Probes for nuclear medicine imaging

Abstract

[Problem] To provide a novel compound that is promising as a probe for nuclear medical testing. [Solution] Provided is a compound represented by general formula (I) or a salt thereof.

Description

Technical Field

[0001] The present invention relates to a novel compound promising as a probe for nuclear medicine examinations, and a pharmaceutical composition for nuclear medicine examinations using the compound.

Background Art

[0002] The present inventors have hitherto found that the peptidase activity such as γ-glutamyl transpeptidase (GGT) is specifically enhanced in cancer by fluorescence imaging using living cells and clinical specimens, and by locally spraying a fluorescence probe (gGlu-HMRG) having a γ-glutamyl group, etc., succeeded in rapidly visualizing disseminated small tumors (Non-Patent Document 1).

[0003] However, although cancer diagnosis by fluorescence imaging has the advantage that rapid diagnosis is possible due to its high temporal resolution, it is difficult to detect deep cancers due to the low tissue permeability of visible light.

[0004] On the other hand, nuclear medicine examinations such as scintigraphy, SPECT (single photon emission computed tomography), and PET (positron emission tomography) can be used for functional diagnosis of deep inside the living body, and research thereof has been actively conducted in recent years. These nuclear medicine examinations are methods for examining the presence of tumors, etc. in a target tissue or target organ by administering a drug containing a radionuclide to a patient and measuring radiation emitted from the radionuclide contained in the drug localized in the target tissue or target organ. As such a drug, compounds having radionuclides such as iodine ( 123 I) etc. are used, but there are almost no development examples of effective radioisotope (RI) tracers targeting cancer cell-specific hydrolase activity.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

[0006] The present invention aims to provide novel compounds that are promising as probes for nuclear medicine imaging. [Means for solving the problem]

[0007] The fluorescent probe 4-CH2F-HMDiEtR-gGlu, developed by the inventors' laboratory, reacts with GTT to generate a reactive azaquinone methide, which is attacked by nucleophiles in cells, becoming fluorescent and self-fixing, thereby enabling tumor imaging that is resistant to washout.

[0008] Based on these considerations, the inventors incorporated quinone methide chemistry into molecular design and developed a probe for low-molecular-weight nuclear medicine imaging using a new I-125 or similar labeled nuclide. The inventors then concluded that this probe is specifically hydrolyzed by enzymes such as GGT to produce an electrophilic azaquinone methide active intermediate, which forms a covalent bond with intracellular proteins and other substances, thereby undergoing metabolic trapping and accumulating at high concentrations in cancer cells. This led to the completion of the present invention.

[0009] In other words, the present invention has the following configuration. [1] A compound represented by the following general formula (I) or a salt thereof. TIFF0007878747000001.tif49168 (in the formula, X is selected from the group consisting of a fluorine atom, an ester group (-OC(=O)-R'), a carbonate group (-OCO2-R'), a carbamate group (-OCONH-R'), phosphoric acid and its ester group (-OP(=O)(-OR')(―OR''), and sulfuric acid and its ester group (―OSO2―OR'). Here, R’ and R’’ are each independently selected from a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; Y is -NH-CO-L, -NH-L’ or -OL’, where L is a partial structure of an amino acid, L’ is a saccharide or a partial structure of a saccharide, a saccharide or a partial structure of a saccharide having a self-cleaving linker, amino acids or a peptide having a self-cleaving linker; R 1 and R 2 are each independently selected from a hydrogen atom or a monovalent substituent; R 3 is a hydrogen atom or one or two identical or different monovalent substituents present on the benzene ring; R 4 is a hydrogen atom or a substituent or molecule capable of changing the pharmacokinetics, and the substituent or molecule may be bonded to the benzene ring via a linker; Z represents a single bond or a linking group: A represents a radionuclide.) [2] The compound or a salt thereof according to [1], wherein the radionuclide is selected from the group consisting of 125 I, 211 At, 18 F, 15 O, 123 I, 131 I, 124 I, 11 C. [3] The compound or a salt thereof according to [1] or [2], wherein the substituent or molecule capable of changing the pharmacokinetics is introduced into the benzene ring via a linker or directly. [4] The linker is selected from the group consisting of an alkylene group (where one or more -CH2- of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-), arylene (including heteroarylene), cycloalkylene, an alkoxyl group, a polyethylene glycol chain, and a group formed by arbitrarily bonding two or more groups selected from these groups. The compound or a salt thereof according to any one of [1] to [3]. [5] The linking group of Z is selected from the group consisting of alkylene groups (wherein one or more -CH2- groups of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-), arylenes (including heteroarylenes), cycloalkylenes, alkoxyl groups, polyethylene glycol chains, and groups formed by the arbitrary bonding of two or more groups selected from these groups, according to any one of the items in [1] to [4] or a salt thereof. [6] The amino acid substructure of L, together with the C=O to which it is bound, constitutes an amino acid, an amino acid residue, a peptide, or a part of an amino acid, as described in any one of [1] to [5], or a salt thereof. [7] The substructure of the sugar L', together with the O to which it is bound, constitutes a sugar, a part of a sugar, a compound or salt thereof as described in any one of [1] to [6]. [8] In general formula (I), -Y is -C(R 1 )(R 2 A compound or salt thereof described in any one of [1] to [7], bonded to X at the ortho or para position of the benzene ring. [9] Y is a compound or salt thereof according to any one of items [1] to [8], having a structure selected from the following. TIFF0007878747000002.tif196168

[10] X is a fluorine atom or an ester group (-OCO-R'), and is a compound or salt thereof as described in any one of [1] to [9].

[11] R 1 and R 2 Each is independently selected from a hydrogen atom or a fluorine atom, and is a compound or salt thereof as described in any one of [1] to

[10] .

[12] R 3 The monovalent substituents are alkyl groups, alkoxycarbonyl groups (-CO-OR a ), nitro group, amino group, hydroxyl group, alkylamino group (-NHR a , -NR a 2) alkoxy group (-OR a ), ester group (-O-CO-R a ), selected from the group consisting of halogen atoms, boryl groups, and cyano groups (Ra R is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. a If there are 2 or more, each R a The compounds or salts thereof described in any one of items [1] to

[11] (they may be the same or different).

[13] R 3 The compound or salt thereof according to

[12] , wherein the monovalent substituent is an alkyl group (e.g., a methyl group) or an alkoxycarbonyl group (e.g., a methoxycarbonyl group).

[14] R 3 The compound or salt thereof according to

[12] , wherein the monovalent substituent is a halogen atom.

[15] R 3 At least one of the monovalent substituents is an alkyl group (e.g., a methyl group) or an alkoxycarbonyl group (e.g., a methoxycarbonyl group), and R 3 A compound or salt thereof according to any one of

[12] to

[14] , wherein at least one of the monovalent substituents is a halogen atom.

[16] R 3 and R 4 A compound or salt thereof described in any one of items [1] to

[11] , wherein all of the atoms are hydrogen atoms. A pharmaceutical composition comprising any one of the compounds described in

[17] [1] to

[16] or a pharmaceutically acceptable salt thereof.

[18] The pharmaceutical composition described in

[17] , used for nuclear medicine examinations.

[19] The pharmaceutical composition according to

[18] , which can be accumulated in cancer cells by acting selectively on cells through cancer cell-specific enzymatic activity.

[20] The pharmaceutical composition according to

[19] , wherein the enzyme is a peptidase or a glycosidase.

[21] The pharmaceutical composition according to any one of

[18] to

[20] , wherein the nuclear medicine examination is at least one selected from the group consisting of scintigraphy, SPECT (single-photon emission computed tomography), and PET (positron emission tomography).

[22] A method for diagnosing a disease or a condition that may lead to a disease, (A) The step of administering a drug containing a compound described in any one of items [1] to

[15] or a pharmaceutically acceptable salt thereof to a subject who has or is suspected of having a disease or symptoms, and (B) A step of measuring the radiation emitted from radionuclides contained in the drug that are localized in the target tissue or target organ of the subject, in order to determine the presence of one or more selected from the group consisting of tumors, cancer cells and cancer tissue in the target tissue or target organ. The method, including the method described above.

[23] The diagnostic method according to

[22] , wherein the drug is administered intravenously, intraperitoneally, or intratumorally to the subject. A kit comprising any one of the compounds described in item

[24] [1] to

[15] or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0010] The present invention provides novel compounds that are promising as probes for scintigraphy and nuclear medicine imaging such as SPECT (single-photon emission computed tomography) and PET (positron emission tomography). [Brief explanation of the drawing]

[0011] [Figure 1] A schematic diagram is shown illustrating how gGlu-4125I-FMA, an example of the compound of the present invention, remains inside cells through the process of "metabolic trapping". [Figure 2] The results of the purification of gGlu-4125I-FMA after the 125I labeling reaction, performed using an HPLC equipped with a radiation detector, are shown. [Figure 3] The results of the enzymatic reaction between gGlu-4125I-FMA and GGT, performed using an HPLC with a radiation detector, are shown. The top left shows the reaction before GGT, the top right shows the reaction after GGT, and the bottom right shows the detection of the unlabeled 2-Amino-5-iodobenzylalcohol using PDA. [Figure 4] The procedure for intracellular uptake of gGlu-4125I-FMA is shown below. [Figure 5]The results of the intracellular uptake test of the gGlu-4125I-FMA probe are shown. [Figure 6] The results of intratumor administration experiments of the probe to a subcutaneous tumor model mouse are shown. [Figure 7] This document outlines the procedure for visualizing peritoneal metastasis using intraperitoneal administration (IP) of a probe. [Figure 8] This image shows the results of an experiment visualizing peritoneal metastasis by intraperitoneal administration (ip) of a probe. The mouse on the left is a peritoneal dissemination model mouse, and the mouse on the right is a mouse without cancer. Both mice were administered approximately 3 MBq of gGlu-4125I-FMA intraperitoneally, and the SPECT / CT images shown were taken 5 hours later. [Figure 9] Figure 8 shows the results of dissecting the peritoneal dissemination model mouse on the left, removing the intestines and mesentery, and imaging them using autoradiography (ARG). [Modes for carrying out the invention]

[0012] In this specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0013] In this specification, "alkyl" may be any aliphatic hydrocarbon group consisting of a linear, branched, cyclic, or combination thereof. The number of carbon atoms in an alkyl group is not particularly limited, but for example, it may have 1 to 6 carbon atoms (C1 to 6), 1 to 10 carbon atoms (C1 to 10), 1 to 15 carbon atoms (C1 to 15), or 1 to 20 carbon atoms (C1 to 20). When a number of carbon atoms is specified, it means an alkyl group having a number of carbon atoms within that range. For example, C1 to 8 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, etc. In this specification, an alkyl group may have one or more substituents. Examples of such substituents include, but are not limited to, alkoxy groups, halogen atoms, amino groups, mono- or disubstituted amino groups, substituted silyl groups, or acyl groups. If an alkyl group has two or more substituents, they may be the same or different. The same applies to the alkyl portion of other substituents containing an alkyl moiety (e.g., alkosy groups, arylalkyl groups, etc.).

[0014] In this specification, when a functional group is defined as "may be substituted," the type of substituent, the position of substitution, and the number of substituents are not particularly limited, and if there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. These substituents may have further substituents. Examples of such substituents include, but are not limited to, alkyl halides and dialkylamino groups.

[0015] In this specification, "aryl" may be either a monocyclic or fused polycyclic aromatic hydrocarbon group, or an aromatic heterocycle containing one or more heteroatoms (e.g., oxygen, nitrogen, or sulfur atoms) as ring constituent atoms. In this case, it may also be referred to as "heteroaryl" or "heteroaromatic." Whether the aryl is monocyclic or fused, it can be bonded at all possible positions. Non-limiting examples of monocyclic aryls include phenyl (Ph), thienyl (2- or 3-thienyl), pyridyl, furyl, thiazolyl, oxazolyl, pyrazolyl, 2-pyradinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyridadinyl, 3-isothiazolyl, 3-isoxazolyl, 1,2,4-oxadiazole-5-yl, or 1,2,4-oxadiazole-3-yl. Non-limiting examples of fused polycyclic aryl groups include 1-naphthyl group, 2-naphthyl group, 1-indenyl group, 2-indenyl group, 2,3-dihydroinden-1-yl group, 2,3-dihydroinden-2-yl group, 2-anthuryl group, indazolyl group, quinolyl group, isoquinolyl group, 1,2-dihydroisoquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, indolyl group, isoindolyl group, phthalazinyl group, quinoxalinyl group, benzofuranyl group, 2,3-dihydrobenzofuran-1-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzothiophen-1-yl group, 2,3-dihydrobenzothiophen-2-yl group, benzothiazolyl group, benzimidazolyl group, fluorenyl group, or thioxanthenyl group. In this specification, an aryl group may have one or more substituents on its ring. Examples of such substituents include, but are not limited to, alkoxy groups, halogen atoms, amino groups, mono- or disubstituted amino groups, substituted silyl groups, or acyl groups. If an aryl group has two or more substituents, they may be the same or different. The same applies to the aryl moiety of other substituents containing an aryl moiety (e.g., aryloxy groups or arylalkyl groups).

[0016] In this specification, "alkoxy group" refers to a structure in which the alkyl group is bonded to an oxygen atom, and examples include saturated alkoxy groups that are linear, branched, cyclic, or combinations thereof. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, cyclobutoxy group, cyclopropylmethoxy group, n-pentyloxy group, cyclopentyloxy group, cyclopropylethyloxy group, cyclobutylmethyloxy group, n-hexyloxy group, cyclohexyloxy group, cyclopropylpropyloxy group, cyclobutylethyloxy group, or cyclopentylmethyloxy group are examples of preferred groups.

[0017] In this specification, "alkylene" means a divalent group consisting of a linear or branched saturated hydrocarbon, for example, methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2 Examples include dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, and 2,2-di-n-propyltrimethylene.

[0018] 1. Compounds represented by general formula (I) or salts thereof One embodiment of the present invention is a compound represented by the following general formula (I) or a salt thereof (hereinafter also referred to as "the compound of the present invention"). TIFF0007878747000003.tif50165

[0019] While not intended to be constrained by theory, the present invention has found that by targeting cancer biomarker enzymes, incorporating their substrate sites into a drug molecule, and cleaving them by an enzymatic reaction, an azaquinone methide active intermediate is generated. This intermediate then forms covalent bonds with intracellular proteins, leading to metabolic trapping and accumulation in cancer cells at high concentrations. Figure 1 shows gGlu-4, an example of the compound of the present invention. 125 A schematic diagram illustrating how I-FMA remains inside cells through the process of "metabolic trapping" is shown.

[0020] In general formula (I), Y is an enzyme recognition site, and a portion of it is cleaved by cancer cell-specific enzyme activity, inducing the formation of a quinone methide. Y can be selected depending on the type of target enzyme. If the target enzyme, which is a cancer biomarker enzyme, is a plutidase, Y is selected from groups derived from amino acids or groups containing amino acids. If the target enzyme is a glycosidase, Y is selected from groups derived from sugars.

[0021] In general formula (I), Y is preferably -NH-CO-L, -NH-L', or -OL'. Here, L represents a substructure of an amino acid. The term "substructure of an amino acid" means that L, together with the C=O atom it is bound to, constitutes an amino acid, an amino acid residue, a peptide, or a part of an amino acid.

[0022] In this specification, "amino acid" can refer to any compound having both an amino group and a carboxyl group, including both natural and unnatural compounds. It may be a neutral amino acid, a basic amino acid, or an acidic amino acid. In addition to amino acids that function as neurotransmitters themselves, it may also refer to amino acids that are components of physiologically active peptides (including dipeptides, tripeptides, tetrapeptides, and oligopeptides) or polypeptide compounds such as proteins. For example, α-amino acids, β-amino acids, and γ-amino acids may also be used. It is preferable to use optically active amino acids as the amino acid. For example, for α-amino acids, either D- or L-amino acids may be used, but it may be preferable to select optically active amino acids that function in living organisms.

[0023] In this specification, "amino acid residue" refers to the structure corresponding to the remaining substructure obtained by removing the hydroxyl group from the carboxyl group of an amino acid. Amino acid residues include α-amino acid residues, β-amino acid residues, and γ-amino acid residues. Preferred amino acid residues include the γ-glutamyl group of the GGT substrate and the dipeptide (amino acid-proline dipeptide) of the DPP4 substrate.

[0024] In this specification, "peptide" refers to a structure in which two or more amino acids are linked by peptide bonds. Preferred peptides include the DPP4 substrate dipeptides mentioned above (dipeptides consisting of an amino acid and proline; where the amino acid is, for example, glycine, glutamic acid, or proline).

[0025] In cases where L is bonded to a C=O group and forms part of an amino acid, an example is the γ-glutamyl group mentioned above, where the carboxyl group of the amino acid's side chain is bonded to -NH2 to form a carbonyl group and thus part of the amino acid.

[0026] L' is a sugar or a substructure of a sugar, a sugar or a substructure of a sugar having a self-cleaving linker, or an amino acid or peptide having a self-cleaving linker. Here, the L' substructure of a sugar refers to the structure that corresponds to the remaining substructure after removing one hydroxyl group from the sugar. The L' substructure of a sugar, together with the oxygen atom to which it is bonded, constitutes the sugar or a part of the sugar.

[0027] Examples of sugars include β-D-glucose, β-D-galactose, β-L-galactose, β-D-xylose, α-D-mannose, β-D-fucose, α-L-fucose, β-L-fucose, β-D-arabinose, β-L-arabinose, β-DN-acetylglucosamine, and β-DN-acetylgalactosamine, with β-D-galactose being preferred.

[0028] Self-cleaving linkers refer to linkers that spontaneously cleave or decompose, such as carbamates, ureas, para-aminobenzyloxy groups, and ester groups (-CO-O-, -O-CO-).

[0029] In one preferred aspect of the present invention, Y has a structure selected from the following: TIFF0007878747000004.tif206159

[0030] In general formula (I), X acts as a leaving group that is released from the benzene ring when a portion of the enzyme recognition site of Y is cleaved by cancer cell-specific enzymatic activity, resulting in the formation of a quinone methide.

[0031] X is selected from the group consisting of fluorine atoms, ester groups (-OC(=O)-R'), carbonate groups (-OCO2-R'), carbamate groups (-OCONH-R'), phosphoric acid and its ester groups (-OP(=O)(-OR')(―OR''), and sulfuric acid and its ester groups (―OSO2―OR'). Here, R' and R'' are each independently selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups.

[0032] X is preferably a fluorine atom or an ester group (-OCO-R'). Although not intended to be theoretically bound, when X is a fluorine atom or an ester group (-OC(=O)-R'), a quinone methide is rapidly formed when Y is cleaved.

[0033] R 1 and R 2 Each of these is independently selected from a hydrogen atom or a monovalent substituent. Examples of monovalent substituents include halogen atoms and alkyl groups having one or more carbon atoms (for example, alkyl groups having approximately 1 to 6 carbon atoms). R 1 and R 2 Preferably, each is independently selected from a hydrogen atom or a fluorine atom.

[0034] In general formula (I), -Y is -C(R 1 )(R 2 It is preferable that -Y and -C(R 1 )(R 2 When X is in this positional relationship on the benzene ring, a quinone methide structure can be formed when Y is cleaved.

[0035] R 3 These are one or two identical or different monovalent substituents located on a hydrogen atom or a benzene ring. R 3 Monovalent substituents include alkyl groups having 1 or more carbon atoms (for example, alkyl groups with approximately 1 to 6 carbon atoms) and alkoxycarbonyl groups (-C(=O)-OR a ), nitro group, amino group, hydroxyl group, alkylamino group (-NHR a , -NR a 2) alkoxy group (-OR a ), ester group (-O-CO-R a ), amide group (-NHCOR a), selected from the group consisting of halogen atoms, boryl groups, and cyano groups. Here, R a R is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. a If there are 2 or more, each R a They may be the same or different.

[0036] In one aspect of the compound of the present invention, R 3 The monovalent substituents are alkyl groups (e.g., methyl groups) or alkoxycarbonyl groups (e.g., methoxycarbonyl groups). Introducing an electron-donating alkyl group into the benzene ring is preferable because it provides excellent intracellular retention.

[0037] In one aspect of the compound of the present invention, R 3 The monovalent substituent is a halogen atom (preferably an iodine atom). 3 However, if the atom is a halogen atom (preferably an iodine atom), it is possible to enhance the trapping effect on cells.

[0038] In one aspect of the compound of the present invention, R 3 At least one of the monovalent substituents is an alkyl group (e.g., a methyl group) or an alkoxycarbonyl group (e.g., a methoxycarbonyl group), and R 3 At least one of the monovalent substituents is a halogen atom.

[0039] R 3 If R is a monovalent substituent as described above, particularly an alkyl group, then 3 The position is -C(R 1 )(R 2 The 5th position, which corresponds to the para position of X, and / or the 4th position, which corresponds to the meta position, are preferred.

[0040] In another aspect of the compound of the present invention, R 3 All of them are hydrogen atoms.

[0041] R in general formula (I) 4This refers to a hydrogen atom, or a substituent or molecule that can alter its dynamics in the body.

[0042] Substituents or molecules that can alter the pharmacokinetics in the body may be any substituents or molecules known to alter the pharmacokinetics in the body. Examples of such substituents or molecules include structures known to bind to serum albumin, such as substituted or unsubstituted biphenyl groups; monovalent or divalent substituents derived from bicyclic compounds (e.g., naphthalene, quinoline, etc.); dye molecules such as Evans blue; and monovalent or divalent substituents derived from p-iodophenylbutyrate. Here, a monovalent substituent derived from a bicyclic compound means a monovalent substituent obtained by removing one hydrogen atom from the bicyclic compound (for example, a naphthyl group), and a divalent substituent derived from a bicyclic compound means a divalent substituent obtained by removing two hydrogen atoms from the bicyclic compound. Monovalent or divalent substituents derived from bicyclic compounds may be unsubstituted or substituted. Examples of these substituents include alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. Furthermore, substituents or molecules that can alter the pharmacokinetics in the body also include groups formed by the arbitrary bonding, sometimes via linking groups, of two or more identical or different substituents or molecules listed above. For example, groups formed by the arbitrary bonding, sometimes via linking groups, of two or more identical or different substituted or unsubstituted biphenyl groups; groups formed by the arbitrary bonding, sometimes via linking groups, of two or more identical or different substituted or unsubstituted naphthyl groups; and groups formed by the arbitrary bonding, sometimes via linking groups, of one or more substituted or unsubstituted biphenyl groups and one or more substituted or unsubstituted naphthyl groups (if there are two or more of either or both, they may be identical or different) are also included in substituents or molecules that can alter the pharmacokinetics in the body (but are not limited to these).

[0043] The linking group can be any metabolically stable group that functions as a linker, but is preferably selected from the group consisting of alkylene groups (wherein one or more -CH2- groups of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-), arylenes (including heteroarylenes), cycloalkylenes (e.g., cyclohexylene), alkoxyl groups, polyethylene glycol chains, and groups formed by the arbitrary bonding of two or more groups selected from these groups.

[0044] By introducing substituents or molecules that can alter the pharmacokinetics into the benzene ring, it becomes easier to increase and / or adjust the half-life in the blood, thereby increasing the degree of freedom in the administration route when administering pharmaceutical compositions containing the compound of the present invention to a subject.

[0045] Substituents or molecules that can alter the above-mentioned pharmacokinetics can be introduced to the benzene ring via a linker or directly.

[0046] The linker is selected from the group consisting of alkylene groups (wherein one or more -CH2- groups of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-), arylenes (including heteroarylenes), cycloalkylenes, alkoxyl groups, polyethylene glycol chains, and groups formed by the arbitrary bonding of two or more groups selected from these groups.

[0047] In one aspect of the compound of the present invention, R 4 This is a hydrogen atom.

[0048] In one aspect of the compound of the present invention, R 3 and R 4 All of them are hydrogen atoms.

[0049] In general formula (I), A represents a radionuclide. Examples of radionuclides include: 125 I, 211 At, 18 F, 15 O,123 I, 131 I, 124 I and 11 Selected from the group consisting of C.

[0050] In general formula (I), Z represents a single bond or a linking group. Here, if Z is a "single bond," it means that A is directly bonded to the benzene ring without a linking group.

[0051] The linking group can be any metabolically stable group that functions as a linker, but is preferably selected from the group consisting of alkylene groups (wherein one or more -CH2- groups of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-), arylenes (including heteroarylenes), cycloalkylenes (e.g., cyclohexylene), alkoxyl groups, polyethylene glycol chains, and groups formed by the arbitrary bonding of two or more groups selected from these groups. The number of carbon atoms in the alkylene group is not particularly limited, but it is preferably 5 to 20, and more preferably 5 to 15. Note that even if the -CH2- in the alkylene group is substituted with -O-, -S-, -NH-, or -CO-, these groups are considered to have one carbon atom and are included in the "number of carbon atoms in the alkylene group" as described above. Furthermore, arylenes include those with benzene rings such as phenylene groups as linkers, as well as divalent linkers derived from heterocyclic aromatic and cyclic hydrocarbons.

[0052] In one preferred embodiment of the compound of the present invention, the linking group is an alkylene group (wherein one or more -CH2- groups of the alkylene group may be substituted with -O-, -S-, -NH-, or -CO-).

[0053] While there are no particular limitations on the position where AZ- is introduced, it is preferable that it is attached to the meta or para position of the benzene ring relative to Y, given that it must be metabolically stable and that if it is too close to the enzyme recognition site, it may not become a substrate for the target enzyme.

[0054] Non-limiting examples of the compounds of the present invention are shown below, but the compounds of the present invention are not limited to these. TIFF0007878747000005.tif157160

[0055] Compounds represented by general formula (I) include stereoisomers such as tautomers, geometric isomers (e.g., E-isomer, Z-isomer, etc.), and enantiomers, unless otherwise specified. That is, if a compound represented by general formula (I) contains one or more chiral carbons, the stereochemistry of each chiral carbon can independently take either the (R) or (S) form, and may exist as stereoisomers such as enantiomers or diastereoisomers of the derivative. Therefore, any stereoisomer in its pure form, any mixture of stereoisomers, a racemic mixture, etc., can be used as the active ingredient of the nuclear medicine probe of the present invention, and all of these are included within the scope of the present invention.

[0056] The method for producing compounds represented by general formula (I) is not particularly limited, but the examples of this specification specifically show the synthesis methods for representative compounds among those included in general formula (I). Those skilled in the art can produce compounds included in formula (I) by referring to the examples of this specification and the scheme below, and by appropriately modifying or altering the starting materials, reaction reagents, reaction conditions, etc. as needed.

[0057] 2. Pharmaceutical compositions, nuclear medicine imaging agents, and imaging reagents Since the compounds of the present invention contain radionuclides, they can be used in pharmaceutical compositions, nuclear medicine diagnostic imaging, and imaging applications. Therefore, another embodiment of the present invention is a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "the pharmaceutical composition of the present invention"). A preferred embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition used in nuclear medicine examinations.

[0058] Nuclear medicine diagnostic tests include scintigraphy, SPECT (single-photon emission computed tomography), and PET (positron emission tomography).

[0059] Another embodiment of the present invention is a nuclear medicine imaging agent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0060] In this specification, "nuclear medicine imaging agent" refers to an agent containing the compound of the present invention used in in vivo nuclear medicine examinations, which involve administering the agent into the body and measuring and imaging the radiation (radioactive signal) emitted from the body from outside the body to evaluate or examine the biological function of organs or tissues, or to diagnose diseases, or an agent containing the compound of the present invention used in in vitro nuclear medicine examinations, which involve reacting the agent with a sample such as tissue or blood collected from the body in a test tube to evaluate or examine the biological function of organs or tissues, or to diagnose diseases. Examples of in vivo nuclear medicine examinations include the above-mentioned methods using nuclear medicine imaging probes such as scintigraphy, SPECT (single-photon emission computed tomography), and PET (positron emission tomography).

[0061] Another embodiment of the present invention is an imaging reagent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0062] In this specification, "imaging" includes administering a compound of the present invention (imaging probe) containing a radioactive isotope (RI), i.e., a radionuclide, into the body and measuring and imaging the radiation (radioactive signal) emitted from within the body from outside the body. In other embodiments, "imaging" also includes measuring and imaging the radiation (radioactive signal) emitted from within a living organism to which a compound of the present invention (imaging probe) containing a radioactive isotope (RI) has been administered from outside the body. "Imaging" includes acquiring measurement data and / or image data for nuclear medicine diagnostic imaging.

[0063] The pharmaceutical composition, nuclear medicine imaging agent, and imaging reagent of the present invention (hereinafter collectively referred to as "the pharmaceutical composition, etc.") can preferably be accumulated in cancer cells by acting selectively on cells through cancer cell-specific enzymatic activity.

[0064] In the pharmaceutical compositions of the present invention, the cancer cell-specific enzyme is preferably a peptidase or a glycosidase. Examples of peptidases include gamma-glutamyl transpeptidase (GGT), dipeptidyl peptidase IV (DPP-IV), cathepsin B / L, and calpain. Examples of glycosidases include β-galactosidase, β-glucosidase, α-mannosidase, α-L-fucosidase, β-hexosaminidase, and β-N-acetylgalactosaminidase.

[0065] The pharmaceutical compositions of the present invention may include not only compounds represented by general formula (I), but also salts thereof or solvates or hydrates thereof. The salts are not particularly limited as long as they are pharmaceutically acceptable, but examples include base addition salts, acid addition salts, and amino acid salts. Examples of base addition salts include alkaline earth metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, ammonium salts, or organic amine salts such as triethylamine salts, piperidine salts, and morpholine salts. Examples of acid addition salts include mineral salts such as hydrochloride salts, hydrobromide salts, sulfates, nitrates, and phosphates; and organic salts such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid. Examples of amino acid salts include glycine salts, aspartate salts, and glutamate salts. Metal salts such as aluminum salts may also be used.

[0066] The type of solvent that forms the solvate is not particularly limited, but examples of solvents include ethanol, acetone, and isopropanol.

[0067] The pharmaceutical composition of the present invention is used in nuclear medicine examinations (preferably at least one selected from the group consisting of scintigraphy, SPECT (single-photon emission computed tomography), and PET (positron emission tomography)). In other words, the pharmaceutical composition of the present invention is administered into the body of a human or non-human animal (such as a mouse, rat, hamster, rabbit, cat, dog, cow, sheep, or monkey), and used to evaluate or examine the biological function of an organ or tissue by measuring and imaging the radiation (radioactive signal) emitted from the body from outside the body. Diseases to be evaluated or examined include, but are not limited to, brain tumors, malignant melanoma, head and neck cancer, breast cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, testicular cancer, glioblastoma, sarcoma, bone cancer, brain cancer, head and neck cancer, skin cancer, thyroid cancer, bladder cancer, mesothelioma, meningioma, and sarcoma.

[0068] When used as a pharmaceutical composition, etc. (i.e., pharmaceutical composition, nuclear medicine imaging agent, imaging reagent) containing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, it can be formulated by mixing it with a pharmaceutically acceptable carrier or diluent according to known methods. The dosage form is not particularly limited and can be an orally administered pharmaceutical composition in the form of an injection, tablet, powder, granule, capsule, liquid, suppository, sustained-release, etc.

[0069] The pharmaceutical composition of the present invention may be administered locally or systemically. The route of administration can be appropriately determined depending on the condition of the subject, etc., but it can also be prepared as a parenteral pharmaceutical composition in the form of an injectable preparation for intravenous, intra-arterial, intradermal, intramuscular, intraperitoneal, or intratumor administration.

[0070] The dosage of the pharmaceutical composition of the present invention is not particularly limited, and it is sufficient to administer an amount sufficient to obtain the desired contrast for imaging, for example, 1 μg or less.

[0071] The pharmaceutical compositions of the present invention may be in the form of solutions or powders. These formulations are prepared according to conventional methods. In the case of liquid formulations, they may be dissolved or suspended in water or other suitable solvents at the time of use. Tablets and granules may be coated by well-known methods. In the case of injectable formulations, the compounds of the present invention are prepared by dissolving them in water, but they may also be dissolved in physiological saline or glucose solution as needed, and buffers and preservatives may be added.

[0072] 3. Diagnostic Methods Another embodiment of the present invention is a method for diagnosing a disease or symptoms that may lead to a disease, (A) A step of administering a drug containing the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject who has or is suspected of having a disease or symptoms, and (B) A step of measuring the radiation emitted from radionuclides contained in the drug that are localized in the target tissue or target organ of the subject, in order to determine the presence of one or more selected from the group consisting of tumors, cancer cells and cancerous tissue in the target tissue or target organ. The method includes the above (hereinafter also referred to as "the diagnostic method of the present invention"). Here, "pharmaceutical agent" refers to one of the pharmaceutical compositions, nuclear medicine imaging agents, or imaging reagents of the present invention described above.

[0073] The subjects are not particularly limited, but may be humans or non-human animals (such as mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.).

[0074] Subjects with or suspected of having a disease or symptom include subjects with or suspected of having cancer.

[0075] The drug of the present invention may be administered orally or parenterally. Parenteral administration may be local or systemic. The route of administration can be appropriately determined depending on the condition of the subject, but for example, it can be administered by injecting a drug for intravenous, intra-arterial, intradermal, intramuscular, intraperitoneal, or intratumor administration.

[0076] In this specification, the terms “cancer” or “tumor” refer to any neoplastic growth in a subject, including initial tumors and any metastases. Cancer can be a liquid or solid type of tumor. Liquid tumors include tumors of hematological origin, such as myeloma (e.g., multiple myeloma), leukemia (e.g., Waldenström syndrome, chronic lymphocytic leukemia, and other leukemias), and lymphoma (e.g., B-cell lymphoma, non-Hodgkin lymphoma). Solid tumors can occur in organs and include cancers of the lungs, brain, breast, prostate, ovaries, colon, kidneys, and liver.

[0077] The types of cancer cells or tissues targeted by the diagnostic method of the present invention include brain tumors, malignant melanoma, head and neck cancer, breast cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, testicular cancer, glioblastoma, sarcoma, bone cancer, brain cancer, head and neck cancer, skin cancer, thyroid cancer, bladder cancer, mesothelioma, meningioma, and sarcoma cells or tissues. In this specification, the term “cancer tissue” means any tissue containing cancer cells. The term "organization" must be interpreted in its broadest sense, including all or part of an organ, and must not be interpreted restrictively in any way.

[0078] One aspect of the diagnostic method of the present invention includes detecting a radioactive signal of the compound from a subject who has been previously administered a drug containing the compound of the present invention or a pharmaceutically acceptable salt thereof. The detection of the signal is preferably performed, for example, after a sufficient amount of time has elapsed since the administration of the compound.

[0079] One embodiment of the diagnostic method of the present invention includes reconstructing the detected signal to convert it into an image and displaying it, and / or quantifying the detected signal and presenting the accumulated amount. In this specification, "displaying" includes displaying on a monitor and / or printing. In this specification, "presenting" includes storing the calculated accumulated amount and / or outputting it externally.

[0080] Signal detection can be appropriately determined depending on the type of radionuclide of the compound of the present invention used, and can be performed, for example, using scintigraphy, SPECT, PET, etc. Scintigraphy and SPECT include, for example, measuring the gamma rays emitted from a subject administered with the radioactive compound of this disclosure using a gamma camera. The measurement using a gamma camera includes, for example, measuring the radiation (gamma rays) emitted from the radionuclide of the administered compound in time intervals, preferably including measuring the direction from which the radiation is emitted and the amount of radiation in time intervals. The diagnostic method of the present invention may further include representing the distribution of the measured radioactive compound obtained by radiation measurement as a cross-sectional image, and reconstructing the obtained cross-sectional image.

[0081] PET may include, for example, the simultaneous counting of gamma rays produced by the annihilation of positrons and electrons from a subject administered with the radioactive compound relating to this disclosure using a PET detector, and further including the depiction of the three-dimensional distribution of the positions of positron-emitting radionuclides based on the measured results.

[0082] X-ray CT and / or MRI measurements may be performed in conjunction with scintigraphy, SPECT, or PET measurements. This allows for the creation of fused images, for example, by combining images obtained by scintigraphy, SPECT, or PET (functional images) with images obtained by CT or MRI (morphological images).

[0083] Another embodiment of the present invention is a kit comprising the compound of the present invention or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "Kit of the Present Invention"). The Kit of the Present Invention is used in nuclear medicine imaging. The kit of the present invention may further include one or more selected components for preparing the probe of the present invention, such as buffers and osmotic pressure modifiers, and instruments used for administering compounds, such as syringes. [Examples]

[0084] The present invention will be described in detail below with reference to examples, but the scope of the present invention is not limited thereto.

[0085] material • Reagents (distributor, product code) Bis(tributyltin) (Sigma-Aldrich, 251127-10G) Tris(dibenzylideneacetone)dipalladium(0) (Wako, 209-18401) N,N-dimethylformamide, deoxygenated (DMF) (wako, 042-32071) Acetic acid (AcOH) (wako, 017-00256) Methanol (MeOH) (wako, 131-01826) N-chlorosuccinimide (NCS) (wako, 354-13862) Iodine-125 radionuclide (Perkin Elmer, Inc., NEZ033A) Acetonitrile (Sigma-Aldrich, 34888-2.5L) Formic acid (FA) (Nacalai Tesque, 08965-82) GGT (γ-GT) (wako, 307-50673)

[0086] measuring equipment Automatic setting medium-pressure preparative liquid chromatograph (Yamazen, AI-580) Preparative HPLC (JASCO, LC-2000Plus series) Separation using a C18 column (GL Sciences, 5020-06822) Shaker (eppendorf Thermomixer comfort) HPLC for analysis (SHIMADZU, LC-20AB) Analysis C18 column (GL Sciences, 5020-07345) Radioactivity-HPLC-flow monitor (GABI Star, Elysia-raytest) Curie meter (ALOKA CURIEMETER IGC-8, HITACHI) γ counter (2480 Wizard 2 , Perkin Elmer) SPECT / CT (NanoSPECT / CT, Bioscan)

[0087] [Synthesis Example 1] According to the following Scheme 1, gGlu-4 125 I-FMA was synthesized.

[0088] Scheme 1 TIFF0007878747000006.tif56168

[0089] <Synthesis of gGlu-4SnBu3-FMA>[[]] gGlu-4I-FMA (150.4 mg, 0.396 mmol) was placed in a 50 mL two-neck eggplant flask and purged with argon. It was dissolved in 5 mL of deoxygenated DMF, and bis(tributyltin) (1.5 mL, 1.148 g / mL, 2.97 mmol, 7.5 eq) was added. Degassing and argon replacement were repeated three times. Tris(dibenzylideneacetone)dipalladium(0) (36.3 mg, 0.0396 mmol, 0.1 eq) was added, and after degassing and argon replacement were performed three times again, the reaction was carried out at 60 °C overnight (20 hours). After the reaction, it was allowed to cool to room temperature, filtered through celite with MeOH, and the filtrate was concentrated with an evaporator. The obtained crude was subjected to flash column chromatography to remove lipophilic impurities under the conditions of flowing hexane / ethyl acetate = 50 / 50 for 10 minutes and then MeOH for 10 minutes. After concentration using an evaporator, it was purified by preparative HPLC. Purification was carried out with a gradient of A solution being H2O, B solution being MeCN + 1% H2O, A / B = 40 / 60 → 0 / 100 (40 min), and a flow rate of 10 mL / min, and 11.1 mg (yield 5%) of gGlu-4SnBu3-FMA was obtained.

[0090] <gGlu-4 125 Synthesis of I-FMA ( 125 I labeling) Na 125 I solution (8.90 MBq in 6.5 μL 10 -5 M NaOHaq.) was dispensed into a 1.5 mL Eppendorf tube. To this, 0.5 μL was added from a solution of approximately 2 mg of NCS dissolved in 1000 μL of MeOH, 10 μL was added from a solution of 2.7 mg of gGlu-4SnBu3-FMA dissolved in 540 μL of MeOH, and 1.7 μL of AcOH was added in this order, and the mixture was stirred at 25 °C and 500 rpm for 30 minutes using a shaker. The entire volume of this solution was injected into an HPLC equipped with a Radioactivity-HPLC-flow monitor (GABI Star) for purification. Details regarding the purification are described below. Also, when labeling is carried out using higher radioactivity Na 125 I such as 100 MBq, the labeling reaction can be carried out according to the same procedure.

[0091] <gGlu-4SnBu3-FMA instrument data> 1H NMR (400 MHz, CD3OD): δ 0.80 (t, 9H, J = 7.3 Hz), 1.00 (t, 6H, J = 8.2 Hz), 1.19 - 1.30 (m, 6H), 1.43 - 1.51 (m, 6H), 2.10 (dt, 2H, J = 7.0, 6.6 Hz), 2.59 (t, 2H, 7.4 Hz), 3.65 (t, 1H, J = 6.2 Hz), 5.29 (d, 2H, J = 48 Hz), 7.28 (d, 1H, J = 7.7 Hz), 7.37 (d, 1H, J = 7.8 Hz), 7.43 (s, 1H) HRMS (ESI+): Calculated for [M + Na]+, 567.20197, Found, 567.20011 (1.9 mDa)

[0092] <gGlu-4I-FMA machine data (cold standard, TFA salt)> 1H NMR (400 MHz, CD3OD): δ 2.20 (m, 2H), 2.74 (t, 2H, J = 7.1 Hz), 4.09 (t, 1H, 6.5 Hz), 5.36 (d, 2H, J = 47 Hz), 7.23 (d, 1H, J = 8.4 Hz), 7.72 (d, 1H, J = 8.4 Hz), 7.82 (s, 1H) 13C NMR (100 MHz, CD3OD): 26.9, 32.5, 53.4, 81.6 (d, J = 165 Hz), 91.2, 128.8, 135.0 (d, J = 17 Hz), 135.9 (d, J = 3.9 Hz), 138.2 (d, J = 8.8 Hz), 139.3 (d, J = 2.2 Hz), 171.5, 173.2 HRMS (ESI+): Calculated for [M + H]+, 381.01059, Found, 381.01103 (-0.4 mDa); Calculated for [M + Na]+, 402.99253, Found, 402.99272 (-0.2 mDa)

[0093] gGlu-4 125The purification of I-FMA was performed using an HPLC with a radiation detector. The results are shown in Figure 2. The analytical HPLC described above was used for purification. Solution A was H2O + 0.1% FA, and solution B was MeCN / H2O = 8 / 2 + 0.1% FA. Purification was performed using a gradient of A / B = 70 / 30 → 0 / 100 (20 min) at a flow rate of 1 mL / min. The upper figure shows the radiation detector, and the lower figure shows the PDA at 254 nm. Note that there is a lag of about 10 seconds due to the flow path. The peak with a retention time of 5.7 minutes, marked with a circle in the figure, was collected in a pear-shaped flask. The purified gGlu-4 125 I-FMA was dried overnight in a freeze-dryer.

[0094] [Example 1] gGlu-4 125 HPLC analysis of I-FMA and its metabolites gGlu-4 after purification 125 I-FMA was dissolved in DPBS(-) to prepare a solution of approximately 5 kBq / μL. 5 μL of this solution was mixed with 20 μL of DPBS(-), and the entire 25 μL was injected into an analytical HPLC. The radiation detector results are shown in the upper left of Figure 3. The HPLC analysis conditions were exactly the same as those used during purification in Figure 2. Metabolite analysis is performed using the above gGlu-4 125 10 μL of I-FMA solution was mixed with 40 μL of 100 U / mLGGT solution (final concentration 80 U / mL) and stirred using a shaker at 37°C and 500 rpm for 3.5 hours. The results of a radiation detector obtained by injecting half of this reaction solution (25 μL) into the analyzer are shown in the upper left of Figure 3. The lower right shows the results for gGlu-4. 125 This is the result of extracting the 254 nm portion of the cold standard of 2-Amino-5-iodobenzyl alcohol (2-amino-5-iodobenzyl alcohol), which is produced when I-FMA is metabolized by GGT to generate azaquinone methide and reacts with water, which will likely be the main nucleophile in this enzymatic reaction experiment, under the same analytical conditions, using PDA. Due to the reaction with GGT, the retention time has shifted from 5.4 minutes to 7.5 minutes, and since the product after the reaction has the same retention time as the cold standard of 2-Amino-5-iodobenzylalcohol, gGlu-4 125 It is suggested that I-FMA reacts with GGT and is converted to 2-Amino-5-iodobenzylalcohol, and this result supports the generation of an azakinone methide intermediate by the metabolic enzyme reaction.

[0095] [Example 2] cells with high / low GGT activity and gGlu-4 inhibitors 125 Evaluation of intracellular uptake of I-FMA probes Using the procedure shown in Figure 4, with cells having high or low GGT activity and GGsTop, an inhibitor of GGT, the cellular uptake of gGlu-4 125 I-FMA was evaluated. First, SHIN3 (high GGT activity) and SKOV3 (low GGT activity) cells were seeded in 12-well culture plates and incubated for 1 day. Next, the medium in each well was changed to fresh medium containing gGlu-4 125 I-FMA (and GGsTop), and incubated for 6 hours. Then, the medium was removed, and the cells were washed 3 times with PBS(-). The cells were then collected, and the radioactivity from the cells was measured using a gamma counter, and the cell count was determined. The results are shown in Figure 5.

[0096] Figure 5 shows the 125 count number of Iγ-rays from the cells measured using a gamma counter (ratio to SHIN3 + GGsTop standardized by the total count of the entire fraction including the medium and 3 washes and the cell count). Since there was almost no radioactivity in the third wash fraction and the radioactivity from the cell fraction was much higher than that, the radioactivity from the cell fraction is considered to be derived from the radionuclide retained inside the cells. In SHIN3, the uptake rate was approximately 30 times higher when the inhibitor was not added compared to when it was added. Furthermore, in SKOV3, which has low GGT activity, the uptake rate was kept low, indicating that this probe is taken up into cells in a GGT activity-dependent manner. In addition, since the signal remained in the cells even after washing, it is thought that a certain percentage of the taken-up probe remains in the cells and withstands washout.

[0097] [Example 3] Intratumoral administration experiment of probes to subcutaneous tumor model mice Based on the results of Example 2, probes were administered into the tumors of subcutaneous tumor model mice, and SPECT / CT imaging was performed. A mouse model was created in which A549 cells with high GGT activity were transplanted into the subcutaneous tissue on the left side of the body, and H226 cells with low GGT activity were transplanted into the subcutaneous tissue on the right side of the body. Approximately 150 kBq in 30 μL of PBS(-) of gGlu-4 was placed in the subcutaneous tumors of A549 (high GGT activity, left side) and H226 (low GGT activity, right side), respectively. 125 I-FMA was administered directly. SPECT / CT images were acquired 30 minutes, 2 hours, and 5 hours after administration. The results are shown in Figure 6. Figure 6 shows that in tumors with low GGT activity (H226 tumors), radioactivity rapidly decreases, but in tumors with high GGT activity (A549 tumors), radioactivity clearly remains. From these results, gGlu-4 125 When I-FMA is applied in a localized environment, it is evident that a metabolic trap utilizing GGT activity was achieved in vivo.

[0098] [Example 4] Visualization experiment of peritoneal metastasis by intraperitoneal administration of probe (IP) Next, following the procedure shown in the left diagram of Figure 7, a peritoneal dissemination model mouse and gGlu-4 125 Intraperitoneal administration of I-FMA was performed. First, A549-luc-C8 cells with high GGT activity were transplanted into the peritoneal cavity of mice and reared for one week. Luciferin potassium was administered intraperitoneally, and tumor growth was confirmed by luminescence imaging using IVIS (right panel in Figure 7). Next, gGlu-4 125I-FMA was administered intraperitoneally (~3 MBq) to peritoneal model mice and tumor-free mice, and SPECT / CT imaging was performed using NanoSPECT / CT. Figure 8 shows the imaging results 5 hours after administration; the left figure is from the peritoneal dissemination model mouse, and the right figure is from tumor-free mice. The images are shown as Maximum Intensity Projection (MIP) images. SPECT / CT images showed that after 30 minutes, a large number of signals had accumulated in the bladder, and almost all of the probe had been removed from the abdominal cavity. This rapid excretion is a major characteristic of this probe. As shown in Figure 8, 5 hours after administration, only scattered signals remained in the abdomen of the peritoneal dissemination model mouse, and such signals were not observed in mice without tumors. Furthermore, the peritoneal dissemination model mouse shown in the left figure was dissected after 5 hours of imaging, and the intestines and mesentery were removed and imaged using autoradiography (ARG) (Figure 9). The left figure shows the ARG image, and the right figure shows the white light image. Uptake of radionuclides was observed in the mesentery, corresponding to the minute peritoneal dissemination foci indicated by several arrows. From this, it is thought that the signals scattered within the abdominal cavity in the SPECT / CT image in Figure 8 (left) correspond to peritoneal dissemination foci. These results suggest that the probe developed in this study has the property of strongly accumulating in tumors while unresponsive probes are rapidly excreted from the peritoneal cavity, potentially enabling high-contrast visualization of peritoneal dissemination lesions.

Claims

1. A compound represented by the following general formula (I) or a salt thereof. (In the formula, X is selected from a fluorine atom or an ester group (-OC(=O)-R'), Here, R' is independently selected from a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group; The substituents of the alkyl group are selected from alkoxy groups, halogen atoms, amino groups, mono- or disubstituted amino groups, substituted silyl groups, or acyl groups; The substituents of the aryl group are selected from alkoxy groups, halogen atoms, amino groups, mono- or disubstituted amino groups, substituted silyl groups, acyl groups, alkyl groups, hydroxyl groups, carboxyl groups, sulfo groups, alkoxycarbonyl groups, or oxo groups. Y is an enzyme recognition site, and a portion of it is cleaved by the enzymatic activity of cancer cell-specific glycosidase or peptidase, which induces the formation of quinone methide. Y is -NH-CO-L, -NH-L', or -OL', Here, L, together with the C=O to which it is bound, constitutes an amino acid residue or a peptide. L' is a substructure of a sugar, a substructure of a sugar having a self-cleaving linker, an amino acid residue having a self-cleaving linker, or a peptide; When Y is -NH-L', and L' is an amino acid residue or peptide having a self-cleaving linker, or a substructure of a sugar having a self-cleaving linker, the self-cleaving linker spontaneously cleaves and / or decomposes to form an aniline structure, after which X is eliminated to form a quinone methide. When Y is -OL', L' is an amino acid residue or / or a peptide having a self-cleaving linker, a substructure of a sugar having a self-cleaving linker, or, in the case of a substructure of a sugar, the self-cleaving linker spontaneously cleaves and / or decomposes, or hydrolysis directly generates a phenol structure, after which X is eliminated to form a quinone methide. Here, the partial structure of a sugar is a structure obtained by removing one hydroxyl group from a sugar. R １ and R ２ Each of these is independently either a hydrogen atom or a halogen atom, except R １ and R ２ At least one of them is a hydrogen atom; R ３ These are one or two identical or different monovalent substituents located on a hydrogen atom or a benzene ring; R ３ The monovalent substituent of is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group (—C(═O)—OR ａ ), and a halogen atom (R ａ is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, and when there are two or more R ａ s, each R ａ may be the same or different) In general formula (I), -Y is -C(R １ ) (Caution ２ ) It is bonded to X at the ortho or para position of the benzene ring, R ４ This refers to a hydrogen atom, or a substituent or molecule that can alter its dynamics in the body. The substituent or molecule may be bonded to the benzene ring via a linker. The substituent or molecule is selected from the group consisting of: substituted or unsubstituted biphenyl groups; monovalent or divalent substituents derived from substituted or unsubstituted bicyclic compounds selected from naphthalene or quinoline; dye molecules such as Evans blue; monovalent or divalent substituents derived from p-iodophenylbutyric acid; and groups formed by the arbitrary, and sometimes via linking groups, bonding two or more of these substituents or molecules, one or more of the same or different substituents or molecules. The substituents that the biphenyl group and the bicyclic compound may have are selected from the group consisting of alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups; Z represents a single bond or linking group. The linking group of Z is an alkylene group (wherein one or more of the alkylene groups are -CH ２ - may be substituted with -O-, -S-, -NH-, or -CO-.) Selected from the group consisting of arylene (including heteroarylene), cycloalkylene, alkoxyl group, polyethylene glycol chain, and groups formed by the arbitrary bonding of two or more groups selected from these groups: A is, １２５ I, １２３ I, １３１ I, １２４ I and １８ (Represents a radioactive nuclide selected from the group consisting of F.)

2. The compound or salt thereof according to claim 1, wherein a substituent or molecule capable of altering the in vivo dynamics is introduced to the benzene ring via a linker or directly.

3. The linker is an alkylene group (wherein one or more of the alkylene groups are -CH ２ - may be substituted with -O-, -S-, -NH-, or -CO-.), arylene (including heteroarylene), cycloalkylene, alkoxyl group, polyethylene glycol chain, and a group selected from the group consisting of two or more groups selected from these groups that are arbitrarily bonded together. The compound or salt thereof according to any one of claims 1 to 2.

4. A compound or salt thereof according to any one of claims 1 to 3, wherein Y has a structure selected from the following.

5. R １ and R ２ The compound or salt thereof according to any one of claims 1 to 4, wherein each is independently selected from a hydrogen atom or a fluorine atom.

6. R ３ The compound or salt thereof according to claim 1, wherein the monovalent substituent is an alkyl group or an alkoxycarbonyl group.

7. R ３ The compound or salt thereof according to claim 1, wherein the monovalent substituent is a halogen atom.

8. R ３ At least one of the monovalent substituents is an alkyl group or an alkoxycarbonyl group, R ３ The compound or salt thereof according to claim 1, wherein at least one of the monovalent substituents is a halogen atom.

9. R ３ and R ４ The compound or salt thereof according to any one of claims 1 to 5, wherein all of them are hydrogen atoms.

10. A compound selected from the following compounds, or a salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition according to claim 11, used in nuclear medicine examinations.

13. The pharmaceutical composition according to claim 12, which can be accumulated in cancer cells by acting selectively on cells through the enzymatic activity of cancer cell-specific peptidase or glycosidase.

14. The pharmaceutical composition according to any one of claims 12 to 13, wherein the nuclear medicine examination is at least one selected from the group consisting of scintigraphy, SPECT (single-photon emission computed tomography), and PET (positron emission tomography).

15. A method for diagnosing a disease or symptoms that may lead to a disease, (A) A step of administering a drug containing the compound described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof to a subject (excluding humans) who has or is suspected of having a disease or symptoms, and (B) A step of measuring the radiation emitted from radionuclides contained in the drug that are localized in the target tissue or target organ of the subject, in order to determine the presence of one or more selected from the group consisting of tumors, cancer cells and cancer tissue in the target tissue or target organ. The method, including the method described above.

16. The diagnostic method according to claim 15, wherein the drug is administered intravenously, intraperitoneally, or intratumorally to the subject.

17. A kit comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

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