interest was set in the pancreas identified from the PET accumulation image 40-60 minutes after administration of [C]MT, and the [ 18 The amount of F]BCPP-BF 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-BF accumulated in the pancreas was calculated. 18 The accumulation amount of [F]BCPP-BF was defined as the standardized average radiation exposure (SUV).

[0053] (Measurement of radioactivity accumulation (SUV) by autopsy method) Immediately after PET measurement, the pancreas was removed from the rats and the weight of the removed pancreas was measured. The radioactivity of the removed pancreas was then measured using a gamma counter (Perkin Elmer, 1480 WIZARD). The measured radioactivity was normalized by the rat body weight, pancreas weight, and administered radioactivity, and the sustained uptake value (SUV) was calculated.

[0054] (Measurement of blood glucose and blood triglyceride concentrations) Immediately after PET measurement, blood was collected from the rats and the blood glucose and neutral fat concentrations were measured using an automatic biochemical analyzer (Hitachi High-Tech 7180).

[0055] (Measurement of insulin-positive cell count) After measuring the weight and radioactivity, the excised pancreas was used to count the number of insulin-positive cells (cells / μm) by immunohistochemistry. 2Specifically, pancreatic tissue sections were stained with anti-insulin monoclonal antibody (Nichirei Biosciences, K36aC10) as the primary antibody, Histofine Simple Stain (Nichirei Biosciences, MAX-PO(M)) as the secondary antibody, and DAB (DOJINDO, D006) as the color developer. Five islets were randomly selected from the tissue sections, and the islets were photographed at 100x magnification using an optical microscope (OLYMPUS, BX41) and a microscope camera (OLYMPUS, DP22). The number of insulin-positive cells (cells / μm ) was then counted using dedicated image software (OLYMPUS, cell SensV1.15). 2 ) was measured.

[0056] (result) Figure 1 shows the effect of 18 This is a graph plotting the radioactivity accumulation (SUV) measured by the PET measurement method against the radioactivity accumulation (SUV) measured by the autopsy method for the accumulation of [F]BCPP-BF. As shown in Figure 1, there is a good correlation (R 2 = 0.777, p < 0.001). MC-I measurements of the pancreas were 18 It can be seen that this can be performed non-invasively using [F]BCPP-BF. 18 F]BCPP-BF uptake (SUV) is the radioactivity accumulation (SUV) measured by PET counting.

[0057] Figure 2 shows the effect of 18 2 shows graphs showing the results of measuring the uptake (SUV) of [F]BCPP-BF (Fig. 2(A)), pancreas weight (Fig. 2(B)), and blood glucose concentration (Fig. 2(C)) in lean and fatty rats of each week of age. In Fig. 2, "★" indicates that the difference between the data from fatty rats and the data from lean rats was statistically significant (p<0.05).

[0058] As shown in Figure 2(B), in Fatty rats, pancreatic hypertrophy was observed at 8 weeks of age, followed by atrophy of the pancreas. As shown in Figure 2(C), abnormalities in blood glucose concentration were detected in Fatty rats from 16 weeks of age onwards. On the other hand, as shown in Figure 2(A), in Fatty rats, the [ 18 F]BCPP-BF uptake (SUV) was decreased. 18 The decrease in F]BCPP-BF uptake (SUV) indicates a decrease in MC-I activity in the pancreas. 18 It can be seen that the PET measurement method using [F]BCPP-BF can detect a decline in pancreatic function before abnormalities in blood glucose concentrations are detected (here, at 5 and 8 weeks of age).

[0059] Figure 3 shows the effect of 18 3(A) is a graph showing the relationship between the uptake (SUV) of [F]BCPP-BF and the blood glucose concentration or blood neutral fat concentration. 18 Fig. 3(B) is a graph plotting the uptake (SUV) of [F]BCPP-BF in 5-week-old rats (lean and fatty rats) and the serum triglyceride concentration and the uptake (SUV) of [F]BCPP-BF in the pancreas. 18 Fig. 3(C) is a graph plotting the uptake (SUV) of [F]BCPP-BF in 16-week-old rats (lean and fatty rats) and the uptake (SUV) of [F]BCPP-BF. 18 Fig. 3(D) is a graph plotting the uptake (SUV) of [F]BCPP-BF in 16-week-old rats (lean and fatty rats) and the serum triglyceride concentration and the uptake (SUV) of [F]BCPP-BF in the pancreas. 18 F]BCPP-BF uptake (SUV) is plotted against

[0060] It has been reported that high blood glucose or triglyceride concentrations induce pancreatic dysfunction (e.g., FEBS J., 2013, Vol. 280, pp. 1039-1050; Endocr Rev., 2008, Vol. 29, pp. 351-366; Kidney Int., 2006, Vol. 70, pp. 1560-1566). As shown in Figure 3, this phenomenon is called [ 18 F]BCPP-BF could be used to detect impairment of MC-I activity.

[0061] Figure 4(A) is a graph showing the number of insulin-positive cells per unit area in the pancreas of 5-week-old and 16-week-old rats. In Figure 4(A), the white bars show the results for lean rats, and the black bars show the results for fatty rats. Figure 4(B) shows the effect of insulin on the pancreas of 16-week-old rats (lean rats and fatty rats). 18 F]BCPP-BF uptake (SUV) versus the number of insulin-positive cells per unit area.

[0062] As shown in Figure 4(A), the number of insulin-positive cells, an existing indicator of pancreatic function, was counted by immunohistochemistry. No significant difference was observed between Lean and Fatty rats at 5 weeks of age, but a significant decrease was detected in Fatty rats at 16 weeks of age. As shown in Figure 2(A), 18 PET measurements using [F]BCPP-BF were able to detect a decrease in pancreatic MC-I activity in Fatty rats at 5 weeks of age.

[0063] As shown in FIG. 4(B), in 16-week-old rats (lean rats and fatty rats), 18 Pancreatic MC-I activity ([ 18 F]BCPP-BF uptake (SUV) showed a significant positive correlation with the number of insulin-positive cells per unit area (R 2 =0.649, p=0.001).

Claims

1. A diagnostic agent for pancreatic 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 from 1 to 5, Q １ is F or -OCH ３ indicates.]

2. 2. The diagnostic agent according to claim 1, wherein the active ingredient is a compound represented by general formula (1-0'). 【Chemistry 2】 [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.]

3. The diagnostic agent according to claim 1, wherein the active ingredient is a compound represented by general formula (1-0''). 【Chemistry 3】 [In the general formula (1-0″), n and Q １ represents n and Q in general formula (1-0). １ is equivalent to.]

4. The diagnostic agent according to claim 1 , wherein the active ingredient is a compound represented by the following formula (1): 【Chemistry 4】 [In formula (1), Q １ represents Q in general formula (1-0). １ is equivalent to.]

5. Q １ but １８ F or -O １１ CH ３ The diagnostic agent according to any one of claims 1 to 4,

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