Radioisotope-labeled therapeutic drugs

Abstract

To provide a radioisotope-labeled diagnostic drug, which is a compound labeled with a radioactive halogen on an aromatic ring, can be effectively used as a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, is stable when administered to a living body, does not cause de-astatination of a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, particularly a compound having a therapeutic nuclide 211At on an aromatic ring, so as not to weaken the therapeutic effect, has the same distribution in the body of the therapeutic nuclide and the diagnostic nuclide, can be easily manufactured with high purity, and can be applied to radiotheranostics.SOLUTION: A radioisotope-labeled therapeutic drug comprises a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound represented by Chemical formula 1 (X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a radioisotope-labeled diagnostic agent that can be used as a radiotheranostic agent in combination with nuclear medicine diagnosis and nuclear medicine therapy. [Background technology]

[0002] Nuclear medicine diagnosis involves the use of radioisotopes that emit diagnostic radiation such as highly penetrating gamma rays and positrons (β + This method diagnoses the primary site and progression of a tumor by administering a probe diagnostic compound labeled with a positron nuclide that emits gamma rays. This has been put to practical use as SPECT (Single Photon Emission Computed Tomography) or PET (Positron Emission Tomography), in which a probe diagnostic compound having a tumor target affinity group that binds to a tumor target receptor such as a protein produced in the primary site of a tumor and a radioactively labeled nuclide that emits gamma rays or a positron nuclide that emits positrons is administered, and the annihilation radiation emitted by the combination of diagnosable gamma rays or positrons with electrons is detected by a detector, and an image is produced by a dedicated scintigraphy camera.

[0003] On the other hand, nuclear medicine therapy uses alpha and beta rays, which are highly cytotoxic. - The therapeutic probe compound is administered to shrink the primary tumor or metastatic lesion or to kill tumor cells. The therapeutic probe compound is a compound that is labeled with a radioisotope that emits alpha or beta radiation and binds to a tumor targeting receptor, such as a protein produced by tumor cells in the primary tumor or metastatic lesion. - A probe therapeutic compound having a radionuclide that emits short-range alpha rays (range less than 100 μm) or beta rays is administered to accumulate in the primary tumor or metastatic lesion. - The method involves selectively irradiating tumor cells from within the body with radiation, selectively reducing or killing the tumor cells while causing little or no damage to nearby normal cells, thereby achieving an antitumor effect with few side effects.

[0004] Nuclear medicine diagnosis is primarily focused on diagnosis, while nuclear medicine therapy is primarily focused on treatment. However, in tumor treatment using nuclear medicine therapy, various tests and diagnoses must be performed before treatment begins to determine the appropriate treatment method.

[0005] For this reason, in recent years, a diagnostic and therapeutic method called radiotheranostics, which combines nuclear medicine diagnostics and therapeutics, has been used to use radioisotopes (RI), which are radionuclides with different properties, to perform diagnosis and treatment with compounds having the same or similar skeletons. According to radiotheranostics, a compound containing a diagnostic radionuclide used for diagnosis can be used to predict the therapeutic effect and side effects and set the dosage for each patient, while a compound containing a different therapeutic radionuclide with the same or similar skeleton can be used for treatment, and personalized medicine can be performed with high therapeutic effect and low side effects, and appropriate dosages can be administered to reduce the burden on patients and provide effective treatment or avoid side effects appropriately according to predicted side effects.

[0006] Radiotheranostics, currently being used clinically, is used for the diagnosis and treatment of neuroendocrine tumors. 111 In-DTPA-Octreotide (Octreoscan®) 177 Lu-DOTATATE (Lutathera®) for the diagnosis and treatment of pheochromocytoma 123 I]meta-iodobenzylguanidine (MIBG) (Myo MIBG-I 123 (Myo MIBG is a registered trademark)) and [ 131 I]MIBG (Riot MIBG-I 131) is used.

[0007] on the other hand, 211 At is a radioactive halogen that is the only α-particle emitting nuclide for which a manufacturing method has been established in Japan, and is particularly useful for radiotheranostics because it allows drug design and labeling similar to radioactive iodine. For example, 211A phase I investigator-initiated clinical trial using NaAt for differentiated thyroid cancer is currently underway. 211 In Non-Patent Document 1, which describes the efficacy of NaAt, 211 Correlation between time elapsed after administration / tumor size in K1-NIS tumor-bearing SCID mice administered NaAt, and [ 211 At]NaAt or [ 131 A correlation between time since administration and relative tumor size using I]NaI has been disclosed. 211 At]NaAt is a radiopharmaceutical that utilizes the property of At being taken up by thyroid cancer via the NaI symporter, and the element itself is the active entity of the drug.

[0008] [ 211 At]NaAt instead, 211 A phase I investigator-initiated clinical trial using At-MABG (metastatobenzylguanidine) is underway in patients with melanocytoma / paraganglioma.

[0009] In addition, Non-Patent Document 2 describes the following: 211 A compound labeled with At has been disclosed. 211 When At is released, it exhibits behavior somewhat similar to that of free iodine. However, as shown in Figure 6, 211 At-labeled compound (a) corresponds to 125 Compared with the I-labeled compound (b), it is less stable in vivo and is detected not only in the kidney, which is responsible for excretion, but also in all organs, particularly 211 There was a problem of high accumulation in the stomach and thyroid due to At elimination.

[0010] In addition, the method described in Non-Patent Document 3 211 At-labeled compound ( 211 At-labeled N-[2,2-Bis(hydroxymethyl)-2-(iodomethyl)ethyl]-2-nitroimidazole: 1a) is a compound that has a neopentyl glycol group as the base structure. 211 The At-labeled site is 211 Responding to nucleophilic attack and metabolic enzymes that are thought to be the cause of At loss125 I-labeled compound ( 125 I-labeled N-[2,2-Bis(hydroxymethyl)-2-(iodomethyl)ethyl]-2-nitroimidazole: 1b) can stably retain astatine in vivo, but 211 At compound ( 211 At-labeled N-[N-(meta-iodobenzoyl)-2-aminoethyl]-2-nitroimidazole: 4c) has a hippuric acid derivative group instead of a neopentyl glycol group. 211 The At-labeled sites correspond to 125 I-labeled compound ( 125 I-labeled N-[N-(meta-Iodobenzoyl)-2-aminoethyl]-2-nitroimidazole: 4b) in vivo 211 At cannot be held stable.

[0011] On the aromatic ring 211 The At-labeled compounds have the same structure and are located on the aromatic ring. 125 Compared to compounds labeled with radioactive halogens such as I, 211 The stability of At in vivo 125 In many cases, the stability is much lower than that of radioactive halogens such as I. 211 At-labeled hippuric acid derivatives or analogs, 125 There has been a demand for a substance that exhibits in vivo stability equal to or greater than that of I-labeled hippuric acid derivatives or analogues. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] T. Watanabe, et al., Journal of Nuclear Medicine, 60(9), p.1301-1307 (2021) [Non-Patent Document 2] S. Wilbur, et al., Bioconjugate Chemistry, 15(1), p.203-223 (2004) [Non-Patent Document 3] H. Suzuki, et al., Journal of Medicinal Chemistry, 64(21), p.15846-15857 (2021) Summary of the Invention [Problem to be solved by the invention]

[0013] On the aromatic ring 211 At 125 A compound labeled with a radioactive halogen such as I, which can be effectively used as a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, is stable when administered to a living body, and does not cause a decrease in therapeutic effect, and is a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, particularly a compound having a therapeutic nuclide on an aromatic ring. 211 The object of the present invention is to provide a radioisotope-labeled therapeutic drug that does not cause deastatinization of At-containing compounds, has equivalent distribution in the body between therapeutic and diagnostic nuclides, can be produced easily and with high purity, and can be applied to radiotheranostics. [Means for solving the problem]

[0014] In order to achieve the above object, the present invention provides a radioisotope-labeled therapeutic drug having the following chemical formula (I): [ka] (In the formula (I), X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18.)

[0015] In this radioisotope-labeled therapeutic agent, for example, W is a dimethylcarbamoyl group.

[0016] The radioisotope labeled therapeutic agent may be a radiotheranostic agent having a combination of the radioisotope labeled probe diagnostic compound and the radioisotope labeled probe therapeutic compound.

[0017] This radioisotope-labeled diagnostic drug is a radioisotope-labeled probe diagnostic compound comprising the X 18 F is fluorine, 76 Br, bromine, and 123 I or 124 I is iodine, and the radioisotope-labeled probe therapeutic drug compound is 77 Br is bromine, 125 I or 131 Iodine, which is I; and 211 Preferably, the radioisotope halogen element is selected from astatine, where At is At.

[0018] It is even more preferred that the radioisotope-labeled diagnostic drug is for in vivo kinetic studies and the radioisotope-labeled probe therapeutic drug compound is for internal radiation therapy.

[0019] The radioisotope halogen element-containing compound of the present invention is represented by the following chemical formula (I): [ka] (In the formula (I), X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18.) Effect of the Invention

[0020] The radioisotope-labeled diagnostic agent of the present invention can be effectively used as a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, and can be applied to radiotheranostics.

[0021] This radioisotope-labeled therapeutic drug was developed in consideration of the fact that iodohippuric acid is stable, whereas astatohippuric acid is unstable, and that radioactive halogens are introduced onto aromatic rings in the structure of many probe compounds.Since radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compound compounds are stable even if they have a benzoylamino fatty acid skeleton such as the hippuric acid (benzoylglycine) skeleton shown in chemical formula (I), they can be used as model compounds for radiotheranostics that can be easily applied to other compounds.

[0022] Further, the radioisotope-labeled diagnostic drug is a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, which is provided on an aromatic ring. 211 At 131 I or 125 By being a compound labeled with a radioactive halogen such as I, it is stable even when administered to a living body for diagnosis or treatment, and does not undergo decomposition such as elimination from the aromatic ring.

[0023] In particular, astatine (I), which is generally said to be easy to remove from an aromatic ring, is more difficult to remove from an aromatic ring than iodine (I), etc. 211 At and other elements are difficult to release and decompose, and do not show high accumulation in the stomach or thyroid gland due to release. As a result, there is no reduction in the diagnostic or therapeutic effects even in target tissues.

[0024] Since the radioisotope-labeled medical drug has the same in vivo distribution and absorption of the therapeutic nuclide and diagnostic nuclide of the radioisotope-labeled probe diagnostic compound and the radioisotope-labeled probe therapeutic drug compound, respectively, it is possible to predict the therapeutic effect and side effects and set the dosage for each patient by using the radioisotope-labeled probe diagnostic compound containing the diagnostic radionuclide used for diagnosis, while by administering an appropriate dosage of the radioisotope-labeled probe therapeutic drug compound having the same or a similar skeleton used for treatment and containing a different radionuclide for treatment, it is possible to perform personalized medicine that has a high therapeutic effect and low side effects, reduces the burden on patients, and aims for effective treatment or appropriate avoidance according to predicted side effects.

[0025] According to this radioisotope-labeled diagnostic drug, the radioisotope-labeled probe diagnostic compound and / or the radioisotope-labeled probe therapeutic compound can be primarily circulated throughout the body via the bloodstream by oral ingestion or intravenous injection, and secondarily can be used as a model experiment in which the compound reaches the primary tumor or metastatic lesion in an organ via the bloodstream, or in which nuclear medicine diagnosis or nuclear medicine treatment is performed.

[0026] This radioisotope-labeled diagnostic drug has the same or a similar skeleton as the radioisotope-labeled probe diagnostic compound and the radioisotope-labeled probe therapeutic drug compound, and is absorbed, distributed, metabolized, and excreted in approximately the same manner. Therefore, a model experiment can be conducted in which the radioisotope-labeled probe diagnostic compound is administered in advance as a diagnostic drug to confirm the predicted efficacy, dosage, and method of use of radiation therapy and / or the organ specificity and accumulation at the primary tumor site, and then an appropriate amount of the radioisotope-labeled probe therapeutic drug compound is administered as a therapeutic drug to use the compound as a radiotheranostic drug for radiation therapy.

[0027] This radioisotope-labeled therapeutic drug does not undergo decomposition such as the elimination of the radioisotope halogen element from the radioisotope-labeled probe diagnostic compound and / or the radioisotope-labeled probe therapeutic compound, and is therefore extremely useful as an evaluation model for the diagnostic and therapeutic performance of radioisotope halogen elements.

[0028] This radioisotope-labeled therapeutic drug has not been shown to cause weight loss or serious side effects, at least in in vivo animal experiments, and is therefore safe to use as an evaluation model.

[0029] This radioisotope-labeled therapeutic drug can be produced easily and with high purity, making it applicable to radiotheranostics.

[0030] This radioisotope-labeled therapeutic drug can be produced simply and with high purity by introducing a radioisotope element in the final process to convert it into a radioisotope-labeled probe diagnostic compound or a radioisotope-labeled probe therapeutic compound, which is easy to handle in the medical field. [Brief description of the drawings]

[0031] [Figure 1] 1 is a chromatogram showing the HPLC measurement results of radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compounds in radioisotope-labeled diagnostic drugs to which the present invention is applied, as well as the corresponding non-radioisotope compounds. [Diagram 2] 1 is a chromatogram showing the HPLC measurement results of radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compounds in radioisotope-labeled medical drugs to which the present invention is not applicable, and the corresponding non-radioisotope compounds. [Diagram 3] 1 is a chromatogram showing the HPLC measurement results of radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compounds in radioisotope-labeled medical drugs to which the present invention is not applicable, and the corresponding non-radioisotope compounds. [Figure 4] 1 is a graph showing the distribution of radioisotope-labeled probe diagnostic compounds in a radioisotope-labeled medical drug to which the present invention is applied and a radioisotope-labeled probe diagnostic compound to which the present invention is not applied, and the distribution of radioisotope-labeled probe therapeutic compound in a radioisotope-labeled medical drug to which the present invention is applied and a radioisotope-labeled probe therapeutic compound to which the present invention is not applied, in each organ. [Diagram 5]1 is a graph showing the distribution of radioisotope-labeled probe diagnostic compounds in a radioisotope-labeled diagnostic drug to which the present invention is applied and a radioisotope-labeled probe diagnostic compound to which the present invention is not applied, and the distribution of radioisotope-labeled probe therapeutic compound in a radioisotope-labeled diagnostic drug to which the present invention is applied and a radioisotope-labeled probe therapeutic compound to which the present invention is not applied, in each organ, and the distribution of radioisotope-labeled probe therapeutic compound in a radioisotope-labeled diagnostic drug to which the present invention is applied and a radioisotope-labeled probe therapeutic compound to which the present invention is not applied, in the stomach and thyroid gland. [Figure 6] 1 is a graph showing the distribution in each organ of a radioisotope-labeled probe diagnostic compound in a radioisotope-labeled medical drug to which the present invention is not applied and a radioisotope-labeled probe therapeutic drug compound to which the present invention is not applied. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Examples of the present invention will be described in detail below, but the scope of the present invention is not limited to these examples.

[0033] A preferred embodiment of the radioisotope-labeled therapeutic agent for carrying out the present invention is represented by the following chemical formula (I): [ka] The radioisotope-labeled therapeutic drug is a combination of a radioisotope-labeled probe diagnostic compound which is a benzoylamino fatty acid labeled with a radioisotope halogen element at position 4 and substituted with an electron-withdrawing group (W) at positions 3 and 5, represented by formula (I): (in which X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18), and a radioisotope-labeled probe therapeutic compound.

[0034] A preferred example of these compounds is one in which W in formula (I) is an N,N-dimethylcarbamoyl group (-CO-N(CH3)2) and n=1, and is represented by the following formula (II): [ka] The hippuric acid derivative (benzoylglycine: benzoylaminoacetic acid) represented by the formula (4) is a radioisotope halogen-labeled 3,5-bis(N,N-dimethylcarbamoyl)benzoylglycine. Specifically, in the case of a radioisotope-labeled probe diagnostic compound, X is 125 I, and in the case of a radioisotope-labeled probe therapeutic compound, X is 211 At.

[0035] As a preferred example of these compounds, those represented by the chemical formula (II) are given, but they may also be hippuric acid derivatives having W and X (benzoylglycine: benzoylaminoacetic acid), and hippuric acid analogues having W and X (benzoylamino fatty acid; where the fatty acid is -(CH2) n -COOH (n is 1 to 18, where n=1 corresponds to chemical formula (II)).

[0036] Among the electron-withdrawing groups, W is preferably N,N-dimethylcarbamoyl. When W is an electron-withdrawing group, it is preferable to use a radioisotope halogen atom, especially a methoxymethyl group, on an aromatic ring, rather than a hydroxymethyl group or a methoxymethyl group, which are not electron-withdrawing groups. 211 The stability of At is improved, and it is less likely to be removed from the aromatic ring even when administered to the body. Although the details are not entirely clear, it is presumed that this is because the radioisotope halogen element on the aromatic ring delocalizes electrons together with the aromatic ring due to the electron-withdrawing group: W, contributing to stability.

[0037] X is not particularly limited as long as it is a radioisotope halogen element. In the case of a radioisotope-labeled probe diagnostic compound, 125 In addition to I, 18 F is fluorine, 76 Br and / or bromine, 123 I, and 124 I, and in the case of a radioisotope labeled probe therapeutic compound, 77 Br is bromine, 125 I or 131 Iodine, which is I; and 211 It may be astatine, where At is At.77 Br and 125 I is an Auger electron emitting nuclide.

[0038] Among these radioisotope-labeled diagnostic drugs, the radioisotope-labeled probe diagnostic compound and the radioisotope-labeled probe therapeutic compound have a hippuric acid derivative or hippuric acid analog skeleton having an electron-withdrawing group, particularly N,N-dimethylcarbamoyl, thereby enhancing their biostability.

[0039] The synthesis method will be described using the radioisotope-labeled probe diagnostic compound and radioisotope-labeled probe therapeutic compound represented by chemical formula (II) as examples. First, 4-hydroxybenzoic acid alkyl ester is 3,5-bis(formyl)-converted, the hydroxyl group is converted to trifluoromethanesulfonic acid ester (i.e., Tf ester), and then iodized to obtain a 4-iodo compound. The formyl group is oxidized to a carboxy group, which is then derived into an N,N-dimethylamide compound (i.e., an N,N-dimethylcarbamoyl group). The 4-iodo group is replaced with a tributyltin group. The carboxy group obtained by hydrolyzing the benzoic acid ester group is converted to succinimidyl and replaced with glycine. Finally, the tributyltin group is 125 I or 211 By substituting At,

[0040] In the case where W in chemical formula (I) is an electron-withdrawing group other than an N,N-dimethylcarbamoyl group, the compound can be similarly synthesized using a raw material having an electron-withdrawing group at the 3- and 5-positions of the aromatic ring or a raw material that can be derived to such an electron-withdrawing group.

[0041] Also X 125 I or 211 Radioisotope halogen elements other than At can also be synthesized in the same manner by substituting the tributyltin group in the final step.

[0042] Although radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compounds differ in whether they are radioactive or non-radioactive isotopes, they share a common or similar basic structure, and therefore, together with the equivalent stability of the respective radioisotope halogen elements, they exhibit similar pharmacokinetics.

[0043] Therefore, by administering a radioisotope-labeled probe diagnostic compound in advance, the radioisotope-labeled probe diagnostic compound can be administered as a diagnostic drug to confirm properties such as predicted efficacy, dosage, administration method, and organ specificity of radiation therapy, or to examine properties such as accumulation in the primary tumor or metastatic lesion.

[0044] These properties can be confirmed by dissolving or suspending the radioisotope-labeled probe diagnostic compound in saline, injecting the solution intravenously into a patient, and measuring the radioactivity distribution using a SPECT or PET camera 5 minutes to 3 hours, preferably 1 to 3 hours, after injection.

[0045] By administering and detecting the radioisotope-labeled probe diagnostic compound, the properties of the radioisotope-labeled probe therapeutic compound, such as the dosage, can be confirmed, or the tumor accumulation can be predicted.

[0046] This allows the radioisotope-labeled probe therapeutic compound to be used in studies to shrink or kill primary tumor lesions or tumor cells by appropriately adjusting the dose and administration method according to the predicted efficacy of radiation therapy and the predicted organ-specific accumulation of the compound in the primary tumor lesion.

[0047] In this way, radioisotope-labeled therapeutic drugs, which are radiotheranostics drugs that combine radioisotope-labeled probe diagnostic compounds and radioisotope-labeled probe therapeutic compounds, can provide customized treatment according to the type of tumor and the location, range, and progression of the primary lesion for each patient. It is not always necessary to use a radioisotope-labeled probe diagnostic compound and a radioisotope-labeled probe therapeutic compound together, and if it becomes possible to study universal efficacy prediction and organ-specific accumulation prediction at the primary lesion of tumors with the radioisotope-labeled probe diagnostic compound, it will be sufficient to only administer the radioisotope-labeled probe therapeutic compound. EXAMPLES

[0048] The following describes an example of the radioisotope-labeled medical drug to which the present invention is applied, which is used as a radiotheranostics drug. The radioisotope-labeled medical drug is synthesized with a radioisotope-labeled probe diagnostic compound and a radioisotope-labeled probe therapeutic compound, and the radioisotope-labeled probe therapeutic compound are used in combination. Comparative examples to which the present invention is not applied are also described.

[0049] (Synthesis Example 1: Synthesis of radioisotope-labeled probe diagnostic compound (C10-a) and radioisotope-labeled probe therapeutic compound (C10-b)) The following chemical reaction formula (III) [ka] As shown in Figure 1, a radioisotope-labeled probe diagnostic compound (C10-a) and a radioisotope-labeled probe therapeutic compound (C10-b) according to the present invention were synthesized. The details of the synthesis are as follows.

[0050] (Synthesis Example 1-1: 125 Synthesis of I-substituted radioisotope-labeled probe diagnostic compound (C10-a) [Synthesis of Methyl 3,5-diformyl-4-hydroxybenzoate (B1)] 5.08 g (33.4 mmol) of methyl 4-hydroxybenzoate was dissolved in 25 mL of trifluoroacetic acid (TFA) and stirred at 80° C. for 84 hours. The completion of the reaction was confirmed by TLC, and 100 mL of water was added and further stirred at 90° C. The precipitated solid was collected by suction filtration and washed with water to obtain 4.39 g of compound B1 as a yellow solid (yield 63.0%). 1 H-NMR (CDCl3): δ 12.1 (1H, s) 10.3 (2H, s) 8.66 (2H, s), 3.97 (3H, s) HRMS (ESI + ) (m / z calcd for C 10 H9O5[M+H] + ): 209.0445 found: 209.0450.

[0051] [Synthesis of Methyl 3,5-diformyl-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (B2)] Under a nitrogen atmosphere, dichloromethane and pyridine were added to 1.0 g (4.8 mmol) of B1, and the mixture was stirred. The mixture was then placed in an ice bath and 1.05 mL of trifluoromethanesulfonic anhydride (1.04 mL) was added dropwise at 70 μL / min. The mixture was stirred in an ice bath for 5 minutes and then stirred at room temperature for 3.5 hours. The mixture was quenched by adding 23 mL of 1.5 M HCl, extracted with dichloromethane, and the solvent was distilled off under reduced pressure to obtain 1.27 g of compound B2 as a brown oily substance. (Yield 80.8%) 1 H-NMR (CDCl3): δ 10.31 (2H, s), 8.88 (2H, s), 4.02 (3H, s).

[0052] [Synthesis of Methyl 3,5-diformyl-4-iodobenzoate (B3)] Compound B2 (465 mg, 1.37 mmol) and sodium iodide (1.39 g, 9.31 mmol, 6.3 eq) were dissolved in N,N-dimethylformamide (DMF), shielded from light, stirred, and stirred under a nitrogen atmosphere at 80°C for 5 hours. Extraction was performed with 30 mL of ethyl acetate:hexane (1:1), and the organic phase was collected and the solvent was removed under reduced pressure to obtain compound B3 (277.9 mg) as a brown solid (yield 63.7%). 1 H-NMR (CDCl3): δ 10.3 (2H, s), 8.65 (2H, s), 3.99 (3H, s).

[0053] [Synthesis of 2-Iodo-5-(methoxycarbonyl)isophthalic acid (C4)] Compound B3 (200 mg, 62.9 mmol) was dissolved in t-butyl alcohol, isobutene was added, and the mixture was left under ice cooling. Sodium chlorite (341.0 mg, 3.77 mmol, 6 eq) and disodium hydroxide dihydrate (294.0 mg, 1.89 mmol, 3 eq) dissolved in 800 μL of HO were added, and the mixture was stirred at room temperature for 3 hours. 0.1 M HCl was added in small portions to adjust the pH to 3, and the mixture was extracted with 10 mL of ethyl acetate. The solvent was removed under reduced pressure to obtain 195.0 mg of compound C4 as a white solid. (Yield 88.6%) 1 H-NMR (CD3OD): δ 8.12 (2H, s), 3.91 (3H, s) HRMS (ESI + ) (m / z calcd for C 10 H7INaO6[M+Na] + ): 372.9180 found: 372.9185.

[0054] [Synthesis of methyl 3,5-bis(dimethylcarbamoyl)-4-iodobenzoate (C5)] Compound C4 (20 mg, 57 μmol) was dissolved in 300 μL of dichloromethane, thionyl chloride (16.4 μL, 22.8 μmol) was slowly added dropwise, 5 μL of DMF was added, and the mixture was stirred at room temperature for 4.5 hours. The solvent was removed by distillation using nitrogen gas, and 285 μL of dichloromethane was added. N,N-diisopropylethylamine (DIPEA) (199 μL, 1.14 mmol) and dimethylamine hydrochloride (46.6 mg, 571.2 μmol) were dissolved in 285 μL of dichloromethane solution, and the mixture was placed under ice cooling, added to the solution, and stirred at room temperature for 1.5 hours. After stirring, the solvent was removed under reduced pressure, and the residue was subjected to silica gel chromatography using a solvent that changed from dichloromethane:methanol (100:0) to (50:1) as the elution solvent, and 18.4 mg of compound C5 was obtained as a white solid (yield 20.0%). 1 H-NMR (CDCl3): δ 7.82 (2H, s), 3.91 (3H, s), 3.16 (6H, s), 2.86 (6H, s). HRMS (ESI + ) (m / z calcd for C 14 H 18 IN2O4[M+H] + ): 405.0306 found: 405.0311.

[0055] [Synthesis of Methyl 3,5-bis(dimethylcarbamoyl)-4-(tributylstannyl)benzoate (C6)] Compound C5 (15 mg, 37.1 μmol) was dissolved in 200 μL of 2-propanol, and bistributyltin (111 μL, 223.6 μmol, 6 eq), tris(dibenzylideneacetone)dipalladium (0) (3.4 mg, 3.72 μmol, 0.1 eq), and DIPEA (16 μL, 92.8 μmol, 2.5 eq) were added under a nitrogen atmosphere, and the mixture was stirred at 85 ° C for 48 hours. After filtration through Celite and washing with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography containing 10% potassium carbonate using a solvent that changes from hexane:ethyl acetate (1:0) to (1:1) as an elution solvent, to obtain 4.2 mg of compound C6 as a colorless oily substance (yield 20.0%). 1 H-NMR (CDCl3): δ7.87 (2H, s), 3.92 (3H, s), 3.12 (6H, s), 2.98 (6H, s), 1.56-1.40 (2H, m), 1.37-1.26 (6H, m), 1.11-1.00 (6H, m), 0.92-0.87 (9H, m)

[0056] [Synthesis of 3,5-Bis(dimethylcarbamoyl)-4-(tributylstannyl)benzoic acid (C7)] Compound C6 (4.0 mg, 7.1 μmol) was dissolved in 21 μL of 1,4-dioxane, and 1 M NaOH (21 μL, 21 μmol, 3 eq) was added and stirred at room temperature for 1 hour. Under ice cooling, 1 M HCl was added in small portions to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The solvent was then distilled off under reduced pressure to give 3.4 mg of compound C7 as a colorless oil (yield 87.1%). 1 H-NMR (CDCl3): δ 7.87 (2H, s), 3.10 (6H, s), 2.96 (6H, s), 1.55-1.39 (6H, m), 1.35-1.24 (6H, m), 1.10-0.94 (6H, m), 0.93-0.85 (9H, m)

[0057] [Synthesis of 2,5-Dioxopyrrolidin-1-yl 3,5-bis(dimethylcarbamoyl)-4-(tributylstannyl)benzoate (C8)] Compound C7 (3.4 mg, 6.1 μmol), N-hydroxysuccinimide (NHS) (0.85 mg, 7.4 μmol, 1.2 eq), and EDCI·HCl (1.8 mg, 9.21 μmol, 1.5 eq) were dissolved in 200 μL of dichloromethane and stirred at room temperature for 1.5 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was subjected to silica gel chromatography using ethyl acetate as an eluent to obtain 4.2 mg of compound B9 as a colorless white solid (yield 102%). Although impurities were present, purification was performed after the next reaction. 1 H-NMR (CDCl3): δ 7.93 (2H, s), 3.12 (6H, s), 2.98 (6H, s), 2.86 (4H, brs), 1.54-1.41 (6H, m), 1.36-1.21 (6H, m), 1.11-0.97 (6H, m), 0.94-0.84 (9H, m)

[0058] [Synthesis of (3,5-Bis(dimethylcarbamoyl)-4-(tributylstannyl)benzoyl)glycine (C9)] Compound C8 (2.5 mg, 3.8 μmol) was dissolved in 100 μL of dimethylformamide, DIPEA (5.3 μL, 30.4 μmol, 8 eq) was added, and glycine (1.4 mg, 19.2 μmol, 5 eq) dissolved in 8 μL of water was added dropwise and stirred at room temperature for 30 minutes. The yield of the reaction was confirmed by TLC, and purification was performed by reversed-phase HPLC to obtain 1.5 mg of compound C9 as a white solid (yield 62.4%). Cosmosil 5C was used for the reversed-phase HPLC. 18The elution was performed using an AR-II (10 × 150 mm) column with a gradient of 20 min from water:methanol (20:80) containing 0.01% TFA to (0:100) over a 20-minute period at UV = 254 nm and a flow rate of 4.0 mL / min. 1 H-NMR (CDCl3): δ 7.70 (2H, s), 4.11 (2H, m), 3.12 (6H, s), 2.94 (6H, s), 1.49-1.39 (6H, m), 1.38-1.28 (6H, m), 1.02-0.93 (6H, m), 0.91-0.86 (9H, m) HRMS (ESI + ) (m / z calcd for C 27 H 45 N3NaO5Sn[M+Na] + ): 634.2274 found: 634.2279.

[0059] [ [ 125 I]Synthesis of (3,5-Bis(dimethylcarbamoyl)-4-iodobenzoyl)glycine (C10-a) 50 μg of compound C9 was dissolved in 20 μL of acetonitrile, and the solution was diluted with 20 μL of 0.5 M HCl, 25 μL of 6% H2O2, and [ 125 The mixture was stirred with [I]NaI (1.5 MBq), heated at 80°C for 15 min, and purified by reversed-phase HPLC. 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.1% TFA-containing water:methanol, changing from 85:15 to 65:35 in 20 minutes, at a flow rate of 1.0 mL / min. This structure is supported by the fact that the retention time in reversed-phase HPLC matches that of the non-radioactive iodine compound C13.

[0060] (Synthesis Example 1-2: 211 Synthesis of At-substituted radioisotope-labeled probe therapeutic compound (C10-b) In the final step of the chemical reaction formula (III) in Synthesis Example 1-1, 125 I]NaI instead of: 211 The same procedure as in Synthesis Example 1-1 was repeated except that NaAt was used. 211 A At-substituted radioisotope-labeled probe therapeutic compound (C10-b) was synthesized. The details of the synthesis are as follows.

[0061] [ [ 211 Synthesis of (3,5-Bis(dimethylcarbamoyl)-4-astatobenzoyl)glycine (C10-b) 50 μg of compound C9 was dissolved in 20 μL of acetonitrile, and the solution was diluted with 20 μL of 0.5 M HCl, 25 μL of 6% H2O2, and [ 211 At]At - (1.5 MBq) was added, stirred, heated at 95°C for 15 min, and purified by reversed-phase HPLC. 18 The column was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient of 0.1% TFA-containing water:methanol, changing from 85:15 to 65:35 in 20 minutes, at a flow rate of 1.0 mL / min. The compound was identified based on the similar retention time in reversed-phase HPLC to that of the non-radioactive iodine compound C13.

[0062] (Synthesis Reference Example 1-3: Synthesis of I-substituted non-radioisotope compound (C13)) In the chemical reaction formula (III) in Synthesis Examples 1-1 and 1-2, the intermediate (C5) is not stannylated, and [ 125 I]NaI / [ 211 An I-substituted non-radioisotope compound (C13) was synthesized in the same manner as in Synthesis Example 1-1, except that radioisotope substitution with At]NaAt was not performed (not shown in chemical reaction formula (III)). The details of the synthesis are as follows.

[0063] [Synthesis of 3,5-Bis(dimethylcarbamoyl)-4-iodobenzoic acid (C11)] Compound C5 (30.0 mg, 72.4 μmol) was dissolved in 1,4-dioxane (100 μL), 6 M NaOH (80.5 μL, 483 μmol, 6.7 eq) was added, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, 1 M HCl was added in small portions to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The solvent was then distilled off under reduced pressure to obtain 13.9 mg of compound C11 as a white solid (yield 48.0%). 1 H-NMR (CDCl3): δ7.83 (2H, s), 3.17 (6H, s), 2.87 (6H, s).

[0064] [Synthesis of 2,5-Dioxopyrrolidin-1-yl 3,5-bis(dimethylcarbamoyl)-4-iodobenzoate (C12)] Compound C11 (13.9 mg, 35.6 μmol), NHS (4.9 mg, 42.7 μmol, 1.2 eq), and EDCI·HCl (10.2 mg, 53.4 μmol, 1.5 eq) were dissolved in 200 μL of dichloromethane and stirred at room temperature for 1.5 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was subjected to silica gel chromatography using ethyl acetate as an eluent to obtain 6.2 mg of compound B9 as a white solid (yield 35.7%). 1 H-NMR (CDCl3): δ 7.90 (2H, s), 3.16 (6H, s), 2.91 (4H, brs), 2.87 (6H, s).

[0065] [Synthesis of (3,5-Bis(dimethylcarbamoyl)-4-iodobenzoyl)glycine (C13)] Compound C12 (6.2 mg, 12.7 μmol) was dissolved in 200 μL of DMF, DIPEA (17.7 μL, 101.6 μmol, 8 eq) was added, and glycine (4.7 mg, 63.6 μmol, 5 eq) dissolved in 20 μL of water was added dropwise and stirred at room temperature for 1 hour. The yield of the reaction was confirmed by TLC, and purification was performed by reversed-phase HPLC to obtain 1.7 mg of compound C13 as a white solid (yield 29.9%). Cosmosil 5C was used for the reversed-phase HPLC. 18 The elution was performed using an AR-II (10 × 150 mm) column with a gradient of 0.1% TFA in water:methanol (80:20) to (70:30) in 10 min at UV = 254 nm and a flow rate of 4.0 mL / min. 1 H-NMR (CDCl3):δ 4.02 (2H, s), 3.13 (6H, s), 2.90 (3H, S), 2.88 (3H, s) HRMS (ESI + ) (m / z calcd for C 15 H 18 IN3NaO5[M+Na] + ): 470.0184 found: 470.0189. NMR and mass spectrometry data were consistent with the predicted values, supporting this structure.

[0066] (Purity Test I: High Performance Liquid Chromatography Analysis of Compounds (C10-a)·(C10-b)·(C13)) Obtained 125 I-substituted radioisotope-labeled probe diagnostic compounds (C10-a); 211 High performance liquid chromatography (HPLC) analysis was performed on the At-substituted radioisotope-labeled probe therapeutic drug compound (C10-b) and the I-substituted non-radioisotope compound (C13). The analytical conditions were as follows: Column: COSMOSIL 5C 18-AR-II 4.6ID × 150 mm (Nacalai Tesque, Inc.; product name), flow rate: 1.0 mL / min, temperature: 40°C, mobile phase: A) 0.1% TFA in H2O and B) 0.1% TFA in MeOH, mixture of solution A / solution B: 85 / 15 → 65 / 35 (20 min). The chromatogram is shown in Figure 1. In addition, 125 The radiochemical yield of the I-substituted radioisotope-labeled probe diagnostic compound (C10-a) was 38% when fractionated by HPLC and measured with a gamma counter, and the radiochemical purity was 96%. 211 The radiochemical yield of the At-substituted radioisotope labeled probe therapeutic compound (C10-b) was 22% and the radiochemical purity was 98%.

[0067] As is clear from Figure 1, the high-performance liquid chromatogram using radioactivity as an index 125 I-substituted radioisotope-labeled probe diagnostic compound (C10-a) 211 The structures of these compounds are supported by the fact that the retention time was almost the same as that of the At-substituted radioisotope-labeled probe therapeutic drug compound (C10-b), the high-performance liquid chromatograms of the iodine-substituted and astatine-substituted compounds, which generally have the same structure, are almost identical, the I-substituted non-radioisotope compound (C13) was identified by mass spectrometry (MS), and the iodine-astatine substitution from the tributyltin group reacts quantitatively.

[0068] (Comparative Synthesis Example 1: Synthesis of radioisotope-labeled probe diagnostic compound (B10-a) and radioisotope-labeled probe therapeutic compound (B10-b)) The following chemical reaction formula (IV) [ka] As shown in Figure 1, a radioisotope-labeled probe diagnostic compound (B10-a) and a radioisotope-labeled probe therapeutic compound (B10-b) to which the present invention is not applicable were synthesized. The details of the synthesis are as follows.

[0069] (Comparative Synthesis Example 1-1: 125 Synthesis of I-substituted radioisotope-labeled probe diagnostic compound (B10-a) In the above Synthesis Example 1-1, intermediate B3 was synthesized in the same manner. Using this intermediate B3 as a raw material, the subsequent synthesis of methyl 3,5-bis(hydroxymethyl)-4-iodobenzoate (B4) was carried out.

[0070] [Synthesis of Methyl 3,5-bis(hydroxymethyl)-4-iodobenzoate (B4)] Compound B3 (277.9 mg, 0.8 mmol) was dissolved in 10 mL of methanol, and NaBH4 (40 mg, 1 mmol, 1.2 eq) was added in an ice bath, and the mixture was stirred at room temperature for 1.7 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with 20 mL of ethyl acetate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography using a solvent that changed from hexane:ethyl acetate (4:1) to (1:1) as the elution solvent, and 113.4 mg of compound B4 was obtained as a white solid (yield 44.0%). 1 H-NMR (CD3OD) δ 8.05 (2H, s), 4.65 (4H, s), 3.92 (3H, s)

[0071] [Synthesis of Methyl 4-iodo-3-(2-methoxyethyl)-5-((methoxymethoxy)methyl)benzoate (B5)] Compound B4 (78.8 mg, 240 μmol), lithium bromide (2.1 mg, 24 μmol, 0.1 eq), and toluenesulfonic acid (4.2 mg, 24 μmol, 0.1 eq) were dissolved in 720 μL of dimethoxymethane, placed under nitrogen, and stirred at room temperature for 20 hours. 3 mL of ethyl acetate was added, and the mixture was quenched by adding 50 μL of saturated sodium bicarbonate water in an ice bath. The target product was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using a solvent that changed from hexane:ethyl acetate (5:1) to (2:1) as the elution solvent, and 35.1 mg of compound B5 was obtained as a white solid (yield 35.7%). 1 H-NMR (CDCl3): δ 8.03 (2H, s), 4.81 (2H, s), 4.66 (2H, s), 3.93 (3H, s) 3.44 (6H, s) HRMS (ESI + ) (m / z calcd for C 14 H 19 INaO6[M+Na] + ): 433.0119 found: 433.0124.

[0072] [Synthesis of Methyl 3,5-bis((methoxymethoxy)methyl)-4-(tributylstannyl)benzoate (B6)] Compound B5 (30.0 mg, 73 μmol) was dissolved in 1.5 mL of 2-propanol, and bistributyltin (296 μL, 292 μmol, 4 eq), tris(dibenzylideneacetone)dipalladium (0) (13.4 mg, 14.6 μmol, 0.2 eq), and DIPEA (30 μL, 36 μmol, 2.5 eq) were added under a nitrogen atmosphere, and the mixture was stirred at 110 ° C for 48 hours. After filtration through Celite and washing with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using a solvent that changes from hexane:ethyl acetate (20:1) to (8:1) as an elution solvent, and 35.0 mg of compound B6 was obtained as a colorless oily substance (yield 83.6%). 1 H-NMR (CDCl3): δ 7.97 (2H, t, J = 5.8 Hz), 4.66 (2H, s), 4.62 (2H, s), 3.91 (3H, s), 3.44 (6H, s), 1.52-1.42 (6H, m), 1.40-1.27 (6H, m), 1.15-1.10 (6H, m), 0.95-0.86 (9H, m) HRMS (ESI + ) (m / z calcd for C 26 H 46 NaO6Sn [M+Na] + ): 597.2299 found: 595.2300

[0073] [Synthesis of 3,5-Bis((methoxymethoxy)methyl)-4-(tributylstannyl)benzoic acid (B7)] Compound B6 (25 mg, 44 μmol) was dissolved in 208 μL of 1,4-dioxane, 1 M NaOH (118 μL, 118 μmol, 2.7 eq) was added, and the mixture was stirred at room temperature for 30 hours. 1 M HCl (242 μL, 242 μmol, 5.5 eq) was added under ice cooling, and the solvent was distilled off under reduced pressure. The residue was changed from hexane:ethyl acetate (9:1) to (3:1), and then subjected to silica gel chromatography using dichloromethane:methanol (20:1) as the eluent, to obtain 10.5 mg of compound B7 as a colorless oily substance (yield 42.7%). 1 H-NMR (CDCl3): δ 8.03 (2H, t, J = 5.6 Hz), 4.67 (2H, s), 4.63 (2H, s), 3.41 (6H, s), 1.54-1.43 (6H, m), 1.40-1.20 (6H, m), 1.22-1.04 (6H, m), 0.91-0.84 (9H, m)

[0074] [Synthesis of 2,5-Dioxopyrrolidin-1-yl-3,5-bis((methoxymethoxy)methyl)-4-(tributylstannyl)benzoate (B8)] Compound B7 (13.1 mg, 23.6 μmol), NHS (3.2 mg, 28.3 μmol, 1.2 eq), and EDCI·HCl (6.8 mg, 35.4 μmol, 1.5 eq) were dissolved in 472 μL of dichloromethane and stirred at room temperature for 2 hours. The mixture was subjected to silica gel chromatography using a solvent that changed from hexane:ethyl acetate (4:1) to (2:1) as the eluent to obtain 5.8 mg of compound B8 as a colorless oil (yield 37.4%). 1H-NMR (CDCl3): δ 8.07 (2H, t, J = 5.2 Hz), 4.68 (2H, s), 4.64 (2H, s), 3.41 (6H, s), 2.91 (4H, brs) 1.55-1.44 (6H, m), 1.39-1.30 (6H, m), 1.21-1.07 (6H, m), 0.92-0.87 (9H, m)

[0075] [Synthesis of (3,5-Bis((methoxymethoxy)methyl)-4-(tributylstannyl)benzoyl)glycine (B9)] Compound B8 (5.0 mg, 7.6 μmol) was dissolved in 76 μL of dimethylformamide, DIPEA (10.0 μL, 2.9 μmol, 8 eq) was added, and glycine (4 mg, 53.2 μmol, 7 eq) dissolved in 50 μL of water was added dropwise and stirred at room temperature for 2.5 hours. Purification by reversed-phase HPLC was performed to obtain 1.0 mg of compound B9 as a colorless oily substance (yield 21.3%). Cosmosil 5C was used for the reversed-phase HPLC. 18 The column was an AR-II (10 × 150 mm) and the mobile phase was a gradient method changing from water:methanol (0:90) containing 0.1% TFA to (0:100) in 10 minutes at UV = 254 nm and a flow rate of 4.0 mL / min. LRMS (ESI + ) (m / z calcd for C 27 H 48 NO7Sn [M+H] + ): 618.1 found: 618.1

[0076] [ [ 125 I]Synthesis of 4-Iodo-3,5-bis((methoxymethoxy)methyl)benzoyl)glycine (B10-a) 50 μg of compound B9 was dissolved in 10 μL of acetonitrile, and 10 μL of 3% acetic acid / acetonitrile solution was added. 125I]NaI (1.5 MBq) and 15 μL of N-chlorosuccinimide / acetonitrile solution (1 mg / mL) were added, and the mixture was left at room temperature for 15 minutes, after which it was purified by reversed-phase HPLC. 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.01% TFA-containing water:methanol, changing from 60:40 to 30:70 in 20 minutes, at a flow rate of 1.0 mL / min. The identity of the compound is supported by a similar retention time on reversed-phase HPLC to that of the non-radioactive iodine compound, B14.

[0077] (Comparative Synthesis Example 1-2: 211 Synthesis of At-substituted radioisotope-labeled probe therapeutic compound (B10-b) In the final step of the chemical reaction formula (IV) in Comparative Synthesis Example 1-1, 125 I]NaI instead of: 211 The same procedure as in Comparative Synthesis Example 1-1 was repeated except that NaAt was used. 211 A At-substituted radioisotope-labeled probe therapeutic compound (B10-b) was synthesized. The details of the synthesis are as follows.

[0078] [ [ 211 At](Preparation of 4-Astato-3,5-bis((methoxymethoxy)methyl)benzoyl)glycine (B10-b) 50 μg of compound B9 was dissolved in 10 μL of acetonitrile, and 20 μL of 3% acetic acid / acetonitrile solution was added. 211 At]At - 25 μL of 1.1 MBq N-chlorosuccinimide (NCS) / acetonitrile solution (1 mg / mL) was added and the mixture was left to stand at room temperature for 15 minutes. The solvent was then removed with nitrogen gas, and 50 μL of a mixed solution of 1,4-dioxane:HCl = 1:4 was added, the mixture was left to stand for 10 minutes, and the mixture was purified by reversed-phase HPLC. Cosmosil 5C was used for the reversed-phase HPLC. 18The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.01% TFA-containing water:methanol, changing from 60:40 to 30:70 in 20 minutes, at a flow rate of 1.0 mL / min. The compound was identified based on its similar retention time in reversed-phase HPLC to that of the non-radioactive iodine compound B14.

[0079] (Synthesis Comparative Example 1-3: Synthesis of I-substituted non-radioisotope compound (B14)) In the chemical reaction formula (IV) in Comparative Synthesis Examples 1-1 and 1-2, the intermediate (B5) is not stannylated, and [ 125 I]NaI / [ 211 An I-substituted non-radioisotope compound (B14) was synthesized in the same manner as in Comparative Synthesis Example 1-1, except that radioisotope substitution with At]NaAt was not performed (not shown in Chemical Reaction Formula (IV)). The details of the synthesis are as follows.

[0080] [Synthesis of 4-Iodo-3,5-bis((methoxymethoxy)methyl)benzoic acid (B12)] Compound B5 (100 mg, 0.24 mmol) was dissolved in 1,4-dioxane (1.2 mL), 1 M NaOH (580 μL, 0.58 mmol, 2.4 eq) was added, and the mixture was stirred at room temperature for 3 hours. 1 M HCl (370 μL, 370 μmol, 1.5 eq) was added under ice cooling, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using a solvent that changed from hexane:ethyl acetate (3:1) to dichloromethane:methanol (20:1) as the elution solvent, and 77.6 mg of compound B12 was obtained as a white solid (yield 81.6%). 1 H-NMR (CDCl3): δ 8.07 (2H, s), 4.82 (2H, s), 4.67 (2H, s), 3.45 (6H, s) HRMS (ESI + ) (m / z calcd for C 13 H 17 INaO6[M+Na]+ ):418.9962 found: 418.9975.

[0081] [Synthesis of 2,5-Dioxopyrrolidin-1-yl 4-iodo-3,5-bis((methoxymethoxy)methyl)benzoate (B13)] Compound B12 (70 mg, 0.18 mmol), NHS (24.4 mg, 0.21 μmol, 1.2 eq), and EDCI·HCl (50.8 mg, 0.265 mmol, 1.5 eq) were dissolved in 3.5 mL of dichloromethane and stirred at room temperature for 2 hours. Silica gel chromatography using hexane:ethyl acetate (1:1) as the eluent gave 74.7 mg of compound B13 as a white solid (yield 85.6%). 1 H-NMR (CDCl3): δ 8.13 (2H, s), 4.81 (2H, s), 4.66 (2H, s), 3.45 (6H, s), 2.91 (4H, brs)

[0082] [Synthesis of (4-Iodo-3,5-bis((methoxymethoxy)methyl)benzoyl)glycine (B14)] Compound B13 (30.4 mg, 61.6 μmol) was dissolved in 600 μL of 1,4-dioxane:water (1:1), NaHCO3 (25.9 mg, 5 eq) and glycine (9.3 mg, 123.2 μmol, 2 eq) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 3 by adding 1 M HCl in small portions, and then extracted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain 23.6 mg of compound B14 as a white solid (yield 84.5%). 1 H-NMR (CDCl3): δ 7.84 (2H, s),6.76 (1H, s) 4.82 (2H, s), 4.66 (2H, s), 4.32 (2H, d, J = 5.6 Hz), 3.45 (6H, s) HRMS (ESI +) (m / z calcd for C 15 H 21 INO7[M+H] + ): 454.0357 found: 454.0363. The I-substituted non-radioactive compound (B14) was obtained. The NMR and mass spectrometry results were consistent with the expected values, supporting this structure.

[0083] (Purity Test II: High Performance Liquid Chromatography Analysis of Compounds (B10-a), (B10-b), and (B14)) Obtained 125 I-substituted radioisotope-labeled probe diagnostic compound (B10-a), 211 High performance liquid chromatography (HPLC) analysis was performed on the At-substituted radioisotope labeled probe therapeutic compound (B10-b) and the I-substituted non-radioisotope compound (B13). The measurements were performed in the same manner as in Purity Test I, except that the mobile phase was A) 0.01% TFA in H2O and B) 0.01% TFA in MeOH, and the mixture of A / B solutions was 60 / 40 → 30 / 70 (20 min). The chromatogram is shown in Figure 2. In addition, 125 The radiochemical yield of the I-substituted radioisotope-labeled probe diagnostic compound (B10-a) was 70% and the radiochemical purity was 96%. 211 The radiochemical yield of the At-substituted radioisotope labeled probe therapeutic compound (B10-b) was 80% and the radiochemical purity was 95%.

[0084] As is clear from Figure 2, the high-performance liquid chromatogram 125 I-substituted radioisotope-labeled probe diagnostic compound (B10-a) 211The structures of these compounds are supported by the fact that the At-substituted radioisotope-labeled probe therapeutic drug compound (B10-b) and the I-substituted non-radioisotope compound (B14) had almost the same retention time and a single peak, that the high-performance liquid chromatograms of the iodine-substituted and astatine-substituted compounds, which generally have the same structure, were almost identical, that the I-substituted non-radioisotope compound (B14) was identified by mass spectrometry (MS), and that the iodine-astatine substitution from the tributyltin group reacted quantitatively.

[0085] (Comparative Synthesis Example 2-1: Synthesis of radioisotope-labeled probe diagnostic compound (B11-a)) The compound obtained by the above-mentioned chemical reaction formula (IV) in Comparative Synthesis Example 1-1 125 The protecting group of the I-substituted radioisotope-labeled probe diagnostic compound (B10-a): MOM is removed, 125 The I-substituted radioisotope-labeled probe diagnostic compound (B11-a) was synthesized. The details of the synthesis are as follows.

[0086] [ [ 125 I]Synthesis of (3,5-Bis(hydroxymethyl)-4-iodobenzoyl)glycine (B11-a) 50 μg of compound B9 was dissolved in 10 μL of acetonitrile, and 10 μL of 3% acetic acid / acetonitrile solution was added. 125 I]NaI (1.5 MBq) and 15 μL of N-chlorosuccinimide / acetonitrile solution (1 mg / mL) were added and left to stand at room temperature for 15 minutes. The solvent was then removed with nitrogen gas, and 50 μL of a mixed solution of 1,4-dioxane: 6 M HCl = 1:4 was added. The mixture was left to stand for 10 minutes, and then purified by reversed-phase HPLC. Cosmosil 5C 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.1% TFA-containing water:methanol, changing from 70:30 to 50:50 in 20 minutes, at a flow rate of 1.0 mL / min. This structure is supported by a match in retention time with the non-radioactive iodine compound B15 in reversed-phase HPLC.

[0087] (Comparative Synthesis Example 2-2: Synthesis of radioisotope-labeled probe therapeutic drug compound (B11-b)) The compound obtained by the above-mentioned chemical reaction formula (IV) in Comparative Synthesis Example 1-1 211 Protecting group of At-substituted radioisotope-labeled probe therapeutic drug compound (B10-b): Remove MOM, 211 A At-substituted radioisotope-labeled probe therapeutic compound (B11-b) was synthesized. The details of the synthesis are as follows.

[0088] [ [ 211 At] Preparation of (3,5-Bis(hydroxymethyl)-4-astatobenzoyl)glycine (B11-b)] 50 μg of compound B9 was dissolved in 10 μL of acetonitrile, and 20 μL of 3% acetic acid / acetonitrile solution was added. 211 At]At - 25 μL of 1.1 MBq N-chlorosuccinimide / acetonitrile solution (1 mg / mL) was added and the mixture was left to stand at room temperature for 15 minutes. The solvent was then removed with nitrogen gas, and 50 μL of a mixture of 1,4-dioxane: 6 M HCl = 1:4 was added. The mixture was left to stand for 10 minutes, and then purified by reversed-phase HPLC. Cosmosil 5C was used for the reversed-phase HPLC. 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.1% TFA-containing water:methanol, changing from 70:30 to 50:50 in 20 minutes, at a flow rate of 1.0 mL / min. This structure is supported by the similar retention time in reversed-phase HPLC with the non-radioactive iodine compound B15.

[0089] (Synthesis Comparative Example 2-3: Synthesis of I-substituted non-radioisotope compound (B15)) [Synthesis of 3,5-Bis(hydroxymethyl)-4-iodobenzoyl)glycine (B15)] Compound B14 (10 mg, 22 μmol) was added to 50 μL of a mixed solution of 6 M HCl: 1,4-dioxane = 1:2, and the mixture was left to stand for 10 minutes. It was then purified by reversed-phase HPLC to obtain 2.5 mg of compound B15 as a colorless oil (yield 21%). Cosmosil 5C was used for the reversed-phase HPLC. 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.1% TFA-containing water:methanol, changing from 70:30 to 50:50 in 20 minutes, at a flow rate of 1.0 mL / min. 1 H-NMR (D2O): δ 7.76 (2H, s), 4.76 (2H, s), 4.11 (2H, s) HRMS (ESI + ) (m / z calcd for C 11 H 12 INNaO5[M+Na] + ): 387.9652 found: 387.9658. NMR and mass spectrometry data were consistent with the predicted values, supporting this structure.

[0090] (Purity Test III: High Performance Liquid Chromatography Analysis of Compounds (B11-a), (B11-b), and (B15)) Obtained 125 I-substituted radioisotope-labeled probe diagnostic compound (B11-a), 211 High performance liquid chromatography (HPLC) analysis was performed on the At-substituted radioisotope labeled probe therapeutic compound (B11-b) and the I-substituted non-radioisotope compound (B15). The measurements were performed in the same manner as in Purity Test I, except that the mobile phase was A) 0.1% TFA in H2O and B) 0.1% TFA in MeOH, and the mixture of A / B solutions was 70 / 30 → 50 / 50 (20 min). The chromatogram is shown in Figure 3. In addition, 125 The radiochemical yield of the I-substituted radioisotope-labeled probe diagnostic compound (B11-a) was 63% and the radiochemical purity was 97%. 211The radiochemical yield of the At-substituted radioisotope labeled probe therapeutic compound (B11-b) was 57% and the radiochemical purity was 97%.

[0091] As is clear from Figure 3, the high-performance liquid chromatogram 125 I-substituted radioisotope-labeled probe diagnostic compound (B11-a) 211 The structures of these compounds are supported by the fact that the At-substituted radioisotope-labeled probe therapeutic drug compound (B11-b) and the I-substituted non-radioisotope compound (B15) had almost the same retention time and a single peak, that the high-performance liquid chromatograms of the iodine-substituted and astatine-substituted compounds, which generally have a common structure, were almost identical, that the I-substituted non-radioisotope compound (B15) was identified by mass spectrometry (MS), and that the iodine-astatine substitution from the tributyltin group reacted quantitatively.

[0092] (Synthesis comparison reference example 3-1: 125 I-substituted radioisotope-labeled probe diagnostic compound (A6-a) and synthesis comparison example 3-2: 211 Synthesis of At-substituted radioisotope-labeled probe therapeutic compound (A6-b) [Synthesis of Methyl 4-iodobenzoate (A1)] 4-iodobenzoic acid (500 mg, 2 mmol) was dissolved in 20 mL of methanol, and then SOCl2 (356.7 mg, 3 eq) was added dropwise and heated in a 60°C water bath for 4 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution to separate the liquid. The organic phase was separated, dried over sodium sulfate, and filtered through a cotton plug. The solvent was distilled off under reduced pressure to obtain 468.6 mg of compound A1 as a white powder. (Yield 89.4%) 1 H-NMR (CDCl3): δ 7.81 (2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.8 Hz), 3.91 (3H, s) HRMS (ESI + ) (m / z calcd for C8H8IO2[M+H]+ ): 262.9564 found: 262.9569.

[0093] [Synthesis of Methyl 4-(tributylstannyl)benzoate (A2)] Compound A1 (300 μg, 1.14 mmol) was dissolved in 10 mL of 2-propanol, and bistributyltin (1.71 mL, 3.41 mmol, 3 eq), tris(dibenzylideneacetone)dipalladium (0) (52.2 mg, 57.0 μmol, 0.05 eq), and N,N-diisopropylethylamine (DIPEA) (492.2 μL, 2.86 mmol, 2.5 eq) were added under a nitrogen atmosphere and stirred at 100 ° C for 21 hours. After filtration through Celite and washing with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using a solvent that changed from dichloromethane:methanol (100:0) to (10:1) as the eluent, and 166.7 mg of compound A2 was obtained as a colorless oily substance (yield 34.4%). 1 H-NMR (CDCl3): δ 7.95 (2H, d, J = 7.6 Hz), 7.55 (2H, d, J = 8.0 Hz), 3.91 (3H, s), 1.64-1.45 (6H, m), 1.41-1.28 (6H, m), 1.17 (6H, m), 0.92-0.86 (9H, m) HRMS (ESI + ) (m / z calcd for C 20 H 35 O2Sn[M+H] + ): 427.1654 found: 427.1659.

[0094] [Synthesis of 4-(Tributylstannyl)benzoic acid (A3)] Compound A2 (127.6 mg, 0.30 mmol) was dissolved in a mixed solvent of 1 mL of 1,4-dioxane and 1 mL of methanol, and 1 mL of 1M NaOH was added dropwise and stirred at 30°C and at room temperature for 20 hours. The reaction solution was adjusted to pH 4 by adding 3 mL of ethyl acetate and 1M HCl, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 99.3 mg of compound A3 as a colorless oily substance (yield 80.5%). 1 H-NMR (CDCl3): δ 7.97 (2H, d, J = 7.6 Hz), 7.51 (2H, d, J = 8.4 Hz), 2.91 (4H, brs), 1.64-1.51 (6H, m), 1.49-1.28 (6H, m), 1.18-1.01 (6H, m), 0.94-0.87 (9H, m) HRMS (ESI + ) (m / z calcd for C 19 H 32 NaO2Sn[M+Na] + ): 435.1317 found:435.1322.

[0095] [Synthesis of 2,5-Dioxopyrrolidin-1-yl 4-(tributylstannyl)benzoate (A4)] Compound A3 (99.0 mg, 0.24 mmol) was dissolved in 2.4 mL of dichloromethane, and NHS (33.4 g, 0.24 mmol, 1.0 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI·HCl) (69.0 mg, 0.36 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 6.5 hours, and then subjected to silica gel chromatography using dichloromethane as an eluent to obtain 91.4 mg of compound A3 as a colorless oily substance (yield 74.9%). 1H-NMR (CDCl3): δ 8.03 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 7.2 Hz), 2.91 (4H, brs, J = 13.2 Hz), 1.64-1.51 (6H, m), 1.49-1.28 (6H, m), 1.18-1.01 (6H, m), 0.94-0.87 (9H, m)

[0096] [Synthesis of (4-(Tributylstannyl)benzoyl)glycine (A5)] Compound A4 (10 mg, 20 μmol) was dissolved in 290 μL of DMF, and DIPEA (26.9 μg, 158 μmol, 8 eq) was added to the reaction solution. Glycine (7.4 mg, 98.5 μmol, 5 eq) dissolved in 50 μL of water was added dropwise and stirred at room temperature for 1 hour. Purification was performed by reversed-phase HPLC to obtain 6.6 mg of compound A5 (yield 71%). Cosmosil 5C was used for the reversed-phase HPLC. 18 The column was an AR-II (10 × 150 mm) and the mobile phase was water:methanol (20:80) containing 0.1% TFA, which was changed to (0:100) in 5 min, followed by elution with (0:100) for 10 min using a gradient method. The UV was measured at 254 nm and the flow rate was 4.0 mL / min. 1 H-NMR (CDCl3): δ 7.73 (2H, d, J = 7.6 Hz), 7.60 (2H, d, J = 8.0 Hz),6.85 (1H, s) 4.25 (2H, s), 1.64-1.43 (6H, m), 1.38-1.29 (6H, m), 1.17-0.98 (6H, m), 0.92-0.85 (9H, m) HRMS (ESI + ) (m / z calcd for C 21 H 36 NO3Sn[M+H] + ): 470.1712found: 470.1715.

[0097] [ [ 125I]Synthesis of (4-Iodobenzoyl)glycine (A6-a)] 50 μg of compound A5 was dissolved in 10 μL of acetonitrile, and 10 μL of 3% acetic acid / acetonitrile solution was added. 125 1.5 MBq of [I]NaI and 15 μL of N-chlorosuccinimide (NCS) / acetonitrile solution (1 mg / mL) were added, and the mixture was left to stand at room temperature for 15 minutes, after which it was purified by reversed-phase HPLC. 18 The column used was an AR-II (4.6 x 150 mm) and the mobile phase was a gradient mixture of 0.1% TFA-containing water:methanol, changing from 75:25 to 55:45 in 20 minutes, at a flow rate of 1.0 mL / min. 125 The I-substituted radioisotope-labeled probe diagnostic compound (A6-a) was obtained. This structure was supported by the fact that the retention time in reversed-phase HPLC was consistent with that of the non-radioactive iodine compound.

[0098] [ [ 211 Synthesis of (4-Astatobenzoyl)glycine (A6-b) Similarly, 50 μg of compound A5 was dissolved in 10 μL of acetonitrile, and 10 μL of 3% acetic acid / acetonitrile solution was added, 211 At]At - 1.1 MBq, 15 μL of NCS / acetonitrile solution (1 mg / mL) was added and the mixture was left to stand at room temperature for 15 minutes, after which it was purified by reversed-phase HPLC. 18 The elution was performed using an AR-II (4.6 × 150 mm) column and a gradient method in which the mobile phase was 0.1% TFA-containing water:methanol, changing from 75:25 to 55:45 in 20 minutes, at a flow rate of 1.0 mL / min. This structure is supported by similar retention times on reversed-phase HPLC with the non-radioactive iodine species.

[0099] (Stability test I: Stability in mouse plasma) Compounds (C10-a) and (C10-b), compounds (B10-a) and (B10-b), and compounds (B11-a) and (B11-b) obtained as described above were mixed with mouse plasma, and incubated in an incubator at 37° C. for 1 hour. After that, acetonitrile was added and the mixture was centrifuged to precipitate protein components. The supernatant was then analyzed by TLC (Sigma-Aldrich: product name TLC Silica gel 60 F). 254 ) and developed with a dichloromethane:methanol solution containing 1% acetic acid for TLC analysis. The stability results in mouse plasma are shown in Table 1 below.

[0100] [Table 1]

[0101] As is clear from Table 1, in Example 1-2, which is an application of the present invention and has an N,N-dimethylcarbamoyl group as W, which is an electron-withdrawing group, 211 At-substituted radioisotope-labeled probe therapeutic compound (C10-b) is easily eliminated from the aromatic ring 211 Although it is substituted with At, as in Example 1-1, 125 I is difficult to remove 125 The stability was approximately equal to that of the I-substituted radioisotope-labeled probe diagnostic compound (C10-a). On the other hand, the comparative examples to which the present invention is not applicable, which have an electron donating group, methoxymethoxymethyl group (MOM methyl group) or hydroxymethyl group as W, 211 At-substituted radioisotope-labeled probe therapeutic drug compounds (B10-b) and (B11-b) are 125 The stability in plasma was significantly decreased by about 10% compared to the I-substituted radioisotope-labeled probe diagnostic compound compounds (B10-a) and (B11-a).

[0102] (Stability test II: in vivo stability in mice) The mixture of compounds (C10-a) and (C10-b) at a concentration of 37 kBq / 100 μL obtained as described above, the mixture of compounds (B10-a) and (B10-b) at a concentration of 37 kBq / 100 μL, and the mixture of compounds (B11-a) and (B11-b) at a concentration of 37 kBq / 100 μL were each intravenously injected into mice, and the mice were sacrificed 10 minutes, 1 hour, and 4 hours after administration, and each organ was removed, and the weight and radioactivity of each organ were measured to determine the distribution in the body. The results are shown in Figures 4(a) and (b).

[0103] As is clear from FIG. 4, in Example 1-2 211 The At-substituted radioisotope-labeled probe therapeutic compound (C10-b) did not distribute or accumulate in the stomach or thyroid gland. 125 The pharmacokinetics of the I-substituted radioisotope-labeled probe diagnostic compound (C10-a) was approximately the same as that of the I-substituted radioisotope-labeled probe diagnostic compound (C10-a). 211 At-substituted radioisotope-labeled probe therapeutic drug compounds (B10-b) and (B11-b) are 125 The I-substituted radioisotope-labeled probe diagnostic compound (B10-a) and (B11-a) show higher distribution and accumulation in each organ, especially 211 Distribution and accumulation in the stomach and thyroid gland was higher than in the control group, where At accumulates when it is removed from the aromatic ring.

[0104] Thus, the distribution and accumulation in the stomach and thyroid gland 4 hours after intravenous administration of each compound (C10-a) and (C10-b), (B10-a) and (B10-b), (B11-a) and (B11-b), and (A6-a) and (A6-b) are shown in Fig. 5(a) and (b). The results of Fig. 4 are further clarified from Fig. 5. [Industrial Applicability]

[0105] The radioisotope-labeled therapeutic drug of the present invention can be used as a therapeutic drug containing a radioisotope-labeled probe diagnostic compound and / or a radioisotope-labeled probe therapeutic compound, particularly as a radiotheranostic drug used in combination with nuclear medicine diagnosis and nuclear medicine therapy, in the treatment of various primary tumor sites and can be applied to shrink or cure tumors by medical means.

Claims

1. The following chemical formula (I) 【Chemistry 1】 (In formula (I), X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18.)

2. 2. The radioisotope-labeled medical drug according to claim 1, wherein said W is an N,N-dimethylcarbamoyl group.

3. The radioisotope-labeled diagnostic drug according to claim 1, which is a radiotheranostics drug having a combination of the radioisotope-labeled probe diagnostic compound and the radioisotope-labeled probe therapeutic compound.

4. The radioisotope-labeled probe diagnostic compound is １８ F is fluorine; ７６ Br, bromine, and １２３ I or １２４ and iodine which is I; The radioisotope-labeled probe therapeutic compound is ７７ Br is bromine, １２５ I or １３１ Iodine, and ２１１ 2. The radioisotope-labeled medical drug according to claim 1, characterized in that the radioisotope halogen element is selected from the group consisting of astatine, At, and naphthalene.

5. The radioisotope-labeled diagnostic drug according to claim 1, characterized in that the radioisotope-labeled probe diagnostic compound is for use in in vivo dynamics studies, and the radioisotope-labeled probe therapeutic drug compound is for use in internal radiation therapy.

6. The following chemical formula (I) 【Chemistry 2】 A radioisotope halogen element-containing compound represented by the formula (I): (wherein X is a radioisotope halogen element, W is an electron-withdrawing group, and n is a number from 2 to 18).

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