Compound, radioactively labeled compound and method for producing same, and radioactive pharmaceutical composition

Abstract

This radioactively labeled compound is represented by formula (1). In formula (1), M represents a radioactive metal ion. A represents a chelate moiety coordinated to the radioactive metal ion. B represents a first atomic group having a structure in which ethyleneimine is polymerized. C represents a second atomic group having a molecular weight of 5000 or less and capable of binding to a molecule expressed in a tumor cell. The second atomic group preferably includes a linear or cyclic peptide. The second atomic group also preferably includes 1-50 amino acid residues.

Description

Compound, radiolabeled compound and method for producing the same, and radiopharmaceutical composition - Patents.com

[0001] The present invention relates to compounds, radiolabeled compounds and methods for their preparation, and radiopharmaceutical compositions.

[0002] Radiolabeled compounds containing radionuclides in their structures are used as reagents for detecting target molecules, diagnostic agents, or pharmaceuticals for treating diseases. To further improve the detection performance and therapeutic efficacy of lesions, studies are underway to improve the specific accumulation in target tissues and sites and to reduce the accumulation in non-target tissues and sites.

[0003] The present applicant previously proposed a radiolabeled compound having in its structure a chelating moiety capable of coordinating with a radioactive metal ion, a first atomic group including an albumin-binding moiety, and a second atomic group including a binding moiety to a PSMA molecule, the first atomic group and the second atomic group being bound via the chelating moiety, and the compound being coordinated to a radioactive metal ion (Patent Document 1). The document describes that such a radiolabeled compound can simultaneously achieve improved accumulation in target tissues (tumor tissues) where PSMA is expressed and reduced accumulation in non-target tissues, particularly the kidney.

[0004] Furthermore, the present applicant has addressed the issue of low tumor-blood ratios due to the blood retention of monoclonal antibodies by directly introducing diethylenetriamine (DETA) or tetraethylenepentamine (TEPA) into metal ligands. １１１ It has been reported that the pharmacokinetics of In-labeled trastuzumab can be improved (Non-Patent Documents 1 and 2).

[0005] US Patent Application Publication No. 2024 / 0174622

[0006] Nakashima, K. et al., Abstracts of the 143rd Annual Meeting of the Pharmaceutical Society of Japan, 27D-pm03SNakashima et al., J. Med. Chem. 2023, 66, 18, 12812-12827

[0007] Low-molecular-weight or medium-molecular-weight radiolabeled compounds have a short blood half-life and are rapidly distributed to excretory organs, tending to accumulate in tumors at lower levels than high-molecular-weight radiopharmaceuticals such as antibodies. Although the radiolabeled compound described in Patent Document 1 has excellent tumor tissue accumulation, there is a demand for further enhancement of this accumulation. To further enhance tumor tissue accumulation, for example, it is conceivable to improve the retention of the radiolabeled compound in tumor cells. However, it was unclear whether applying polyethyleneimine, as described in Non-Patent Documents 1 and 2, to low-molecular-weight or medium-molecular-weight radiolabeled compounds would produce the desired effect. Therefore, an object of the present invention is to provide a radiolabeled compound with excellent retention in tumor cells, and a compound used for producing the radiolabeled compound.

[0008] The present invention provides a radiolabeled compound represented by the following formula (1): (In formula (1), M is a radioactive metal ion, A is a chelating moiety coordinated to the radioactive metal ion, B is a first atomic group having a structure in which ethyleneimine is polymerized, and C is a second atomic group having a molecular weight of 5000 or less and capable of binding to a molecule expressed in tumor cells.)

[0009] The present invention also provides a radiopharmaceutical composition containing the radiolabeled compound as an active ingredient.

[0010] The present invention also provides a compound represented by the following formula (2): (In formula (2), A is a chelating moiety capable of coordinating with a radioactive metal ion, B is a first atomic group having a structure in which ethyleneimine is polymerized, and C is a second atomic group having a molecular weight of 5,000 or less and capable of binding to a molecule expressed in tumor cells.)

[0011] The present invention also provides a method for producing a radiolabeled compound, which comprises coordinating the compound with a radioactive metal ion to obtain the radiolabeled compound.

[0012] FIG. 1 shows the radiolabeled compounds ([ １１１ In] In-PDI2, [１１１ In]In-PDI4 and [ １１１ 2 is a graph showing the time course of the amount of radiolabeled compounds ([In]In-PSMA-617) internalized in cells and the amount of radiolabeled compounds ([ １１１ In] In-PDI2, [ １１１ In]In-PDI4 and [ １１１ 3 is a graph showing the time course of radioactivity accumulation in tumors, kidneys, and blood in an experiment on the distribution of radioactivity in the body of the radiolabeled compounds ([In]In-PSMA-617) of Examples 1-2, 2-2, and Comparative Example 1-1. １１１ In] In-PDI2, [ １１１ In]In-PDI4 and [ １１１ 4 shows SPECT / CT images of the radiolabeled compounds ([In]In-PSMA-617) of Examples 1-3 and 2-3 and Comparative Example 1-2. ２２５ Ac] Ac-PDI2, [ ２２５ Ac]Ac-PDI4 and [ ２２５ 5 is a graph showing the time course of the mean tumor volume in each group in the evaluation of the efficacy of the radiolabeled compounds ([Ac]Ac-PSMA-617) of Examples 1-3 and 2-3 and Comparative Example 1-2. ２２５ Ac] Ac-PDI2, [ ２２５ Ac]Ac-PDI4 and [ ２２５ 4 is a graph showing the time course of the average body weight of each group in the evaluation of the efficacy of the radiolabeled compounds ([Ac]Ac-PSMA-617) of Examples 1-3 and 2-3 and Comparative Example 1-2. ２２５ Ac] Ac-PDI2, [ ２２５ Ac]Ac-PDI4 and [ ２２５ 1 is a graph showing the organ weights of each individual in each group at the end of observation in the evaluation of the efficacy of [Ac]Ac-PSMA-617).

[0013] The radiolabeled compounds and compounds of the present invention will be described below based on their preferred embodiments. In the following description, when it is written "T to U[V]" (T and U are arbitrary numbers, and [V] is a unit), it means "at least T[V] and at most U[V]" unless otherwise specified. Furthermore, when an asymmetric carbon atom is present in the structure, it may each independently be in the S-configuration or the R-configuration unless otherwise specified.

[0014] First, the compound of the present invention will be described. The compound of the present invention can be used to obtain the radiolabeled compound of the present invention by coordinating it with a radioactive metal ion. The structure of the compound of the present invention can be broadly classified into a chelating moiety capable of coordinating with a radioactive metal ion, a first atomic group, and a second atomic group, and the first atomic group and the second atomic group are bonded via the chelating moiety. The first atomic group is an atomic group having a structure in which ethyleneimine is polymerized (PEI structure). The second atomic group is an atomic group capable of binding to a molecule expressed in tumor cells. Details of the first atomic group and the second atomic group will be described later.

[0015] The compound of the present invention is preferably represented by the following general formula (2).

[0016]

[0017] In the formula (2), A is a chelating moiety, B is a first atomic group, and C is a second atomic group. In the formula (2), the second atomic group (C) and the chelating moiety (A) are bonded, for example, via an amide bond. Similarly, the chelating moiety (A) and the first atomic group (B) are bonded, for example, via an amide bond. As is clear from the formula (2), when the chemical structure of the compound of the present invention is viewed macroscopically, the second atomic group (C), the chelating moiety (A), and the first atomic group (B) are arranged in this order on a straight line.

[0018] In the formula (2), it is preferred that the chelating moiety (A) has a cyclic structure containing two or more nitrogen atoms, the nitrogen atoms being linked to each other via two or more adjacent carbon atoms, or that A has a chain structure containing two or more nitrogen atoms, the nitrogen atoms being linked to each other via two or more adjacent carbon atoms. When A has such a structure, the affinity of the compound of the present invention for radioactive metal ions can be sufficiently increased.

[0019] In the formula (2), when A has a cyclic structure, the skeleton of the cyclic structure may be composed only of nitrogen atoms and carbon atoms, or may be composed of oxygen atoms in addition to nitrogen atoms and carbon atoms. The bonds between the carbon atoms in the cyclic structure may be chain-like, or may form a ring structure. Furthermore, in the formula (2), when A has a chain structure, the bonds between the carbon atoms in the chain structure may be interrupted by a nitrogen atom. The bonds between the carbon atoms in the chain structure may be chain-like, or may form a ring structure.

[0020] In addition, in the formula (2), when A has a cyclic structure or a chain structure, it is preferable that A has a nitrogen-bonding atomic group directly bonded to a nitrogen atom constituting the cyclic structure or the chain structure. Specific examples of the nitrogen-bonding atomic group preferably include an atomic group containing one or more of a carboxy group, a phosphate group, an amide group, a benzene ring, and a pyridine ring, and more preferably the atomic group is chain-like. Furthermore, in the formula (2), when A has a cyclic structure or a chain structure, it is preferable that, provided that C is bonded to any site of A and B is bonded to any site of A different from the bonding site of C, when B is bonded to the above-mentioned nitrogen-bonding atomic group, C is bonded to a site other than the nitrogen-bonding atomic group to which B is bonded.

[0021] Specifically, in the formula (2), the chelating moiety capable of coordinating with the radioactive metal represented by the symbol A preferably has a structure derived from a compound represented by any one of the following formulas (A1) to (A9), and more preferably has a structure derived from a compound represented by the following formula (A1). In other words, the compound of the present invention is preferably a derivative of a compound represented by any one of the following formulas (A1) to (A9), and more preferably a derivative of a compound represented by the following formula (A1). These structures can be appropriately selected depending on the type of radioactive metal described below. Any chelating moiety having any of these structures can sufficiently increase the affinity for radioactive metal ions.

[0022] In the formula (2), the chelating moiety represented by the symbol A may be, for example, a structure derived from the following compound, but is not limited to these.

[0023] <DOTA or its derivatives> 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphate (DOTMP) Hydroxypropyltetraazacyclododecanetriacetic acid (HP-DO3A) (1R,4R,7R,10R)-α,α',α”,α'”-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAMA) 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAA)・1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamidomethylene)phosphonic acid (DOTA-A-AMP) ・Tetraazacyclododecanedimethanephosphonic acid (DO2P) ・α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA)

[0024] <HOPO or its derivatives> N,N',N",N'"-tetra(1,2-dihydro-1-hydroxy-2-oxopyridine-6-carbonyl)-1,5,10,14-tetraazatetradodecane (1,2-HOPO)

[0025] <TETA or PEPA or their derivatives> 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (TETPA) 1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N'",N""-pentaacetic acid (PEPA)

[0026] <Chain structures (Octapa, Neunpa, or their derivatives)> Ethylenediaminetetraacetic acid (EDTA) 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa) 6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene))dipicolinic acid (H2bispa2) 1,2-[{6-(carboxy)-pyridin-2-yl}-methylamino]ethane (H2dedpa) N,N"-bis(6-carboxy-2-pyridylmethyl)-diethylenetriamine-N,N',N"-triacetic acid (H5decapa) N,N'-(Methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane (H6phospa) 6,6'-(((((4-Isothiazolinatophenethyl)azanediyl)bis(ethane-2,1-diyl))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (p-SCN-Bn-H4neunpa) 6,6'-(((((4-Nitrophenethyl)azanediyl)bis(ethane-2,1-diyl))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (p-NO2-Bn-H4neunpa) 6,6'-(((azanediylbis(ethane-2,1-diyl))bis((carboxymethyl)azanediyl)bis(methylene))dipicolinic acid (H5neunpa)

[0027] <Macropa and its derivatives> ・6-(1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-N,N'-dimethyl)picolinic acid (H2macropa)

[0028] <NOTA or its derivatives> ・2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid (NOTA)

[0029]

[0030] In formula (A1), R １１ , R１２ , R １３ and R １４ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ , and (CHCOOH)(CH ２ ) ｐ COOH groups, and p represents an integer of 0 or more and 3 or less.

[0031] In formula (A2), R ２１ , R ２２ , R ２３ and R ２４ each independently represents a carboxy group or a carboxyalkyl group having 2 or 3 carbon atoms.

[0032] In formula (A3), R ３１ , R ３２ , R ３３ and R ３４ each independently represents a hydrogen atom and an atomic group having 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R ３５ represents a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0033] In formula (A4), R ４１ , R ４２ , R ４３ and R ４４ each independently represents a hydrogen atom and an atomic group having 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R ４５ represents a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0034] In formula (A5), R ４８ and R ４９each independently represents an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0035] In formula (A6), R ５１ , R ５２ , R ５３ , R ５４ and R ５５ each independently represents an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0036] In formula (A7), R ６１ , R ６２ , R ６３ , R ６４ , R ６５ and R ６６ each independently represents a hydrogen atom and an atomic group having 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R ６７ represents a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0037]

[0038] In formula (A8), R ７１ , R ７２ and R ７３ each independently represents an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0039] In formula (A9), R ８１ and R ８２ each independently represents an alkyl group having 1 to 5 carbon atoms, the terminal of which may be substituted with a pyridyl group substituted with one or more carboxy groups; R ８７ represents an oxygen atom (=O) of a hydroxyl group or a carbonyl group, and R ８３ and R ８４ represents a substituted or unsubstituted pyridyl group, R ８５ and R ８６ are each independently -COO-R ａ represents R ａ represents an alkyl group having 1 to 5 carbon atoms.

[0040] Specific examples of the structure represented by formula (A1) include structures represented by the following formulae (A1-1) to (A1-7).

[0041]

[0042]

[0043]

[0044] Specific examples of the structure represented by formula (A2) include structures represented by the following formulae (A2-1) and (A2-2).

[0045]

[0046] Specific examples of the structure represented by formula (A3) include structures represented by the following formulae (A3-1) to (A3-7).

[0047]

[0048]

[0049] Specific examples of the structure represented by formula (A4) include structures represented by the following formulae (A4-1) and (A4-2).

[0050]

[0051] Specific examples of the structure represented by formula (A5) include structures represented by the following formulae (A5-1) to (A5-3).

[0052]

[0053] A specific example of the structure represented by formula (A6) is a structure represented by the following formula (A6-1).

[0054]

[0055] Specific examples of the structure represented by formula (A7) include structures represented by the following formulae (A7-1) and (A7-2).

[0056]

[0057] Specific examples of the structure represented by formula (A8) include structures represented by the following formulae (A8-1) to (A8-3).

[0058]

[0059] Specific examples of the structure represented by formula (A9) include structures represented by the following formulae (A9-1) to (A9-4).

[0060]

[0061] In the formula (2), the chelating moiety represented by the symbol A preferably has a structure of DOTA or a derivative thereof, and more preferably has a structure represented by the following formula (3):

[0062]

[0063] In the formula (3), R Ｂ１ and R Ｂ２ One of the groups is an atomic group containing a bond to B in the formula (2), and the other is a hydrogen atom, OH, or a carboxy group. Ｃ１ and R Ｃ２ One of these is an atomic group containing a bond with C in the formula (2), and the other is a hydrogen atom, OH, or a carboxy group. Ｂ２ is an atomic group containing a bond to B in the formula (2), and R Ｃ２ is an atomic group containing a bond to C in formula (2), and R Ｂ１ and R Ｃ１ are preferably both hydrogen atoms or each independently a carboxyalkyl group having 1 to 5 carbon atoms. Ｂ１ is an atomic group containing a bond to B in the formula (2), and R Ｃ１ is an atomic group containing a bond to C in formula (2), and R Ｂ２ and R Ｃ２ may both be OH. In this case, the chelating moiety represented by symbol A in formula (2) has a structure represented by formula (4) below.

[0064]

[0065] In the formula (4), R Ｂ１ is an atomic group containing a bond to B (first atomic group) in formula (2), and R Ｃ１ is an atomic group containing a bond to C (second atomic group) in the formula (2). Ｂ１ and R Ｃ１ Each of the —(CH) groups preferably has a structure represented by the following formula (5): ２ ) ｎ -CO-(*2) (5) In formula (5), n is an integer of 1 or more and 4 or less, and (*1) and (*2) represent bonds. Ｂ１ has a structure represented by the formula (5), R Ｂ１ is preferably bonded to B in the formula (2) in (*2). Ｃ１ has a structure represented by the formula (5), R Ｃ１ is preferably bonded to C in the formula (2) in (*2).

[0066] As described above, in formula (2), the first atomic group represented by the symbol B has a structure in which ethyleneimine is polymerized (PEI structure). The PEI structure is protonated in intracellular lysosomes to become positively charged, making it less likely to be excreted outside the cell. In other words, by employing an atomic group having a PEI structure as the first atomic group, the intracellular retention of a radiolabeled compound obtained by coordinating the compound of the present invention with a radioactive metal ion can be improved. From the viewpoint of more reliably improving the intracellular retention of a radiolabeled compound, the lower limit of the degree of polymerization of ethyleneimine in the PEI structure contained in the first atomic group is preferably 1 or more, more preferably 2 or more, and the upper limit of the degree of polymerization of ethyleneimine is preferably 7 or less, more preferably 4 or less.

[0067] The first atomic group may have only one PEI structure or may have a plurality of PEI structures. A specific example of the structure of the first atomic group containing only one PEI structure is a structure represented by the following formula (6):

[0068]

[0069] In formula (6), R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a hydroxyalkyl group having from 2 to 6 carbon atoms, or a bond. n is an integer of 1 or more and represents the degree of polymerization of ethyleneimine. * represents a bond.

[0070] In formula (6), examples of the alkyl group having 1 to 6 carbon atoms represented by R include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.

[0071] In formula (6), examples of the hydroxyalkyl group having 2 to 6 carbon atoms represented by R include a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group, a 4-hydroxybutyl group, a 5-hydroxypentyl group, a 6-hydroxyhexyl group, and a 5-hydroxy-2-methylpentyl group.

[0072] The first atomic group represented by formula (6) is protonated in an acidic environment, such as in a lysosome, to form a (poly)cation having a high ionic charge density, thereby effectively enhancing the intracellular retention of a radiolabeled compound obtained by coordinating the compound of the present invention with a radioactive metal ion.

[0073] Another example of the first atomic group is a structure represented by the following formula (7).

[0074]

[0075] In formula (7), R １ and R ２ The definition of is the same as the definition of R in formula (6). １ and R ２ may be the same or different from each other. n1 and n2 each independently represent the degree of polymerization of ethyleneimine. n3 represents 0 or 1. When n3 is 0, X represents a hydrogen atom, and when n3 is 1, X represents CH ２ * represents a bond.

[0076] As long as the first atomic group has a PEI structure, it may further have a structure other than the PEI structure. Examples of the other structure include one or more amino acid residues and / or one or more albumin binders. The albumin binder is an atomic group having an affinity for albumin, preferably serum albumin, more preferably human serum albumin, and a chemical structure capable of reversibly binding to the albumin. Examples of albumin binder structures include gamma glutamic acid, substituted or unsubstituted phenylbutyric acid, lipids, hematin, bilirubin, clofibric acid, clofibrate, carotenoids, compounds having a steroid skeleton, compounds having an ibuprofen skeleton, linear or branched, saturated or unsaturated hydrocarbons having from 13 to 20 carbon atoms, cyanine dyes, dyes having a sulfonic acid group, diazo dyes, pentamethine cyanine dyes, blue dextran, bromocresol green, and Evans blue, as well as derivatives thereof, and structures derived from one or more of the structures described in WO 2005 / 117984, WO 2010 / 127336, or WO 2010 / 172844. Additionally or alternatively, antibodies or peptides capable of binding to albumin (e.g., peptides described in WO 2007 / 106120) can also be used as albumin binders. When the first atomic group has the other structure, the positional relationship among the chelate moiety, the PEI structure, and the other structure may be, for example, a positional relationship in which the other structure is located between the chelate moiety and the PEI structure, or a positional relationship in which the PEI structure is located between the chelate moiety and the other structure. Among these, it is preferable that the other structure is located between the chelate moiety and the PEI structure.

[0077] As described above, in formula (2), the second atomic group represented by the symbol C is an atomic group capable of binding to a molecule expressed in tumor cells (hereinafter also referred to as a "target molecule"). By providing a second atomic group having such properties, the accumulation in tumor cells of a radiolabeled compound obtained by coordinating the compound of the present invention to a radioactive metal ion can be enhanced. Furthermore, it is preferable that the second atomic group, in addition to the function of binding to a molecule expressed in tumor cells, also has the function of imparting to the radiolabeled compound a tendency for rapid excretion from the body, a tendency for low accumulation in normal organs, or a tendency for high infiltration into tumor tissue.

[0078] Examples of target molecules include prostate-specific membrane antigen (PSMA), somatostatin receptor, cholecystokinin receptor, integrin, fibroblast activation protein-α (FAP), LHRH receptor, gastrin-releasing peptide receptor (GRPR), carbonic anhydrase 9 (CA-IX), and glucagon-like peptide-1. There are five subtypes of somatostatin receptors (SSTR), with SSTR2 or SSTR5 being preferred. Integrins are heterodimers in which an α chain and a β chain associate in a 1:1 ratio. In humans, there are 18 types of α subunits and 8 types of β subunits, with RGD-binding integrins that recognize the Arg-Gly-Asp (RGD) sequence being preferred, and α Ｖ β ３ or α Ｖ β ６ is.

[0079] It is also preferable that the second atomic group has a predetermined molecular weight. Specifically, the molecular weight of the second atomic group is preferably 5,000 or less, more preferably 3,000 or less, and even more preferably 1,500 or less. By setting the molecular weight of the second atomic group to 5,000 or less, the clearance of the radiolabeled compound comprising the atomic group can be improved and the accumulation of the radiolabeled compound in normal organs can be reduced. Furthermore, the molecular weight of the second atomic group is preferably 300 or more, more preferably 400 or more, and even more preferably 500 or more. By setting the molecular weight of the second atomic group to 300 or more, the affinity and specificity for the target molecule can be further increased.

[0080] From the viewpoint of facilitating the structural design and synthesis of the second atomic group, the second atomic group preferably comprises a linear or cyclic peptide. From the viewpoint of setting the molecular weight of the second atomic group within the above-mentioned numerical range, such a linear or cyclic peptide preferably comprises 1 to 50 amino acid residues, more preferably 3 to 40 amino acid residues.

[0081] When the second atomic group includes a linear or cyclic peptide, the amino acid residues constituting the peptide may be bonded to each other via an amide bond, or some of the amino acid residues may be bonded to each other via a bonding mode other than an amide bond. Another bonding mode can be, for example, a bonding mode via a urea structure. When the second atomic group has a urea structure, the second atomic group can have one or more urea structures, but preferably has only one urea structure. Regardless of the bonding mode, when the amino acid residues constituting the peptide are α-amino acid residues, the amino group or carboxy group involved in the bond between the amino acid residues may be located in the main chain or in the side chain of the amino acid residue. Specifically, the bonded amino acid residues may be bonded to each other such that, for example, an amino group or carboxy group located in one main chain and an amino group or carboxy group located in the other main chain form an amide bond, or an amino group or carboxy group located in one side chain and an amino group or carboxy group located in the other side chain form an amide bond. Furthermore, an amino group or a carboxy group located on one main chain and an amino group or a carboxy group located on the other side chain may form an amide bond or the like.

[0082] As described above, the present inventors presume that the PEI structure contained in the first atomic group of the radiolabeled compound of the present invention is protonated in the acidic environment of tumor lysosomes, increasing polarity and reducing membrane permeability, thereby facilitating intracellular retention. Therefore, it is preferable that the second atomic group has the function of being taken up into cells after binding to a target molecule.

[0083] When a PSMA molecule is used as the target molecule, it is preferable that the second atomic group be an atomic group containing a structure represented by the following formula (C1), from the viewpoint of increasing affinity and specificity for the PSMA molecule.

[0084]

[0085] In the formula (C1), a and b each independently represent an integer of 1 or more and 7 or less. In addition, in the formula (C1), the portion indicated by the wavy line is a bonding site with A in the formula (2) or represents an atomic group including a bonding site with A. In the formula (C1), two amino acid residues are bonded via one urea structure.

[0086] In particular, the second atomic group is preferably represented by any one of the following formulae (C1-1) to (C1-4).

[0087]

[0088] In formulas (C1-1) to (C1-4), the portions indicated by wavy lines represent the bonding sites with A in formula (2).

[0089] The compound of the present invention is particularly preferably a compound represented by the following formula (8):

[0090]

[0091] The definition of n in the formula (8) is the same as the definition of n in the formula (6).

[0092] Next, the radiolabeled compound of the present invention will be described. The radiolabeled compound of the present invention has a structure in which the compound of the present invention is coordinated to a radioactive metal ion. Below, differences between the radiolabeled compound of the present invention and the compound of the present invention will be described. For points not specifically mentioned, the above explanations regarding the compound of the present invention also apply appropriately to the radiolabeled compound of the present invention. The radiolabeled compound of the present invention is preferably represented by the following formula (1):

[0093]

[0094] In the formula (1), M is a radioactive metal ion, A is a chelating moiety coordinated to the radioactive metal ion, B is a first atomic group, and C is a second atomic group. The details of the chelating moiety, the first atomic group, and the second atomic group are as described above. In the formula (1), the compound of the present invention is coordinated to the radioactive metal ion (M) at the chelating moiety (A). There are no particular limitations on the coordination form, and it may be, for example, monodentate or multidentate.

[0095] In the formula (1), the radioactive metal ion represented by M can be an ion of a metal nuclide that emits α-rays, β-rays, γ-rays, or a combination thereof. Examples of such radioactive metal nuclides include alkali metals, alkaline earth metals, lanthanides, actinides, transition metals, and radioactive isotopes of metals other than these metals. Among these, from the viewpoint of commercial applicability and improving complex formation ability, the following radioactive metal nuclides are preferred: ４４ Sc, ５１ Cr, ５７ Co, ５８ Co, ６０ Co, ５９ Fe, ６４ Cu, ６７ Cu, ６７ Ga, ６８ Ga, ８９ Sr, ８９ Zr, ９０ Y. ９９ｍ Tc, １０３ Ru, １１１ In, １５３ Sm, １６５ Dy, １６６ Ho, １７７ Lu, １８６ Re, １８８ Re, １９７ Hg, １９８ Au, ２０１ Tl, ２０３ Hg, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac or ２２７ It is preferable to use Th, ６４ Cu, ６８ Ga, ８９ Zr,９９ｍ Tc, １１１ In, １７７ Lu, １８６ Re, １８８ Re or ２２５ It is more preferable to use Ac. These radioactive metals can be produced by conventional methods. These radioactive nuclides are preferably obtained as a solution containing the radioactive metal in an ionized state.

[0096] When a radiolabeled compound is used for the purpose of treating a disease, it is preferable to use an α-ray emitting nuclide or a β-ray emitting nuclide as the radioactive metal in order to enhance the therapeutic effect. － It is preferable to use an α-ray emitting nuclide. The α-ray emitting nuclide may be any nuclide that emits α-rays in the decay process of a radioactive metal. ２１２ Bi, ２１３ Bi, ２２５ Ac or ２２７ Th and the like are preferably used, and more preferably ２２７ Th or ２２５ Ac, more preferably ２２５ Ac. β － The radioactive nuclides are generated by the β － Any nuclide that emits radiation is acceptable. In detail, ５９ Fe, ６０ Co, ６４ Cu, ６７ Cu, ８９ Sr, ９０ Y. ９９ｍ Tc, １０３ Ru, １５３ Sm, １６５ Dy, １６６ Ho, １７７ Lu, １８６ Re, １８８ Re, １９８ Au, ２０３ Hg, ２１２ Pb, ２１２ Bi or ２１３ Bi and the like are preferably used, and more preferably ６４ Cu, ６７ Cu, ８９ Sr, ９０ Y. １７７ Lu, １８６ Re or １８８ Re is used, more preferably１７７ Lu is used.

[0097] In addition, when a radioactively labeled compound is used for the purpose of diagnosing a disease or detecting a lesion, it is preferable to use β as a radioactive metal in order to improve diagnostic performance. ＋ It is preferred to use a β-ray emitting nuclide, an electron capture decay nuclide, or a gamma ray emitting nuclide. ＋ The radiation-emitting nuclide may be any nuclide that emits positrons during the decay process of a radioactive metal. ４４ Sc, ５８ Co, ６８ Ga, ６４ Cu or ８９ Zr and the like are preferably used, and more preferably ６４ Cu or ８９ The electron capture decay nuclide may be any nuclide that emits Auger electrons or characteristic X-rays during the decay process of the radioactive metal. ５１ Cr, ５７ Co, ５８ Co, ６４ Cu, ６７ Ga, ６８ Ga, ８９ Zr, １１１ In, １８６ Re, １９７ Hg or ２０１ The gamma-ray emitting nuclide may be any nuclide that emits gamma rays through gamma decay, and examples of the nuclide that emits gamma rays through gamma decay include: ６８ Ga, ９９ｍ Tc or ２０１ Tl is preferably used.

[0098] When selecting a radioactive metal based on its ionic radius, the following radioactive metals have an ionic radius of about 70 to 130 pm: ６４ Cu, ６７ Cu, ６７ Ga, ６８ Ga, ８９ Zr, ９０ Y. ９９ｍ Tc, １０３ Ru, １１１ In, １５３ Sm, １６５ Dy, １６６ Ho, １７７ Lu, １８６ Re,１８８ Re, １９８ Au, ２０１ Tl, １９７ Hg, ２０３ Hg, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac, etc., which are preferably capable of forming a complex between the compound of the present invention having a chelating moiety having the structure represented by the above formulas (A1) to (A9) and a radioactive metal ion.

[0099] In summary, in the present invention, the radioactive metal ６８ Ga, ６４ Cu, ８９ Zr, ９９ｍ Tc, １１１ In, １７７ Lu, １８６ Re, １８８ Re or ２２５ Ac can be preferably used.

[0100] For example, when a radiolabeled compound is used for the purpose of treating a disease, ２２５ When Ac is used, the compound of the present invention is preferably a compound having a chelate moiety with a structure represented by any one of the formulas (A1), (A3) to (A5), or (A7), and more preferably a compound having a chelate moiety with a structure represented by the formula (A1), (A3), or (A4). ９０ When Y is used, the compound of the present invention is preferably a compound having a chelate moiety having a structure represented by any one of the formulas (A1) to (A3) or (A8), and more preferably a compound having a chelate moiety having a structure represented by the formula (A1). In addition, when the radiolabeled compound is used for the purpose of diagnosing a disease or detecting a lesion, the compound may be a compound having a chelate moiety having a structure represented by the formula (A1). ８９ When Zr is used, the compound of the present invention is preferably a compound having a chelate moiety of the structure represented by any one of the formulas (A1), (A3) and (A4), and more preferably a compound having a chelate moiety of the structure represented by the formula (A1). ６８ Ga or １１１When In is used, the compound of the present invention is preferably a compound having a chelate moiety having a structure represented by any one of formulas (A1) to (A4) or (A9), and more preferably a compound having a chelate moiety having a structure represented by formula (A1).

[0101] Next, a preferred method for producing the radiolabeled compound of the present invention will be described. The radiolabeled compound of the present invention can be obtained by coordinating the compound of the present invention with a radioactive metal ion. Specifically, for example, the compound of the present invention may be dissolved in an aqueous liquid such as a solvent or buffer solution and reacted with the radioactive metal.

[0102] From the viewpoint of increasing the efficiency of complex formation, the radioactive metal to be reacted with the compound is preferably used in the form of an ionizable radioactive metal compound or a radioactive metal ion, and more preferably in the form of a radioactive metal ion (hereinafter, these forms are also collectively referred to as "radioactive metal source"). As the radioactive metal source, for example, a radioactive metal ion-containing liquid in which radioactive metal ions are dissolved or dispersed in a solvent mainly composed of water can be used.

[0103] Furthermore, from the viewpoint of increasing the efficiency of complex formation with the radioactive metal, regardless of the combination of the chelating moiety in the compound and the radioactive metal, it is preferable to heat the compound and the radioactive metal to react in the complex formation. By carrying out the reaction under such reaction conditions, complex formation can proceed satisfactorily even when using low-energy radiation that is difficult to detect or a radioactive metal nuclide that emits α-rays, and therefore the desired radiolabeled compound can be obtained in high yield.

[0104] In obtaining a radiolabeled compound, the order of addition of the compound and the radioactive metal source is not important as long as a complex between the compound and the radioactive metal ion can be formed. For example, one of the compound and the radioactive metal source may be added to a reaction vessel containing a solvent, and then the other may be added and reacted, or one of the compound and the radioactive metal source may be dissolved in a solvent and then the other added to the solution, and then reacted. Alternatively, they may be added simultaneously to a reaction vessel containing a solvent and reacted.

[0105] The reaction conditions for obtaining a radiolabeled compound can be, for example, the following conditions. The solvent used in this step can be, for example, water, saline, or a buffer such as sodium acetate buffer, ammonium acetate buffer, phosphate buffer, phosphate-buffered saline, Tris buffer, HEPES buffer, or tetramethylammonium acetate buffer. The reaction temperature can be, for example, room temperature (25°C), or can be heated.

[0106] The radioactive metal source may be, for example, a solution in which radioactive metal ions are dispersed in a solvent mainly composed of water.

[0107] The volume of the reaction solution in this step is not particularly limited, but from the viewpoint of practicality in the production process, a volume of 0.01 mL to 100 mL is practical at the start of this step. Furthermore, from the viewpoint of the yield of the desired radiolabeled compound, it is preferable that the concentrations of the compound and the radioactive metal ion in the reaction solution are each independently 1 μM to 100 μM at the start of this step.

[0108] The radiolabeled compound obtained may be used as is, or may be purified using a filtration filter, a membrane filter, a column filled with various packing materials, chromatography, or the like. If necessary, a water-based solvent and other pharmaceutically acceptable ingredients may be added to the radiolabeled compound in a subsequent step to produce a radiopharmaceutical composition containing the radiolabeled compound as an active ingredient. A radiopharmaceutical composition can be produced, for example, by dissolving the radiolabeled compound produced by the above-mentioned method in a solvent that is water-based and approximately isotonic with the living body. Radiopharmaceutical compositions are administered to the living body orally or parenterally, such as intravenously, subcutaneously, intraperitoneally, or intramuscularly, and are used for the treatment, diagnosis, or detection of disease.

[0109] In the above-described embodiments, examples of substituents that may substitute for each atomic group, each structure, and each chemical structure of the compound and radiolabeled compound include halogen atoms, saturated or unsaturated hydrocarbon groups having 1 to 20 carbon atoms, hydroxyl groups, formyl groups, carboxyl groups, acyl groups, amino groups, nitro groups, alkoxycarbonyl groups having 1 to 20 carbon atoms, isothiocyanato groups, thioxy groups, cyano groups, aminocarbonyl groups, imido groups, and phosphate groups. These substituents may be used alone or in combination of two or more types. Examples of the saturated or unsaturated hydrocarbon groups having 1 to 20 carbon atoms include alkyl groups having 1 to 20 carbon atoms, alkenyl groups having 2 to 20 carbon atoms, alkynyl groups having 2 to 20 carbon atoms, aryl groups having 1 to 20 carbon atoms, and arylalkyl groups having 2 to 20 carbon atoms. More specific examples include methyl groups, phenyl groups, benzyl groups, pyridyl groups, and naphthyl groups.

[0110] The present invention encompasses the following technical concepts: [1] A radiolabeled compound represented by the formula (1). (In formula (1), M is a radioactive metal ion, A is a chelating moiety coordinated to the radioactive metal ion, B is a first atomic group having a structure in which ethyleneimine is polymerized, and C is a second atomic group having a molecular weight of 5,000 or less and capable of binding to a molecule expressed in tumor cells.) [2] The radiolabeled compound according to [1], wherein the second atomic group comprises a linear or cyclic peptide. [3] The radiolabeled compound according to [1] or [2], wherein the second atomic group comprises 1 to 50 amino acid residues. [4] The radiolabeled compound according to any one of [1] to [3], wherein the first atomic group has a structure in which ethyleneimine is polymerized with a degree of polymerization of 1 to 7. [5] The radiolabeled compound according to any one of [1] to [4], wherein the molecule expressed in tumor cells is prostate-specific membrane antigen (PSMA), somatostatin receptor, cholecystokinin receptor, integrin, fibroblast activation protein-α (FAP), LHRH receptor, gastrin-releasing peptide receptor (GRPR), carbonic anhydrase 9 (CA-IX), or glucagon-like peptide-1. [6] The radiolabeled compound according to any one of [1] to [5], wherein the second atomic group has a structure represented by any one of formulas (C1-1) to (C1-4). [7] The radiolabeled compound according to any one of [1] to [6], wherein the chelating moiety has a structure of DOTA or a derivative thereof.

[0111] [8] The radiolabeled compound according to [7], wherein the chelating moiety has a structure represented by formula (4). (In formula (4), R Ｂ１ is an atomic group containing a bond to the first atomic group, and R Ｃ１ is an atomic group containing a bond to the second atomic group. [9] The radioactive metal is ６８ Ga, ６４ Cu, ８９ Zr, ９９ｍ Tc, １１１ In, １７７ Lu, １８６ Re, １８８ Re or ２２５

[10] A radioactively labeled compound according to any one of [1] to [9], wherein R is R, ...

[0112] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0113] In the following examples, all reagents were commercially available and used as they were, unless otherwise specified. １１１ In]InCl ３ was purchased from Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). For mass spectrometry, low-resolution mass spectrometry (LRMS) was performed using an LCMS 2020 from Shimadzu Corporation (Kyoto, Japan), and high-resolution mass spectrometry (HRMS) was performed using an LCMS-IT-TOF from Shimadzu Corporation. Reverse-phase (RP)-HPLC was performed using a Cosmosil C from Nacalai Tesque, Inc. (Tokyo, Japan). １８ Column (5C １８ The radioactivity was measured using a Shimadzu system (LC-20AT and LC-20AD pumps equipped with an SPD-20A UV detector and a Hitachi Aloka Medical Co., Ltd. TCS-172 scintillation survey meter, detection wavelength: 254 nm) equipped with a 1000-AR-II (4.6 mm ID x 150 mm or 10 mm ID x 250 mm). ２ was used.

[0114] <Cell Culture> PSMA-positive human prostate cancer cells, LNCaP cells, and PSMA-negative human prostate cancer cells, PC-3 cells, were purchased from American Type Culture Collection and DS Pharma Biomedical, respectively. The cells were cultured in Roswell Park Memorial Institute 1640 (RPMI 1640) medium (manufactured by Nacalai Tesque, Inc.) containing 1% by volume of antibiotics (penicillin and streptomycin, 100 U / mL) and 10% by volume of heat-inactivated fetal bovine serum (FBS) at 37°C in a 5% by volume carbon dioxide environment.

[0115] All animal experiments were approved by the Kyoto University Animal Experiment Committee and conducted in accordance with its guidelines. Male BALB / c-nu / nu mice (5 weeks old) were purchased from Shimizu Experimental Materials Co., Ltd. (Shizuoka, Japan). Animals were housed under a 12-hour / 12-hour day / night cycle and provided with food and water ad libitum.

[0116] In the following examples and comparative examples, three types of compounds targeting PSMA as a target molecule and their In complexes were synthesized. Specifically, in Example 1-1, the following compound 7 (PDI2) having a first atomic group having a structure in which ethyleneimine is polymerized with a polymerization degree of 2 and its In complex ([ ｎａｔ In Example 2-1, the following compound 8 (PDI4) having a first atomic group with a structure in which ethyleneimine is polymerized with a degree of polymerization of 4 and its In complex ([ ｎａｔ In Example 1-2, PDI2 was synthesized. １１１ A radioactively labeled compound ([ １１１ In Example 2-2, PDI4 was synthesized. １１１ A radioactively labeled compound ([ １１１ Furthermore, in Comparative Example 1-1, the following radiolabeled compound ([ １１１ [In]In-PSMA-617) was synthesized. １１１

[0049] In—PSMA-617 is a radiolabeled compound that does not have a first atomic group. The synthetic routes for the compounds synthesized in Examples 1-1 to 2-2 and Comparative Example 1-1 are outlined in Schemes 1 and 2 below.

[0117]

[0118] Examples 1-1 and 2-1 (Synthesis of Compound 1) Compound 1 was synthesized according to a previously reported method [1].

[0119] (Synthesis of Compounds 2 and 3) Compounds 2 and 3 were synthesized according to a previous report [2].

[0120] (Synthesis of Compound 4) Compound 1 (700 mg, 0.91 mmol) was dissolved in anhydrous DMF (5 mL), and 1-((1-(cyano-2-ethoxy-2-oxo-ethylideneaminooxy)dimethylaminomorpholino))uronium hexafluorophosphate (COMU, 356 mg, 0.83 mmol) and N,N-diisopropylethylamine (DIPEA, 264 μL, 1.51 mmol) were added at 0° C., followed by stirring at 0° C. for 15 minutes. Compound 2 (229 mg, 0.75 mmol) was then added, followed by stirring at room temperature for 1 hour. The solution was purified by Cosmosil C １８ Column (5C １８ -AR-II, 10 mm ID x 250 mm) and mobile phase [H ２ The resulting mixture was purified by reverse-phase HPLC using a solvent mixture of 200 mL / min (flow rate 4 mL / min) of acetonitrile (MeCN) and trifluoroacetic acid (TFA) at a ratio of 70 / 30 / 0.1 (0 min) to 30 / 70 / 0.1 (40 min) to obtain 109.5 mg of compound 4 (13.7%). HRMS (ESI): m / z calculated for C ５２ H ９６ N ７ O １５ ＋ ,1058.6964[M+H] ＋ ;found, 1058.6961.

[0121] (Synthesis of Compound 5) Compound 1 (936 mg, 1.2 mmol) was dissolved in anhydrous DMF (6.7 mL), and COMU (475 mg, 1.1 mmol) and DIPEA (352 μL, 2.0 mmol) were added at 0° C., followed by stirring at 0° C. for 15 minutes. Compound 3 (595 mg, 1.0 mmol) was then added, followed by stirring at room temperature for 5 hours. The solution was purified by Cosmosil C １８ Column (5C １８ -AR-II, 10 mm ID x 250 mm) and mobile phase [H ２ The resulting mixture was purified by reverse-phase HPLC using a solvent mixture of 2,000 mL of HCl / MeCN / TFA (70 / 30 / 0.1 (0 min) to 30 / 70 / 0.1 (40 min) at a flow rate of 4 mL / min to give 285.8 mg of compound 5 (21.1%). HRMS (ESI) m / z calculated for C ６６ H １２３ N ９ O １９ ２＋ ,672.9468[M+2H] ２＋ ;found, 672.9463.

[0122] (Synthesis of Compound 6) Compound 6 was synthesized according to a previous report [3].

[0123] (Synthesis of Compound 7: PSMA Ligand-DOTADG-PEI2 (PDI2)) Compound 4 (109.5 mg, 0.10 mmol) was dissolved in anhydrous DMF, and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 98.7 mg, 0.26 mmol) and DIPEA (45.5 μL, 0.26 mmol) were added at 0° C., followed by stirring at 0° C. for 15 minutes. Thereafter, the solution thus obtained was added to the resin on which Compound 6 (65 μmol) had been immobilized, and the mixture was shaken overnight at room temperature. The resin was washed with anhydrous DMF (500 μL) three times and anhydrous dichloromethane (DCM, 500 μL) three times. Then, a mixed solution of TFA / triisopropylsilane (TIPS) / ultrapure water = 95 / 2.5 / 2.5 (1 mL) was added to the resin, and the mixture was stirred at room temperature for 3 hours. The solvent was then distilled off under an argon gas stream, and the resulting residue was purified by Cosmosil C １８ Column (5C１８ -AR-II, 10 mm ID x 250 mm) and mobile phase [H ２ The resulting mixture was purified by reverse-phase HPLC using a solvent mixture of 0.05% CO₂ / MeCN / TFA = 90 / 10 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min) (flow rate 4 mL / min) to give 6.0 mg of compound 7 (7.3%). HRMS (ESI): m / z calculated for C ５９ H ９２ N １２ O １９ ２＋ ,636.3301[M+2H] ２＋ ;found, 636.3300.

[0124] (Synthesis of Compound 8: PSMA Ligand-DOTADG-PEI4 (PDI4)) Compound 5 (262.1 mg, 0.20 mmol) was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl uronium hexafluorophosphate (HATU, 98.7 mg, 0.26 mmol) and DIPEA (45.5 μL, 0.26 mmol) were added at 0° C., followed by stirring at 0° C. for 15 minutes. Thereafter, the solution thus obtained was added to the resin on which compound 6 (49 μmol) had been immobilized, and the mixture was shaken at room temperature overnight. The resin was washed with anhydrous DMF (500 μL) three times and anhydrous DCM (500 μL) three times. Then, a mixed solution of TFA / TIPS / ultrapure water = 95 / 2.5 / 2.5 (1 mL) was added to the resin and stirred at room temperature for 3 hours. The solvent was then evaporated under a stream of argon gas, and the resulting residue was mixed with TFA / TIPS / anhydrous DCM = 80 / 5 / 15 (2 mL) and stirred overnight at room temperature. The solvent was evaporated under a stream of argon gas, and the resulting residue was purified by Cosmosil C １８ Column (5C １８ -AR-II, 10 mm ID x 250 mm) and mobile phase [H ２ The resulting mixture was purified by reverse-phase HPLC using a solvent mixture of 0.05% CO₂ / MeCN / TFA = 90 / 10 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min) (flow rate 4 mL / min) to give 26.6 mg of compound 8 (30.1%). HRMS (ESI): m / z calculated for C ６３ H１０２ N １４ O １９ ２＋ ,679.3723[M+2H] ２＋ ;found, 679.3721.

[0125] (Compound 9: PSMA ligand-[ ｎａｔ In]In-DOTADG-PEI2([ ｎａｔ Synthesis of [In]In-PDI2) Compound 7 (2.0 mg, 1.6 μmol) was dissolved in acetate buffer (1.0 M, pH 5.1, 200 μL), and indium(III) chloride (3.9 mg, 18 μmol) containing indium(III) at natural abundance was added, followed by heating at 90°C for 30 minutes. The reaction solution was then centrifuged to remove insoluble matter. The supernatant was purified by Cosmosil C １８ Column (5C １８ -AR-II, 4.6 mm I.D. × 150 mm) and mobile phase [H ２ The residue was purified by reverse-phase HPLC using a solvent mixture of 0 / MeCN / TFA = 90 / 10 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min) (flow rate 1 mL / min) to give 0.25 mg of compound 9 (11.4%). HRMS (ESI): m / z calculated for C ５９ H ８９ １１５ InN １２ O １９ ２＋ ,692.2705[M+3H] ２＋ ;found, 692.2705.

[0126] (Compound 10: PSMA ligand-[ ｎａｔ In]In-DOTADG-PEI4([ ｎａｔ Synthesis of [In]In-PDI4) Compound 8 (4.0 mg, 3.0 μmol) was dissolved in acetate buffer (1.0 M, pH 5.1, 200 μL), and indium(III) chloride (6.5 mg, 30 μmol) was added, followed by heating at 90°C for 30 minutes. The reaction solution was then centrifuged to remove insoluble matter. The supernatant was purified by Cosmosil C １８ Column (5C １８ -AR-II, 4.6 mm I.D. × 150 mm) and mobile phase [H ２The resulting mixture was purified by reverse-phase HPLC using a solvent mixture of 0 / MeCN / TFA = 90 / 10 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min) (flow rate 1 mL / min) to give 0.40 mg of compound 10 (9.3%). HRMS (ESI): m / z calculated for C ６３ H ９９ １１５ InN １４ O １９ ２＋ ,735.3127[M+3H] ２＋ ;found, 735.3127.

[0127]

[0128] <Examples 1-2 and 2-2> ([ １１１ In]In-PDI2 and [ １１１ Synthesis of In]In-PDI4) A dimethyl sulfoxide solution of compound 7 or 8 (1 μg / 1 μL, 8 μL) was dissolved in acetate buffer (0.1 M, pH 5.5, 200-250 μL), １１１ InCl ３ The solution (200 μL) was added and heated at 90° C. for 20 minutes. After returning to room temperature, the reaction mixture was １８ Column (5C １８ -AR-II, 4.6 mm I.D. × 150 mm) and mobile phase [H ２ The product was purified by reverse-phase HPLC using a solvent mixture of 0.05% MeCN / TFA (80 / 20 / 0.1 (0 min) to 65 / 35 / 0.1 (15 min) at a flow rate of 1 mL / min (Scheme 2). １１１ [In]In-PDI2 was obtained in a radiochemical yield of 67.5% and with a radiochemical purity of >95%. １１１ In]In-PDI4 was obtained in a radiochemical yield of 61.4% and with a radiochemical purity of >95%.

[0129]

[0130] (Comparative Example 1-1: [ １１１ Synthesis of In]In-PSMA-617) １１１ In]In-PSMA-617 was synthesized as previously reported [4].

[0131] (Evaluation) <Measurement of distribution coefficient> [１１１ In]In-PDI2 and [ １１１ In]In-PDI4 partition coefficient (log D ７．４ ) was measured by the shake flask method. １１１ A phosphate-buffered saline (PBS) solution (3 mL, 185 kBq) containing [In]In-PDI2 / 4 was mixed in a centrifuge tube, vigorously stirred for 2 minutes, and then centrifuged at 4000 × g for 5 minutes. 1 or 2 mL of the solution was collected from the 1-octanol layer, and 100 μL from the PBS layer. The radioactivity of each was measured using a gamma counter, and the partition coefficient was calculated from the ratio of the radioactivity in the 1-octanol layer to that in the PBS layer. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 log D ７．４ The values ​​were −3.69±0.03 and −3.51±0.08.

[0132] <In vitro stability evaluation using mouse plasma> Blood collected from ddY mice was centrifuged at 4000 × g for 15 minutes, and the supernatant was collected to obtain mouse plasma. １１１ In]In-PDI2 and [ １１１ [In]In-PDI4 (370 kBq) was added to mouse plasma (200 μL), mixed, and then incubated at 37°C for 24 hours. Acetonitrile (300 μL) was added and mixed, and then centrifuged at 12,000 × g for 5 minutes. The supernatant was collected and filtered through a CosmoNice Filter S (0.45 μm, 4 mm), after which the solvent was distilled off under a gas stream, and the residue was analyzed by reverse-phase HPLC. The analytical conditions were: １１１ The conditions were the same as those used in the synthesis of In-labeled drugs. １１１ In]In-PDI2 and [ １１１ After 24 hours of incubation in mouse plasma, 95% or more and 87.4±2.4% of [In]In-PDI4 remained unchanged.

[0133] <Cell binding saturation experiment> LNCaP cells were cultured in a 12-well plate (2 × 10 ５ cells / well) and incubated at 37°C with 5% CO ２After removing the medium, RPMI 1640 medium (500 μL) containing 0.5% by volume of heat-inactivated FBS was added and the mixture was left to stand at 4° C. for 30 minutes. １１１ In]In-PDI2 and [ １１１ The cells were incubated at 4°C for 2 hours in RPMI 1640 medium (500 μL) containing 0.5% by volume of heat-inactivated FBS containing [In]In-PDI4 (7.4 MBq / nmol, 0.195-50 nM). Nonspecific binding was assessed by adding 2-PMPA to a final concentration of 100 μM. The medium was removed, and the cells were washed with RPMI 1640 medium containing 0.5% by volume of heat-inactivated FBS. Then, 1N aqueous sodium hydroxide solution (200 μL) was added twice to lyse the cells. Radioactivity in the cell lysate was measured using a gamma counter, and total protein was measured using a bicinchoninic acid protein assay kit (Thermo Fisher Scientific). １１１ In]In-PDI2 and [ １１１ In]In-PDI4 on LNCaP cells ｄ The values ​​were 22.8±9.2 nM and 12.8±5.2 nM, respectively. １１１ In]In-PSMA-617 ｄ This was similar to the previous value of 5.4±0.8 nM (PLoS One, 2015, 10, e0145755).

[0134] <Cellular internalization experiment> LNCaP cells were cultured in a 6-well plate (3 × 10 ５ The cells were seeded onto the plate (200 x 100 cells / well) and incubated at 37°C in 5% CO ２ After removing the medium, RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS was added and the mixture was left to stand at 4°C for 30 minutes. １１１ In] In-PDI2, [ １１１ In]In-PDI4, or [ １１１RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS containing [In]In-PSMA-617 (37 kBq / well) was added, and the wells were incubated at 4°C for 2 hours. After removing the medium, the wells were washed twice with RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS. Subsequently, RPMI 1640 medium (1 mL) containing 1% by volume of antibiotics and 10% by volume of heat-inactivated FBS was added, and the wells were incubated at 37°C and 5% by volume of CO. ２ The cells were incubated for 0, 1, 2, and 4 hours under ambient conditions. They were then washed twice with RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS. The medium and wash solution were collected together as the medium fraction. To separate the radioactivity bound to the cell surface from the intracellular radioactivity, the cells were washed by adding 1 mL of glycine-HCl buffer (50 mM, pH 2.8) and incubating at 4°C for 3 minutes. Acid washing was performed twice, and the wash solution was collected together as the cell surface fraction. Subsequently, the cells were lysed by adding 1 mL of 1 N sodium hydroxide solution twice, and the cell lysate was collected as the intracellular fraction. The radioactivity of each fraction was measured using a gamma counter. The percentage of radioactivity in each fraction was calculated as a ratio to the total radioactivity of the medium fraction, cell surface fraction, and intracellular fraction. The results are shown in Figure 1 and Table 1. All compounds evaluated were rapidly internalized into the intracellular fraction within 2 hours of incubation. Furthermore, statistical analysis using a two-way analysis of variance combined with Bonferroni post hoc testing revealed no significant differences in internalization rates at subsequent time points.

[0135]

[0136] <Extracellular efflux experiment> LNCaP cells were cultured in a 6-well plate (3 × 10 ５ cells / well) and incubated at 37°C with 5% CO ２ The cells were incubated for 48 hours under ambient conditions. １１１ In] In-PDI2, [ １１１ In]In-PDI4, or [ １１１ RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS containing [In]In-PSMA-617 (37 kBq / well) was added, and the cells were incubated at 37°C with 5% by volume of CO２ The cells were incubated for 1 hour under ambient conditions. Then, to remove radioactivity from the medium, the cells were washed twice with RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS. To remove radioactivity bound to the cell surface, glycine hydrochloride buffer (50 mM, pH 2.8, 1 mL) was added, and the cells were washed twice by standing at 4°C for 3 minutes. Then, the cells were washed twice with RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS. Subsequently, RPMI 1640 medium (1 mL) containing 1% by volume of antibiotics and 10% by volume of heat-inactivated FBS was added, and the cells were incubated at 37°C in 5% by volume of CO. ２ The cells were incubated for 0, 1, 4, and 24 hours under ambient conditions. The cells were then washed twice with RPMI 1640 medium (1 mL) containing 0.5% by volume of heat-inactivated FBS. The medium and wash solution were collected together as the extracellular effluent fraction. The cells were lysed by adding 1 mL of 1 N aqueous sodium hydroxide twice, and the cell lysate was collected as the intracellular retention fraction. The radioactivity of each fraction was measured using a gamma counter. The percentage of radioactivity in the extracellular effluent fraction was calculated as a ratio to the sum of the extracellular effluent fraction and the intracellular retention fraction, and the results are shown in Figure 1 and Table 2. The significance test for the extracellular effluent experiment was performed using a two-way analysis of variance combined with a Bonferroni post-hoc test, with a confidence interval of 0.01. † 95% †† 99% ††† The extracellular effluent fraction was analyzed using a 99.9% ELISA. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 is １１１ Compared with [In]In-PSMA-617, a significant decrease in the extracellular efflux rate was observed after 1 hour of incubation.

[0137]

[0138] <Tumor Model> Tumor-implanted mouse models used in the internal radioactivity distribution experiment and blocking experiment were prepared as follows: LNCaP cells (5.0 × 10 cells) were cultured in a mixture (1:1, 150 μL) of RPMI 1640 and Matrigel (manufactured by Corning Life Sciences, Arizona, USA). ６The tumor-implanted model mice used for SPECT / CT imaging were prepared as follows. LNCaP cells (5.0 x 10 cells / mouse) were suspended and subcutaneously transplanted into the right hip of male BALB / c-nu / nu mice (5 weeks old) under isoflurane anesthesia (2% by volume). The mice were bred for 4-5 weeks, and mice whose tumor diameter reached 0.5 cm were used for the experiment. LNCaP cells (5.0 x 10 cells / mouse) were transplanted subcutaneously into the right hip of male BALB / c-nu / nu mice (5 weeks old) under isoflurane anesthesia (2% by volume). The mice were bred for 4-5 weeks, and mice whose tumor diameter reached 0.5 cm were used for the experiment. The tumor-implanted model mice used for SPECT / CT imaging were prepared as follows. LNCaP cells (5.0 x 10 cells / mouse) were transplanted subcutaneously into the right hip of male BALB / c-nu / nu mice (5 weeks old) under isoflurane anesthesia (2% by volume). The mice were bred for 4-5 weeks, and mice whose tumor diameter reached 0.5 cm were used for the experiment. ６ 18 days after subcutaneous transplantation of PC-3 cells (5.0 × 10 cells / mouse) into the right hip of the mice, ６ The mice were kept for 2 weeks after PC-3 cell transplantation, and mice with tumors reaching 1 cm in diameter on both sides were used for SPECT / CT imaging.

[0139] <Experiment on internal radioactivity distribution using model mice> [ １１１ In]In-PDI2 (111kBq), [ １１１ In]In-PDI4 (111 kBq), or [ １１１ A saline solution (100 μL) containing [In]In-PSMA-617 (115 kBq) was administered via the tail vein of LNCaP tumor-implanted mouse models, and the mice were euthanized 4, 24, and 96 hours after administration. Blood was collected, and each organ was recovered, and the weight and radioactivity of the blood and organs were measured. For the blood and each organ, the percentage of radioactivity relative to the administered radioactivity (%ID) was divided by the blood weight or organ weight (g) to calculate the value (%ID / g). １１１ The results of In]In-PDI2 are shown in Table 3, １１１ The results of In]In-PDI4 are shown in Table 4, and １１１ The results for In]In-PSMA-617 are shown in Table 5 (n=3 for each). ＊ n=4, ＊＊ n=2). Also, １１１ In] In-PDI2, [ １１１ In]In-PDI4, and [ １１１ The results of comparing the radioactivity accumulation of In]In-PSMA-617 in tumors, kidneys, and blood are shown in Figure 2. １１１ In] In-PDI2, [ １１１ In]In-PDI4 and [ １１１The tumor radioactivity accumulation 4 hours after administration of [In]In-PSMA-617 was 20.74±3.46, 23.05±1.72, and 23.60±14.18% ID / g, which were comparable values. １１１ In]In-PDI2 and [ １１１ The radioactivity accumulation in the tumor 24 hours after administration of [In]In-PDI4 was 25.47±6.13 and 15.99±4.00% ID / g, respectively. １１１ This result was generally consistent with the results of the extracellular efflux experiment. １１１ In]In-PDI2 and [ １１１ The radioactivity accumulation in the kidneys 4 hours after administration of [In]In-PDI4 was 52.31±48.8 and 77.68±42.68% ID / g, respectively. １１１ In]In-PSMA-617 (159.54±34.21% ID / g). １１１ In] In-PDI2, [ １１１ In]In-PDI4 and [ １１１ For In]In-PSMA-617, the values ​​were 0.58±0.13, 0.07±0.02, and 0.12±0.03% ID / g at 4 hours after administration, which were comparable values.

[0140]

[0141]

[0142]

[0143] <In vivo blocking experiment using model mice> １１１A saline solution (100 μL) containing [In]In-PDI2 (111 kBq) and 2-(phosphonomethyl)pentanediol (2-PMPA, 200 μg / mouse) was administered via the tail vein of LNCaP tumor-implanted mice. The mice were euthanized 4 hours after administration (n=3 per mouse). After blood collection, each organ was recovered, and the weight and radioactivity of the blood and organs were measured. The percentage of radioactivity relative to the administered radioactivity (%ID) was divided by the blood weight or organ weight (g) to calculate the value (%ID / g). Significance tests for in vivo blocking experiments were performed using Student's t-test with a 95% confidence interval. The results of the in vivo blocking experiments are shown in Table 6. Co-administration of the PSMA inhibitor 2-PMPA significantly increased [ １１１ The tumor accumulation of [In]In-PDI2 was significantly reduced (0.92±0.08% ID / g), and the radioactivity levels in the kidneys, spleen, and salivary glands, which are PSMA-expressing organs, were also reduced.

[0144]

[0145] <SPECT / CT> [ １１１ In] In-PDI2 (3.78MBq), [ １１１ In]In-PDI4 (3.54 MBq), or [ １１１A saline solution (100 μL) containing [In]In-PSMA-617 (3.37 MBq) was administered via the tail vein of LNCaP tumor-implanted mouse models. 24 hours after administration, SPECT / CT was performed using a Gamma Medica-Ideas FX3300 preclinical imaging system. SPECT images were acquired under isoflurane (2% by volume) anesthesia with a rotation radius of 35 mm, a projection time of 70 seconds, and 32 projections using a pinhole collimator with a diameter of 1.0 mm and a focal length of 75 mm. After SPECT imaging, CT imaging (tube voltage: 60 kV, tube current: 270 μA) was performed. The SPECT projection data were reconstructed using the three-dimensional ordered subset expectation maximization (3D-OSEM) method. The SPECT / CT images were analyzed using PMOD software (Version 3.6, PMOD Technologies, Zurich, Switzerland). The maximum intensity projection (MIP) images obtained by SPECT / CT imaging are shown in Figure 3. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 clearly visualized the LNCaP tumor, but not the PC-3 tumor or kidney. １１１ Although [In]In-PSMA-617 clearly visualized LNCaP tumors, radioactivity accumulation was observed in the kidneys, which reflected the results of the radioactivity distribution experiments in the body.

[0146] next,[ ２２５ Ac] Ac-PDI2, [ ２２５ Ac]Ac-PDI4 and [ ２２５ Ac]Ac-PSMA-617 was synthesized and its efficacy was evaluated. ２２５ Ac] Ac-PDI2, [ ２２５ Ac]Ac-PDI4 and [ ２２５ The synthesis scheme for Ac]Ac-PSMA-617 is shown in Schemes 3 and 4 below.

[0147]

[0148]

[0149] <Example 1-3> ([ ２２５ Ac]Synthesis of Ac-PDI2) [ ２２５ Ac]Ac(NO ３ ) ３ To a 0.1 M hydrochloric acid solution (765 kBq, 5 μL) of the compound 7, a 0.1 M acetic acid-sodium acetate aqueous solution (pH 7.0, 246.5 μL) and 0.1 M hydrochloric acid (24 μL) were added. Then, a DMSO solution (0.541 mM, 43.5 μL) of compound 7 was added and vortexed, followed by standing at 70°C for 1 hour to obtain the target radiolabeled compound ([ ２２５ The radiolabeled compound (297 μL) was mixed with 0.13 M acetic acid-sodium acetate aqueous solution (pH 6.5, 0.699 mL) containing 5.0 v / v % ethanol to prepare a formulation.

[0150] <Example 2-3> ([ ２２５ Ac]Synthesis of Ac-PDI4) [ ２２５ Ac]Ac(NO ３ ) ３ To a 0.1 M hydrochloric acid solution (765 kBq, 5 μL) of the compound 8, a 0.1 M acetic acid-sodium acetate aqueous solution (pH 7.0, 246.5 μL) and 0.1 M hydrochloric acid (24 μL) were added. Then, a DMSO solution (0.541 mM, 43.5 μL) of compound 8 was added and vortexed, followed by standing at 70°C for 1 hour to obtain the target radiolabeled compound ([ ２２５ This radiolabeled compound (297 μL) was mixed with 0.13 M acetic acid-sodium acetate aqueous solution (pH 6.5, 0.524 mL) containing 5.0 v / v % ethanol to prepare a formulation.

[0151] <Comparative Example 1-2> ([ ２２５ Synthesis of Ac-PSMA-617 ２２５ Ac]Ac(NO ３ ) ３ To a 0.1 M hydrochloric acid solution (765 kBq, 5 μL) of the above, 0.1 M acetic acid-sodium acetate aqueous solution (pH 7.0, 246.5 μL) and 0.1 M hydrochloric acid (24 μL) were added. Furthermore, a DMSO solution (0.541 mM, 43.5 μL) of PSMA-617, which is a label precursor, was added and vortexed, and then the mixture was left to stand at 70°C for 1 hour to obtain the target radiolabeled compound ([ ２２５The radiolabeled compound (297 μL) was mixed with 0.13 M acetic acid-sodium acetate aqueous solution (pH 6.5, 0.588 mL) containing 5.0 v / v % ethanol to prepare a formulation.

[0152] < ２２５ Evaluation of efficacy of Ac-labeled compound> Tumor-implanted mouse model was prepared as follows. LNCaP cells (5.0 × 10 cells) were cultured in a mixture (1:1, 100 μL) of RPMI 1640 and Matrigel (manufactured by Corning Life Sciences, Arizona, USA). ６ The tumor-implanted model mice prepared by the above method were divided into groups A to F, and one of the formulations prepared in Examples 1-3 and 2-3 and Comparative Example 1-2 was administered via the tail vein to the model mice in each group (n=5 for each group). The formulations administered were as follows: Group A: Control group (Vehicle, 0.13 M acetic acid-sodium acetate aqueous solution (pH 6.5) containing 5.0 v / v% ethanol, 100 μL) Group B: [ ２２５ Ac] Ac-PDI2 (10 kBq, 100 μL) Group C: [ ２２５ Ac] Ac-PSMA-617 (10 kBq, 100 μL) Group D: [ ２２５ Ac]Ac-PDI4 (10kBq, 100μL) Group E: [ ２２５ Ac]Ac-PDI2 (5kBq, 100μL) Group F: [ ２２５ Ac]Ac-PSMA-617 (5kBq, 100μL)

[0153] After administration of each formulation, tumor volume and body weight were measured twice a week. Tumor volume was calculated by multiplying the tumor length by the tumor width. ２ The results were calculated by multiplying the weight of the mice by 0.5. On the final day of observation, the mice were dissected and the weights of the major organs were measured. The results are shown in Figures 4 to 6. ２２５ [Ac]Ac-PDI2 and 4 showed antitumor effects at all doses evaluated in this experiment. No significant difference was observed in body weight changes compared to the control group, and no significant weight loss was observed in any normal organs compared to the control group at the end of observation.

[0154] [Results / Discussion] In the cell binding saturation experiment, １１１ In]In-PDI2 and [ １１１ In]In-PDI4 is １１１ In-PSMA-617 showed similar PSMA binding affinity to that of [In]In-PSMA-617, indicating that the introduction of the polyethyleneimine (PEI) structure does not significantly affect the binding affinity to PSMA. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 is １１１ In]In-PSMA-617 showed an internalization rate equivalent to that of [In]In-PSMA-617, indicating that the introduction of the polyethyleneimine structure does not significantly affect the ability to be internalized in cells. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 is １１１ In]In-PSMA-617 showed a significantly lower extracellular efflux rate than [In]In-PSMA-617, indicating that the introduction of the first atomic group containing the PEI structure contributes to improving the retention of the drug in the target cells. １１１ In]In-PDI2 and [ １１１ In]In-PDI4 is １１１ In]In-PSMA-617 showed higher tumor accumulation than [In]In-PSMA-617. Furthermore, SPECT / CT images also showed images that reflected the distribution experiment. These results indicate that the introduction of the first atomic group containing the PEI structure contributes to improving the retention of the drug in target cells. ２２５ The usefulness of Ac-PDI2 and 4 as antitumor agents was demonstrated.

[0155] <References> [1] Chem. Commun. , 2008, 3248-3250 [2] J. Am. Chem. Soc. , 2008, 130, 14, 4618-4627 [3] J. Med. Chem. , 2023, 66, 8043-8053 [4] J. Med. Chem. ,2021,64,13429-13438

[0156] According to the present invention, there are provided radiolabeled compounds having excellent retention in tumor cells and compounds to be used for the production thereof.

Claims

1. A radiolabeled compound represented by the following formula (1): (In formula (1), M is a radioactive metal ion, A is a chelating moiety coordinated to the radioactive metal ion, B is a first atomic group having a structure in which ethyleneimine is polymerized, and C is a second atomic group having a molecular weight of 5000 or less and capable of binding to a molecule expressed in tumor cells.) 2. The radiolabeled compound of claim 1, wherein the second atomic group comprises a linear or cyclic peptide.

3. The radiolabeled compound according to claim 1 or 2, wherein the second atomic group comprises 1 to 50 amino acid residues.

4. The radiolabeled compound according to claim 1 or 2, wherein the first atomic group has a structure in which ethyleneimine is polymerized with a degree of polymerization of 1 or more and 7 or less.

5. The radiolabeled compound of claim 1 or 2, wherein the molecule expressed in tumor cells is prostate-specific membrane antigen (PSMA), somatostatin receptor, cholecystokinin receptor, integrin, fibroblast activation protein-α (FAP), LHRH receptor, gastrin-releasing peptide receptor (GRPR), carbonic anhydrase 9 (CA-IX), or glucagon-like peptide-1.

6. The radiolabeled compound according to claim 1 or 2, wherein the second atomic group has a structure represented by any one of the following formulas (C1-1) to (C1-4):

7. The radiolabeled compound according to claim 1 or 2, wherein the chelating moiety has the structure of DOTA or a derivative thereof.

8. The radiolabeled compound according to claim 7, wherein the chelating moiety has a structure represented by the following formula (4): (In formula (4), R Ｂ１ is an atomic group containing a bond to the first atomic group, and R Ｃ１ is an atomic group containing a bond to the second atomic group.

9. The radioactive metal is ６８ Ga, ６４ Cu, ８９ Zr, ９９ｍ Tc, １１１ In, １７７ Lu, １８６ Re, １８８ Re or ２２５ 3. The radiolabeled compound of claim 1 or 2, wherein the compound is Ac.

10. A radiopharmaceutical composition comprising the radiolabeled compound of claim 1 or 2 as an active ingredient.

11. A compound represented by the following formula (2): (In formula (2), A is a chelating moiety capable of coordinating with a radioactive metal ion, B is a first atomic group having a structure in which ethyleneimine is polymerized, and C is a second atomic group having a molecular weight of 5,000 or less and capable of binding to a molecule expressed in tumor cells.) 12. A method for producing a radiolabeled compound, comprising coordinating the compound of claim 11 with a radioactive metal ion to obtain the radiolabeled compound of claim 1 or 2.

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