Agent for detecting interaction between tissues and organs

Abstract

To provide an agent for detecting an interaction between tissues and organs, which enables detection of an interaction between tissues and organs of an organism.SOLUTION: An agent for detecting an interaction between tissues and organs 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 from 1 to 5; and Q1 represents F or -OCH3.]SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an agent for detecting the interaction of tissues and organs.

Background Art

[0002] In recent years, it has been found that various organs constituting the living body do not function individually but maintain a healthy state by functioning as a single system while maintaining a balance while being closely related to each other. In addition, it has been found that the disruption of this balance causes various diseases, affects not only the main organs causing the diseases but also the organs closely related to them, and further that recovery from the diseases also depends on factors from other organs (so-called organ correlation).

[0003] As an example of this organ correlation, for example, when the function of the heart deteriorates, the function of the kidneys also deteriorates due to the influence, and conversely, when the function of the kidneys deteriorates, the function of the heart also deteriorates secondarily. The so-called "cardiorenal syndrome" is known. In addition, for example, it has been shown that diabetes is an acquired risk factor for Alzheimer's dementia, suggesting a correlation between the brain and peripheral organs (especially the pancreas) (for example, Non-Patent Documents 1 to 3). In addition, for example, it has been shown that the nervous system via the liver, brain, and pancreas is important for the mechanism of increasing the number of pancreatic β cells (for example, Non-Patent Document 4), suggesting a correlation between the liver, brain, and pancreas.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0005] So - called organ connection is considered to be the result of the interaction between organs through some network such as the interaction between organs via bioactive substances such as hormones, or the interaction between organs via the nervous system.

[0006] Conventionally, as a method for evaluating the function of each organ, a method of measuring and evaluating specific biochemical indices for each organ (for example, blood creatinine concentration, blood urea nitrogen (BUN) concentration, blood aspartate aminotransferase (AST) concentration, blood alanine aminotransferase (ALT) concentration, blood insulin concentration, blood brain natriuretic peptide concentration) is known. However, due to the fact that the time until the functional fluctuations of each organ are reflected in each biochemical index is different, each biochemical index can be affected by multiple factors, and furthermore, the sensitivities of the measurement methods for each biochemical index are different, in the conventional evaluation method using biochemical indices, the correlation between each organ function cannot be accurately grasped, and it has been difficult to detect and evaluate the interaction between organs such as so - called organ connection.

[0007] Therefore, an object of the present invention is to provide a detector for detecting the interaction between tissues and organs of a living body such as so - called organ connection. The present invention also aims to provide a method for detecting the interaction between tissues and organs, a program for detecting the interaction between tissues and organs for detecting the interaction between tissues and organs, and a device for detecting the interaction between tissues and organs for detecting the interaction between tissues and organs. [Means for Solving the Problems]

[0008] The present invention relates to a detector for detecting tissue-organ interaction, which contains a compound represented by the general formula (1-0) (hereinafter also referred to as "compound (1-0)") as an active ingredient.

[0009]

Chemical formula

[0010] Compound (1-0) can be used for the functional evaluation of mitochondrial complex-I (hereinafter also referred to as "MC-I"). Since compound (1-0) accumulates in each organ and the accumulated amount is proportional to the MC-I activity of each organ, the function of each organ can be evaluated from the accumulated amount of compound (1-0).

[0011] Also, as shown in the examples described below, in tests using normal rats (which can be considered as a tissue-organ correlation model in a healthy state) and diabetic model rats (which can be considered as a tissue-organ correlation model in a state where hyperglycemia due to reduced pancreatic function induces reduced function of other organs), the accumulation amount of compound (1-0) in each tissue and organ showed a good correlation (positive correlation) among the tissues and organs. This means that the interaction between each tissue and organ can be detected by determining the presence or absence of the correlation of the functions of each tissue and organ from the accumulation amount of compound (1-0). That is, since the detecting agent for tissue-organ interaction according to the present invention contains compound (1-0) as an active ingredient, it can be used for the purpose of detecting the interaction between each tissue and organ. Furthermore, as shown in the examples described below, even when no correlation is observed with the biochemical indices specific to each tissue and organ that are considered to reflect the functions of each tissue and organ, the accumulation amount of compound (1-0) shows a good correlation (positive correlation) among the tissues and organs. That is, the detecting agent for tissue-organ interaction according to the present invention can detect the interaction between tissues and organs that cannot be detected by the conventional evaluation method using biochemical indices.

[0012] The present invention also relates to a method for detecting tissue-organ interaction, which includes a step of administering the detecting agent according to the present invention to a subject, a step of detecting the active ingredient (compound (1-0)) accumulated in the tissue and / or organ to be evaluated, a step of quantitatively analyzing the accumulation amount of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated, and a step of determining the presence or absence of the correlation of the accumulation amount of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated based on the result of the quantitative analysis.

[0013] The present invention further relates to an acquisition means for acquiring detection data of an active ingredient (compound (1-0)) accumulated in a tissue and / or organ to be evaluated, obtained by measuring a subject administered with the detection agent according to the present invention, a quantitative analysis means for quantitatively analyzing the accumulation amount of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated from the acquired detection data, and a determination means for determining the presence or absence of a correlation between the accumulation amounts of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated based on the result of the quantitative analysis. The present invention also relates to an apparatus for detecting tissue-organ interaction comprising these means.

[0014] The present invention also relates to a program for detecting tissue-organ interaction for causing a computer to function as an acquisition means for acquiring detection data of an active ingredient (compound (1-0)) accumulated in a tissue and / or organ to be evaluated, obtained by measuring a subject administered with the detection agent according to the present invention, a quantitative analysis means for quantitatively analyzing the accumulation amount of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated from the acquired detection data, and a determination means for determining the presence or absence of a correlation between the accumulation amounts of the active ingredient (compound (1-0)) in the tissue and / or organ to be evaluated based on the result of the quantitative analysis.

Advantages of the Invention

[0015] According to the present invention, it is possible to provide a detection agent for tissue-organ interaction that can detect interactions between tissues and organs of a living body such as so-called organ association. According to the present invention, it is also possible to provide a method for detecting tissue-organ interaction, a program for detecting tissue-organ interaction for detecting tissue-organ interaction, and an apparatus for detecting tissue-organ interaction for detecting tissue-organ interaction.

Brief Description of the Drawings

[0016]

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Mode for Carrying Out the Invention

[0017] Hereinafter, the modes for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0018] In this specification, the "agent for detecting tissue-organ interaction" means an agent used for the purpose of detecting the interaction between a plurality of tissues and / or organs of a living body, regardless of the healthy state and the diseased state. The agent for detecting tissue-organ interaction according to the present invention can detect the interaction between a plurality of tissues and / or organs of a living body by evaluating the functions of a plurality of tissues and / or organs of the living body and determining the presence or absence of their correlation. Therefore, the agent for detecting tissue-organ interaction according to the present invention can also be regarded as an agent for detecting the association between the tissues and / or organs due to the interaction between the tissues and / or organs. Note that the "association between tissues and / or organs" includes so-called "organ association".

[0019] 〔Agent for Detecting Tissue-Organ Interaction〕 The agent for detecting tissue-organ interaction according to the present embodiment (hereinafter, also simply referred to as "detecting agent") contains a compound represented by the general formula (1-0) as an active ingredient.

[0020]

Chemical formula

[0021] In the compound (1-0), R is -O(CH2) n -, -O(CH2) n OC2H4-, -CH2O(CH2) n - or -CH2O(CH2) n OC_{2}H_{4}-. R is preferably -O(CH2) n - or -O(CH2) n OC_{2}H_{4}-.

[0022] In the compound (1-0), n is an integer from 1 to 5. When R in the compound (1-0) is -O(CH2) n -, n is preferably an integer from 2 to 5, more preferably an integer from 3 to 5, and still more preferably 4. Also, when R in the compound (1-0) is -O(CH2) nWhen it is OC2H4-, n is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, and still more preferably 2.

[0023] In compound (1-0), Q 1 is F or -OCH3, 18 and preferably F or - 11 OCH3. Q 1 When 18 it is F or - 11 OCH3, compound (1-0) can emit positrons and is thus suitable as a labeling compound (PET probe) for use in the PET method. Also, when Q 1 is - 11 OCH3, since the half-life is as short as 20 minutes, it becomes possible to perform measurements on the same subject multiple times a day. When Q 1 is 18 F, since the half-life is 110 minutes, which is longer than that of - 11 OCH3, it becomes possible to extend the measurement time for a single measurement and further to deliver a PET probe labeled and synthesized at a facility equipped with a cyclotron to another facility equipped with a PET camera.

[0024] In the pyridine ring, the bonding position of -OCH2- bonded to the pyridazine ring and the bonding position of R are not particularly limited, but the bonding position of -OCH2- bonded to the pyridazine ring is preferably the 5-position of the pyridine ring, and the bonding position of R is preferably 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')") is a structural formula when the bonding position of -OCH2- bonded to the pyridazine ring is the 5-position of the pyridine ring and the bonding position of R is the 2-position of the pyridine ring.

[0025]

Chemical formula

[0026] In general formula (1-0'), R, n, and Q 1 have the same meanings as R, n, and Q 1 in general formula (1-0).

[0027] Since it becomes more suitable for the use of detecting the interaction between tissues and organs, the compound (1-0) is preferably a compound represented by the general formula (1-0'') (hereinafter also referred to as "compound (1-0'')"), or a compound represented by the general formula (1-0''') (hereinafter also referred to as "compound (1-0''')"), and more preferably a compound represented by the formula (1'') (hereinafter also referred to as "compound (1'')"), or a compound represented by the formula (1''') (hereinafter also referred to as "compound (1''')").

[0028]

Chemical formula

[0029]

Chemical formula

[0030] In the general formulas (1-0'') and (1-0'''), n and Q 1 are synonymous with n and Q in the general formula (1-0). 1 and have the same meaning.

[0031]

Chemical formula

[0032]

Chemical formula

[0033] In the formulas (1'') and (1'''), Q 1 is synonymous with Q in the general formula (1-0). 1 and have the same meaning.

[0034] The compound (1-0) can be synthesized, for example, from the corresponding precursor. The same applies to the compound (1-0'), the compound (1-0''), the compound (1-0'''), the compound (1'') and the compound (1''').

[0035] Examples of the corresponding precursor of compound (1-0) include a compound represented by the following general formula (2-0) (hereinafter also referred to as "compound (2-0)"). Examples of the corresponding precursors of compound (1-0'), compound (1-0''), compound (1-0'''), compound (1'') and compound (1''') include, for example, in compound (2-0), compounds in which the bonding position of R and -OCH2- bonded to the pyridazine ring in the pyridine ring and the bonding position of R are the same as those in compound (1-0'), compound (1-0''), compound (1-0'''), compound (1'') and compound (1''').

[0036]

Chemical formula

[0037] In general formula (2-0), R has the same meaning as R in general formula (1-0). Q 2 represents a leaving substituent (such as a substituted sulfonyloxy group, a halogen atom or a hydroxyl group, etc.).

[0038] Examples of the substituted sulfonyloxy group include a tosyloxy group (-OTs), a methanesulfonyloxy group (-OMs), a trifluoromethanesulfonyloxy group (-OTf), and a nitrobenzenesulfonyloxy group (-ONs), and -OTs is preferably used.

[0039] Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

[0040] The precursor can be synthesized, for example, by the method described in International Publication No. 2014 / 30709.

[0041] Since compound (1-0) specifically accumulates in each tissue and organ in an MC-I-specific manner, the accumulation amount changes in correlation with the degree of function of each tissue and organ. That is, when the function of each tissue and organ decreases, the accumulation amount of compound (1-0) decreases, and when the function of each tissue and organ increases, the accumulation amount of compound (1-0) increases. Therefore, the detection agent according to the present embodiment can evaluate the function of each tissue and organ through the measurement of the accumulation amount of compound (1-0), and can detect the interaction between a plurality of tissues and / or organs in a living body by determining the presence or absence of a correlation relationship between the functions of the plurality of tissues and organs.

[0042] The measurement of the accumulation amount of compound (1-0) is not limited thereto. For example, a fluorescent dye or the like is bound to compound (1-0), or a single photon nuclide ( 123 I, 99m Tc, etc.) or a positron nuclide is used for labeling to obtain a labeled compound, and the measurement can be carried out by detecting the label. The positron labeling can be performed, for example, by changing the Q 1 of compound (1-0) to -O 11 CH3 or 18 F. When positron-labeled, the in-vivo distribution of compound (1-0) can be quantitatively and time-dependently imaged by measuring the annihilation radiation with an apparatus used in the PET method.

[0043] In addition, the measurement of the accumulation amount of compound (1-0) can be carried out not only by the above-described imaging diagnosis method, but also by, for example, a method of measuring the radioactivity of cells, tissues, organs, etc. collected from a living body administered with a labeled compound by means of a technique such as dissection or biopsy. Even in this case, the correlation between tissues and organs can be evaluated in the same manner as in the imaging diagnosis method.

[0044] The detection agent according to the present embodiment can be produced, for example, by dissolving compound (1-0) in an arbitrary buffer solution. In this case, the detection agent according to the present embodiment is provided as a solution and may contain other components such as a surfactant, a preservative, and a stabilizer in addition to the buffer component.

[0045] 〔Method for Detecting Interaction between Tissues and Organs〕 The method for detecting the interaction between tissues and organs according to this embodiment includes a step of administering the detection agent according to the present invention to a subject, a step of detecting the compound (1-0) accumulated in the tissue and / or organ to be evaluated, a step of quantitatively analyzing the accumulation amount of the compound (1-0) in the tissue and / or organ to be evaluated, and a step of analyzing the presence or absence of a correlation between the accumulation amounts of the compound (1-0) in the tissue and / or organ to be evaluated based on the result of the quantitative analysis.

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

[0047] The method of administering the detection agent is not particularly limited as long as the compound (1-0) reaches the tissue and organ to be evaluated, but is usually intravenous administration.

[0048] The dosage of the detection agent is not particularly limited as long as it is sufficient to detect the compound (1-0) in the tissue and organ to be evaluated, and may be appropriately set according to the subject to be administered and the method of detecting the compound (1-0). For example, when 1 Q 18 is 11 F or -O

[0049] The method for detecting the compound (1-0) accumulated in the tissue and / or organ to be evaluated is not particularly limited and can be carried out according to known methods. For example, Q 1 When 18 the detecting agent contains a compound (1-0) in which Q is F or -O 11 and R is CH3, the compound (1-0) can be detected by the PET method. The measuring method in the PET method is not particularly limited and can be carried out according to known methods. Further, for example, as a method of measuring by the PET method, dynamic measurement may be performed for 60 minutes immediately after administration of the detecting agent, or after waiting for 30 to 40 minutes after administration of the detecting agent until the compound (1-0) is sufficiently accumulated in the tissue and / or organ to be evaluated, PET measurement may be performed for 10 to 20 minutes.

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

[0051] In addition, as a method for detecting and quantitatively analyzing the compound (1-0) accumulated in the tissue and / or organ to be evaluated, for example, a method of measuring the radioactivity or the like of cells, tissues, and organs collected from a living body administered with a labeled compound by means such as dissection or biopsy can also be employed. The method for measuring the radioactivity or the like of the collected cells, tissues, and organs is not particularly limited and can be carried out according to known methods. Specifically, for example, the radioactivity of the collected cells, tissues, and organs can be measured using a radioactivity measuring device. Further, a value obtained by normalizing the measured value of the radioactivity with the body weight of the subject individual and the administered radioactivity amount may be used as the accumulation amount of the compound (1-0) in the tissue and / or organ.

[0052] As a method for determining the presence or absence of a correlation between the accumulation amounts of the compound (1-0) in the tissue and / or organ to be evaluated, there is no particular limitation as long as it is a method capable of determining whether or not the accumulation amounts of the compound (1-0) in a plurality of tissues and / or organs to be evaluated are correlated. Specifically, for example, in a plurality of tissues and / or organs to be evaluated, a correlation formula is calculated in advance from the data of the accumulation amounts in which a correlation is recognized and used as a reference formula, and the presence or absence of a correlation is determined according to the degree of deviation between the data of the accumulation amounts measured in the subject and the reference formula. In this case, for example, when the reference formula is represented by y = ax + b (where x and y are the accumulation amounts in any one of the tissues or organs, and a and b are constants), for example, it may be determined that there is a correlation when ax + 0.9b ≤ y ≤ ax + 1.1b is satisfied, or it may be determined that there is a correlation when ax + 0.95b ≤ y ≤ ax + 1.05b is satisfied, or it may be determined that there is a correlation when ax + 0.97b ≤ y ≤ ax + 1.03b is satisfied. Further, machine learning (for example, deep learning) may be applied to the data of the accumulation amounts of the compound (1-0) in a plurality of tissues and / or organs in a large number of samples to determine the presence or absence of a correlation between the accumulation amounts of the compound (1-0) between arbitrary tissues and organs by machine learning.

[0053] As the tissue and / or organ to be evaluated, since compound (1-0) accumulates specifically in MC-I (that is, it can accumulate in any organ), it is not particularly limited. Specifically, for example, the brain, heart, liver, pancreas, kidney, brown adipocytes (brown adipose tissue), and muscle can be mentioned.

[0054] The present invention also includes a step of quantitatively analyzing the accumulation amount of compound (1-0) in the tissue and / or organ to be evaluated from the detection data of compound (1-0) accumulated in the tissue and / or organ to be evaluated, which is obtained by measuring the subject administered with the detection agent according to the present invention, and a step of determining the presence or absence of a correlation relationship of the accumulation amount of compound (1-0) in the tissue and / or organ to be evaluated based on the result of the quantitative analysis. It can also be regarded as a data collection method for detecting the interaction of tissues and organs. The data indicating the presence or absence of the correlation relationship of the accumulation amount between each tissue and organ obtained in the determination step can be used to detect the interaction between each tissue and organ.

[0055] 〔Tissue-Organ Interaction Detection Device〕 The tissue-organ interaction detection device according to the present embodiment includes an acquisition means for acquiring detection data of the active ingredient accumulated in the tissue and / or organ to be evaluated, which is obtained by measuring the subject administered with the detection agent according to the present invention, a quantitative analysis means for quantitatively analyzing the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated from the acquired detection data, and a determination means for determining the presence or absence of a correlation relationship of the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated based on the result of the quantitative analysis.

[0056] The configuration of the tissue-organ interaction detection device D according to the present embodiment will be described. FIG. 1 is a schematic diagram showing the hardware configuration of the tissue-organ interaction detection device D according to an embodiment. FIG. 2 is a schematic diagram showing the functional configuration of the tissue-organ interaction detection device D according to an embodiment.

[0057] As shown in FIG. 1, the tissue-organ interaction detection device D is physically configured as a normal computer including a main storage device such as a CPU D11, a ROM D12, and a RAM D13, an input device D14 such as a keyboard, a mouse, and a touch screen, an output device D15 such as a display (including a touch screen), a communication module D16 such as a network card for transmitting and receiving data to and from other devices, an auxiliary storage device D17 such as a hard disk, and the like. Each function of the tissue-organ interaction detection device D described later is realized by loading a predetermined computer software onto hardware such as the CPU D11, the ROM D12, and the RAM D13, and operating the input device D14, the output device D15, and the communication module D16 under the control of the CPU D11, and reading and writing data in the main storage devices D12, D13, and the auxiliary storage device D17.

[0058] As shown in FIG. 2, the tissue-organ interaction detection device D includes, as functional components, an acquisition means D1, a quantitative analysis means D2, a determination means D3, and an output means D4.

[0059] The acquisition means D1 acquires detection data of the active ingredient accumulated in the tissue and / or organ to be evaluated, which is obtained by measuring the subject administered with the detection agent according to the present invention. The detection data may be, for example, integrated image data of the active ingredient including information on the signal intensity (e.g., fluorescence intensity, radiation intensity) emitted from the label of the active ingredient in the region including the tissue and / or organ to be evaluated.

[0060] The quantitative analysis means D2 quantitatively analyzes the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated from the detection data obtained by the acquisition means D1. The quantitative analysis is performed, for example, by superimposing the accumulation image of the active ingredient and the morphological image of the tissue and / or organ obtained by CT measurement or the like, identifying the tissue and / or organ in the accumulation image of the active ingredient, and normalizing the signal intensity (for example, fluorescence intensity, radiation intensity) in the identified region by the body weight of the subject individual and the administered radiation dose, and calculating the value as the accumulation amount data of the active ingredient in the tissue and / or organ. The morphological image data of the tissue and / or organ, as well as the body weight and administered radiation dose data of the subject individual, may be obtained in advance by the acquisition means D1.

[0061] The determination means D3 determines the presence or absence of a correlation relationship of the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated based on the accumulation amount data of the active ingredient in the tissue and / or organ obtained by the quantitative analysis means D2. The determination of the presence or absence of the correlation relationship is, for example, in a plurality of tissues and / or organs to be evaluated, a correlation formula calculated in advance from the data of the accumulation amount in which the correlation relationship is recognized is used as a reference formula and stored in the main storage devices D12, D13, or the auxiliary storage device D17, and the degree of deviation between the result of the quantitative analysis by the quantitative analysis means D2 and the reference formula is determined to determine the correlation relationship. The determination of the degree of deviation is, for example, when the reference formula is represented by y = ax + b (where x and y are the accumulation amounts in any tissue or organ, and a and b are constants), for example, it may be determined that there is a correlation relationship when ax + 0.9b ≤ y ≤ ax + 1.1b, it may be determined that there is a correlation relationship when ax + 0.95b ≤ y ≤ ax + 1.05b, and it may be determined that there is a correlation relationship when ax + 0.97b ≤ y ≤ ax + 1.03b. Further, for example, when determining the presence or absence of a correlation relationship using machine learning (for example, deep learning), the result learned in advance by machine learning is stored in the main storage devices D12, D13, or the auxiliary storage device D17, and the accumulation amount data of the active ingredient in the tissue and / or organ obtained by the quantitative analysis means D2 is input to determine the presence or absence of the correlation relationship.

[0062] The output means D4 outputs the result determined by the determination means D3. The result may be output to an output device, output from the communication module to another device, or output to and recorded in an auxiliary storage device.

[0063] 〔Program for detecting interaction between tissues and organs〕 The program for detecting the interaction between tissues and organs according to the present embodiment causes a computer to function as the acquisition means D1, the quantitative analysis means D2, the determination means D3, and the output means D4 described above. By causing the computer to read the program for detecting the interaction between tissues and organs, the computer operates as a tissue-organ interaction detection device D. The program for detecting the interaction between tissues and organs is provided, for example, by being recorded on a computer-readable recording medium. The recording medium may be a non-temporary recording medium. Examples of the recording medium include recording media such as flexible disks, CDs, DVDs, etc., recording media such as ROMs, and semiconductor memories.

[0064] A method for detecting the interaction between tissues and organs performed by the tissue-organ interaction detection device D will be described. FIG. 3 is a flowchart of a method for detecting the interaction between tissues and organs according to an embodiment.

[0065] [Acquisition step S1] First, the acquisition means D1 acquires detection data of the active ingredient accumulated in the tissue and / or organ to be evaluated, which is obtained by measuring the subject administered with the detection agent according to the present invention. If necessary, the acquisition means D1 may acquire morphological image data of the tissue and / or organ, as well as body weight and administered radiation dose data of the subject individual.

[0066] [Quantitative analysis step S2] Next, the quantitative analysis means D2 quantitatively analyzes the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated from the acquired detection data.

[0067] [Determination step S3] Next, the determination means D3 determines the presence or absence of a correlation relationship of the accumulation amount of the active ingredient in the tissue and / or organ to be evaluated based on the accumulation amount data of the active ingredient in the tissue and / or organ calculated in the quantitative analysis step S2.

[0068] [Display step S4] Next, the output means D4 outputs the result determined in the determination step S3 (for example, display on an output device, etc.). For example, data indicating whether or not the tissues and / or organs to be evaluated interact with each other, accumulation amount data of the active ingredient in each tissue and / or organ, graph (image) data obtained by plotting the accumulation amount data and a reference formula, etc. are output by the output means D4.

Example

[0069] Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited thereto.

[0070] [Test Example 1: Detection of interaction between tissues and organs (1)] (Synthesis of PET probe) According to the method described in the non-patent literature (J. Labelled Comp. Radiopharm., 2013, Vol. 56, No. 11, pp. 553-561), 18 F]BCPP-BF was synthesized. The radiochemical purity of the obtained final product was 99.0%, and the specific radioactivity was 73.4 GBq / μmol.

Chemical formula

[0071] In addition, in order to specify the position of the pancreas, a probe (D- 11 C]MT) that recognizes the amino acid transporter (LAT-1) highly expressed in the pancreas of small animals was prepared. D- 11 C]MT was synthesized by the method described in Example 1 of International Publication No. 2005 / 115971. The radiochemical purity of the obtained final product was 99.0%, and the specific radioactivity was 66.4 GBq / μmol.

[0072] (Evaluation of Organ Functions in Type II Diabetic Model Rats) Male Zucker Leprfa / Leprfa rats (hereinafter also referred to as "Fatty rats") that develop a pathological condition similar to that of adult human type II diabetes, and male Zucker Leprfa / + rats (hereinafter also referred to as "Lean rats") as their control were purchased from Charles River Laboratories Japan, Inc. and subjected to PET measurement at 5 weeks of age, 8 weeks of age, 16 weeks of age, and 26 weeks of age, respectively. The 18 accumulation amount of [18F]BCPP-BF in each tissue and organ (brain, heart, kidney, liver, brown adipocytes (brown adipose tissue)) was measured.

[0073] The rats were anesthetized with isoflurane and fixed inside the gantry of an animal PET camera (SHR-38000, manufactured by Hamamatsu Photonics K.K.). After performing a 15-minute transmission measurement for absorption correction, about 20 MBq / 0.5 mL of D- 11 [11C]MT was administered via the tail vein of the rats, and a 60-minute emission measurement was performed. Subsequently, about 20 MBq / 0.5 mL of 18 [18F]BCPP-BF was administered via the tail vein of the rats, and a 60-minute emission measurement was performed.

[0074] After the PET measurement was completed, a region of interest was set for the pancreas identified in the PET accumulation image 40 - 60 minutes after the administration of D- 11 [11C]MT, and the accumulation amount of 18 [18F]BCPP-BF in the region of interest was calculated. Then, the calculated accumulation amount was normalized by the body weight and administered radioactivity of each individual, and the accumulation amount of 18 [18F]BCPP-BF in the pancreas (radioactivity accumulation amount (SUV)) was obtained. For tissues and organs other than the pancreas, a region of interest was set for each tissue and organ identified in the PET accumulation image of 18 [18F]BCPP-BF, and the radioactivity accumulation amount (SUV) was calculated in the same manner as for the pancreas. The radioactivity accumulation amount (SUV) of the brain was calculated by removing the brain from the rat immediately after the PET measurement. Also, the 18The correlation between tissues and organs in terms of the radioactivity accumulation amount (SUV) of F]BCPP-BF was evaluated.

[0075] (Measurement of biochemical indices) Blood was collected from rats immediately after PET measurement, and blood BUN concentration, blood creatinine concentration, blood AST concentration, blood ALT concentration, and blood insulin concentration were measured using an automatic biochemical analyzer (7180 manufactured by Hitachi High-Tech Corporation). Blood BUN concentration, blood creatinine concentration, blood AST concentration, blood ALT concentration, and blood insulin concentration are biochemical indices used to reflect the functions of the pancreas, kidney, and liver.

[0076] (Results) Figure 4 is a graph showing the accumulation amount of F]BCPP-BF in each tissue and organ (brain, heart, brown adipocytes, pancreas, liver, kidney). Except for 5-week-old brown adipocytes (tissue) and kidneys, the accumulation amount in Fatty rats was significantly lower than that in Lean rats in terms of any age and organ. This is considered to indicate that the functions of each tissue and organ decreased with the onset of diabetes. 18 Figure 4 is a graph showing the accumulation amount of F]BCPP-BF in each tissue and organ (brain, heart, brown adipocytes, pancreas, liver, kidney). Except for 5-week-old brown adipocytes (tissue) and kidneys, the accumulation amount in Fatty rats was significantly lower than that in Lean rats in terms of any age and organ. This is considered to indicate that the functions of each tissue and organ decreased with the onset of diabetes.

[0077] Figures 5 to 9 are graphs showing the relationship of the accumulation amount of F]BCPP-BF in each tissue and organ. In Figures 5 to 9, the accumulation amounts in Fatty rats and Lean rats are plotted without distinction. 18 Figures 5 to 9 are graphs showing the relationship of the accumulation amount of F]BCPP-BF in each tissue and organ. In Figures 5 to 9, the accumulation amounts in Fatty rats and Lean rats are plotted without distinction.

[0078] Figure 5(A) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and heart. Figure 5(B) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and brown adipocytes. Figure 5(C) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and pancreas. Figure 5(D) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and liver. Figure 5(E) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and kidney. 18 Figure 5(A) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and heart. Figure 5(B) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and brown adipocytes. Figure 5(C) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and pancreas. Figure 5(D) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and liver. Figure 5(E) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and kidney. 18 Figure 5(A) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and heart. Figure 5(B) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and brown adipocytes. Figure 5(C) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and pancreas. Figure 5(D) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and liver. Figure 5(E) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and kidney. 18 Figure 5(A) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and heart. Figure 5(B) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and brown adipocytes. Figure 5(C) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and pancreas. Figure 5(D) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and liver. Figure 5(E) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and kidney. 18 Figure 5(A) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and heart. Figure 5(B) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and brown adipocytes. Figure 5(C) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and pancreas. Figure 5(D) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and liver. Figure 5(E) is a graph showing the relationship of the accumulation amount of F]BCPP-BF in the brain and kidney. 18It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 6(A) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 6(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 6(C) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 6(D) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 7(A) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 7(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 7(C) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 8(A) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 8(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-BF. Figure 9 shows the 18 relationship of the accumulation amount of F]BCPP-BF to the liver and kidney.

[0079] As shown in FIGS. 5 to 9, the 18 accumulation amounts of F]BCPP-BF in each tissue and organ (brain, heart, brown adipose tissue, pancreas, liver, kidney) showed a significant correlation (positive correlation) between any two tissues and organs. This 18 is considered to mean that the interaction between each tissue and organ can be detected by determining the presence or absence of the correlation of the accumulation amount of F]BCPP-BF.

[0080] Incidentally, FIG. 21 shows the 18 relationship of the accumulation amount of F]BCPP-BF to the brain and heart (FIG. 21(A)), the 18 relationship of the accumulation amount of F]BCPP-BF to the kidney and heart (FIG. 21(B)), the 18This is a graph plotting the relationship of the accumulation amount of F]BCPP-BF (Figure 21(C)), distinguishing between normal rats (Lean rats) and diabetic model rats (Fatty rats). As shown in Figure 21, although there was a tendency for slightly different slopes of the graph between normal rats and diabetic model rats, considering the results in Figures 5 to 9, it was found that there was a good correlation between the accumulation amount data of normal rats and diabetic rats of all ages in each tissue and organ, indicating that it is not necessary to consider the state of the subject.

[0081] Also, Figures 10 and 11 are graphs showing the relationships of various biochemical indices. Figures 10 and 11 plot the biochemical indices in Fatty rats and Lean rats without distinction. Here, Figure 10(A) is a graph showing the relationship between blood insulin concentration and blood BUN concentration. Figure 10(B) is a graph showing the relationship between blood insulin concentration and blood creatinine concentration. Figure 10(C) is a graph showing the relationship between blood insulin concentration and blood AST concentration. Figure 10(D) is a graph showing the relationship between blood insulin concentration and blood ALT concentration. Figure 11(A) is a graph showing the relationship between blood AST concentration and blood BUN concentration. Figure 11(B) is a graph showing the relationship between blood AST concentration and blood creatinine concentration. Figure 11(C) is a graph showing the relationship between blood ALT concentration and blood BUN concentration. Figure 11(D) is a graph showing the relationship between blood ALT concentration and blood creatinine concentration.

[0082] As shown in Figures  10 and 11, no significant correlation was observed among any of the biochemical indices. These results mean that the interaction between tissues and organs that cannot be detected by the conventional evaluation method using biochemical indices can be detected by the detection agent for the interaction between tissues and organs according to the present invention. [[ID= 9]]

[0083] [Test Example 2: Detection of Interaction between Tissues and Organs (2)] (Synthesis of PET Probe) According to the method described in the examples of International Publication No. 2014 / 030709, 18 F]BCPP-EF was synthesized. The radiochemical purity of the obtained final product was 99.8%, and the specific radioactivity was 73.6 GBq / μmol.

Chemical formula

[0084] (Evaluation of the functions of various tissues and organs in type II diabetic model rats) 18 Instead of 18 F]BCPP-BF, the same operations as in Test Example 1 were performed except that 18 F]BCPP-EF was used, and the radioactivity accumulation amount (SUV) of 18 F]BCPP-EF in each tissue and organ was calculated. In addition, the presence or absence of a correlation between the radioactivity accumulation amounts (SUV) of

[0085] (Results) Figures 12 to 16 are graphs showing the relationship between the accumulation amounts of 18 F]BCPP-EF in each tissue and organ. In Figures 12 to 16, the accumulation amounts in Fatty rats and Lean rats are plotted without distinction.

[0086] Figure 12(A) is a graph showing the relationship between the accumulation amounts of 18 F]BCPP-EF in the brain and heart. Figure 12(B) is a graph showing the relationship between the accumulation amounts of 18 F]BCPP-EF in the brain and brown adipocytes. Figure 12(C) is a graph showing the relationship between the accumulation amounts of 18 F]BCPP-EF in the brain and pancreas. Figure 12(D) is a graph showing the relationship between the accumulation amounts of 18 F]BCPP-EF in the brain and liver. Figure 12(E) is a graph showing the relationship between the accumulation amounts of 18 F]BCPP-EF in the brain and kidney. Figure 13(A) is a graph showing the relationship between the accumulation amounts of 18 ​It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 13(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 13(C) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 13(D) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 14(A) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 14(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 14(C) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 15(A) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 15(B) shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF. Fig. 16 shows the 18 It is a graph showing the relationship of the accumulation amount of F]BCPP-EF.

[0087] As shown in Figs. 12 to 16, the 18 accumulation amount of F]BCPP-EF in each tissue / organ (brain, heart, brown adipocyte, pancreas, liver, kidney) showed a significant correlation (positive correlation) between any two tissues / organs. This is 18 considered to mean that the interaction between each tissue / organ can be detected by determining the presence or absence of the correlation of the accumulation amount of F]BCPP-EF.

[0088] [Test Example 3: Detection of Interaction between Tissues / Organs (3)] (Synthesis of PET Probe) As a PET probe for comparison, 11 C]HM represented by the following formula was synthesized. 11 C]HM is a PET probe for detecting reactive oxygen species. [Chemical Formula]

[0089] 11 CHM was synthesized according to the following scheme. [Chemical formula]

[0090] Protons accelerated to 18 MeV by a cyclotron (HM-18, manufactured by Sumitomo Heavy Industries, Ltd.) were irradiated at a current value of approximately 20 μA to a target filled with pure nitrogen gas (Grade G, manufactured by Japan Fine Products Co., Ltd.). 14 N(p,α) 11 12C was produced by a nuclear reaction 11 12C]CO2 was recovered by an automatic synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.) and introduced into 500 μL of a cooled 0.1 M LiAlH4 / tetrahydrofuran (THF) solution (manufactured by ABX advanced biochemical compounds). After distilling off THF, 0.5 mL of hydroiodic acid (manufactured by Nacalai Tesque) was added, and the resulting 11 12C]methyl iodide was distilled and passed through a silver triflate column heated to 200 °C to 11 12C]convert it to methyl triflate.

[0091] 1.5 mg of the precursor (compound C1-1) was dissolved in 0.2 mL of methyl ethyl ketone, and the above 11 12C]methyl triflate was introduced and methylated at 50 °C for 3 minutes to synthesize compound C1-2. Then, 133 μL / 320 μL of 6N hydrochloric acid / ethanol was added, and a deprotection reaction was carried out at 80 °C for 4 minutes to synthesize compound C1-3. Then, 8 mg / 820 μL of sodium borohydride / 1N sodium hydroxide was added, and 11 12C]CHM (compound C1) was synthesized.

[0092] ​The reaction solution was fractionated by high performance liquid chromatography (column: YMC Pack Pro C18, 10 * 250 mm, 5 μm (YMC, USA), mobile phase: 20 mM phosphate buffer pH 2.8 (0.5% ascorbic acid + 0.05% NaHSO3) / acetonitrile = 500 / 500, flow rate: 6 mL / min, detection wavelength: 254 nm). The solvent was distilled off, and 0.1% Tween80 / saline was added to the residue to obtain the final preparation.

[0093] The radioactivity of the final preparation was measured with a curie meter (IGC-7, manufactured by Hitachi Aloka Co., Ltd.), and a part of it was analyzed by high performance liquid chromatography for analysis (column: Finepak C18-S, 4.6 * 150 mm (manufactured by JASCO Corporation), mobile phase: acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) / 30 mM ammonium acetate (manufactured by Nacalai Tesque, Inc.) / acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) = 500 / 500 / 2, flow rate: 2 mL / min, detection wavelength: 254 nm) (n = 4). The results were as follows. Production amount: 2.54 ± 1.18 GBq (EOS) Average specific radioactivity: 50.4 ± 16.9 GBq / μmol (EOS) Average synthesis time: 30.1 ± 3.8 minutes

[0094] (Evaluation of functions of each tissue and organ in type II diabetic model rats) 18 Instead of [18F]BCPP-BF, 11 [11C]HM was used, and the same operations as in Test Example 1 were performed to calculate the radioactivity accumulation amount (SUV) of [11C]HM in each tissue and organ. Also, regarding the radioactivity accumulation amount (SUV) of [11C]HM in each tissue and organ, the presence or absence of a correlation between each tissue and organ was evaluated. 11 C]HM's radioactivity accumulation amount (SUV) was calculated. Also, regarding the 11 C]HM's radioactivity accumulation amount (SUV) of each tissue and organ, the presence or absence of a correlation between each tissue and organ was evaluated.

[0095] (Results) Figures 17 to 20 are graphs showing the relationship of the accumulation amount of 11 C]HM in each tissue and organ. In Figures 17 to 20, the accumulation amounts in Fatty rats and Lean rats are plotted without distinction. ​

[0096] Figure 17(A) is a graph showing the relationship between the accumulation amount of 11 C]HM in the heart and brown adipocytes. Figure 17(B) is a graph showing the relationship between the accumulation amount of 11 C]HM in the heart and pancreas. Figure 17(C) is a graph showing the relationship between the accumulation amount of 11 C]HM in the heart and liver. Figure 17(D) is a graph showing the relationship between the accumulation amount of 11 C]HM in the heart and kidney. Figure 18(A) is a graph showing the relationship between the accumulation amount of 11 C]HM in brown adipocytes and pancreas. Figure 18(B) is a graph showing the relationship between the accumulation amount of 11 C]HM in brown adipocytes and liver. Figure 18(C) is a graph showing the relationship between the accumulation amount of 11 C]HM in brown adipocytes and kidney. Figure 19(A) is a graph showing the relationship between the accumulation amount of 11 C]HM in pancreas and liver. Figure 19(B) is a graph showing the relationship between the accumulation amount of 11 C]HM in pancreas and kidney. Figure 20 is a graph showing the relationship between the accumulation amount of 11 C]HM in liver and kidney.

[0097] As shown in FIGS. 17 to 20, when 11 C]HM, a PET probe for detecting reactive oxygen species, was used, no significant correlation was observed among the accumulation amounts in any tissues or organs.

[0098] From the results of Test Examples 1 to 3, it can be understood that by using a probe that specifically accumulates in MC-I, the interaction between tissues and organs can be detected based on the accumulation amount of the probe.

Claims

Claim 1 A step of administering a detection agent for tissue-organ interaction to a subject, a step of detecting the active ingredient accumulated in the tissue and / or organ to be evaluated, a step of quantitatively analyzing the amount of the active ingredient accumulated in the tissue and / or organ to be evaluated, and a step of determining whether there is a correlation between the amounts of the active ingredient accumulated in the tissue and / or organ to be evaluated based on the result of the quantitative analysis, and the detection agent contains, as an active ingredient, a compound represented by the general formula (1-0), 【Chemical 1】 In general formula (1-0), R is -O(CH ２ ), -O(CH ｎ ), -O(CH ２ ), -OCH ｎ -OCH ２ H ４ -, -CH ２ O(CH ２ ), -CH ｎ O(CH ２ ), -CH ２ O(CH ｎ ), -OCH ２ H ４ -, n represents an integer from 1 to 5, and Q １ represents F or -OCH ３ .] A method for detecting tissue-organ interaction.

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