Compound and radioactive labeling compound

Abstract

The compound according to the present invention has, within its structure, a chelate moiety that can coordinate with a radioactive metal ion, a first atomic group including an albumin binding site, and a second atomic group including a binding site with a PSMA molecule, wherein the first atomic group and the second atomic group bind via the chelate moiety, or the chelate moiety binds so as to be branched from between the first atomic group and the second atomic group. The present invention also provides a radioactive labeling compound in which a radioactive metal ion coordinates with a compound, and a method for producing the radioactive labeling compound.

Description

Compounds and Radiolabeled Compounds

[0001] The present invention relates to compounds and radiolabeled compounds.

[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 being conducted to improve the specific accumulation in target tissues and sites and to reduce the accumulation in non-target tissues and sites.

[0003] Patent Document 1 describes a derivative (HTK01169) in which an iodophenylbutyryl group, which is an albumin-binding site, is added so as to branch from the structure of PSMA-617. It also describes that this derivative binds to prostate-specific membrane antigen (PSMA) as a target and can be used for the detection and treatment of prostate cancer.

[0004] Furthermore, Patent Document 2 describes an albumin-binding PSMA inhibitor. It also describes that this inhibitor, like Patent Document 1, binds to PSMA as a target and can be used for the detection and treatment of prostate cancer.

[0005] International Publication No. WO 2019 / 075583 International Publication No. WO 2018 / 098390

[0006] In order to improve specific accumulation in target tissues and sites and reduce accumulation in non-target tissues and sites, it is important to control pharmacokinetics such as blood retention, and further optimization of chemical structure is desired as one method for effectively controlling pharmacokinetics. Generally, compounds with small molecular weights have poor blood retention, which may result in insufficient accumulation in target tissues or unintended accumulation in normal tissues. In addition, the compounds described in Patent Documents 1 and 2 largely accumulate non-specifically in the kidney, leaving room for improvement in this regard.

[0007] Therefore, the present invention relates to a compound and a radiolabeled compound that can achieve both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly reduced accumulation in the kidney.

[0008] The present invention provides a 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, wherein the first atomic group and the second atomic group are bound to each other via the chelating moiety.

[0009] The present invention provides a compound represented by the following general formula (2):

[0010] (In formula (2), A ２ is a chelating moiety capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding moiety, and C is an atomic group containing a binding moiety to a PSMA molecule; ２ is Neunpa or Octapa or a derivative thereof, L ｃ is a linker structure, and A ２ When is Octapa, L ｃ contains a polyethylene glycol structure.)

[0011] The present invention provides a radiolabeled compound in which the compound is coordinated with a radioactive metal ion.

[0012] The present invention provides a method for producing a radiolabeled compound, which comprises coordinating the compound with a radioactive metal ion to obtain a radiolabeled compound.

[0013] FIG. 1 shows Example 1-1 ([ 111 In]In-PSMA-DA1) and Comparative Example 1-1 ([ 111 FIG. 2 is a graph showing the results of a cell binding experiment using [In]In-PSMA-DB. 111 In]In-PSMA-DA1 and [ 111 3 is a graph showing the results of an albumin binding experiment for [In]In-PSMA-DB. 111 In]In-PSMA-DA1 and [ 111 4 is a graph showing the results of an experiment on the distribution of radioactivity in the body of [In]In-PSMA-DB. 111 In]In-PSMA-DA1 and [ 111In]In-PSMA-DB. 90 Y]Y-PSMA-DA1) and Comparative Example 1-2 ([ 90 6 is a graph showing the changes in tumor volume and mouse body weight in Example 1-3 ([Y]Y-PSMA-DB). 225 Ac]Ac-PSMA-DA1) and Comparative Examples 1-3 ([ 225 7 is a graph showing the changes in tumor volume and mouse body weight in Example 2 ([ Ac] Ac-PSMA-DB). 111 FIG. 8 is an HPLC chart showing the results of plasma stability of [In]In-PtDA. 111 9 is a graph showing the results of a cell binding experiment using [In]In-PtDA. 111 10 is a graph showing the results of an albumin binding experiment for [In]In-PtDA. 111 In]In-PtDA. 111 In]In-Octapa-2), Example 3-2 ([ 111 In]In-Octapa-3), Example 3-3 ([ 111 In]In-Neunpa-2), and Comparative Example 2-1 ([ 111 In]In-Octapa-1), Comparative Example 2-2 ([ 111 FIG. 12 is a graph showing the results of an albumin binding experiment in Examples 3-1 to 3-3 and Comparative Examples 2-1 to 2-2. FIG. 13 is a graph showing the results of an experiment on radioactivity distribution in the body in Examples 3-1 to 3-3 and Comparative Examples 2-1 to 2-2. FIG. 14 is a graph showing the results of an experiment on radioactivity distribution in the body in Example 3-1 ([ 111 In]In-Octapa-2). 111 16 is a graph showing the results of a cell binding experiment using Example 4-1 ([In]In-PSMA-NAT-DA1). 111 17 is a graph showing the results of an albumin binding experiment for Example 4-1 ([In]In-PSMA-NAT-DA1). 111In]In-PSMA-NAT-DA1).

[0014] The compounds of the present invention and radiolabeled compounds using the same will be described below based on 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.

[0015] The compound of the present invention has three atomic groups in its chemical 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 with a prostate specific membrane antigen (hereinafter also referred to as PSMA) molecule. Due to this chemical structure, a radiolabeled compound in which a radioactive metal ion is coordinated to the compound of the present invention achieves both improved accumulation in target tissues expressing PSMA molecules and reduced accumulation in non-target tissues, particularly the kidney. The compound of the present invention is a precursor compound used for labeling with a radioisotope such as a radioactive metal, i.e., a compound preferably used as a labeled precursor. Radioactive metals will be described later.

[0016] In one embodiment, the compound of the present invention has a first atomic group comprising an albumin binding moiety and a second atomic group comprising a binding moiety to a PSMA molecule linked via a chelating moiety, and such a compound is preferably represented by the following general formula (1):

[0017]

[0018] In formula (1), A １ is a chelating moiety capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding moiety, and C is an atomic group containing a binding moiety to a PSMA molecule. ａ is a linker structure. ｂ Is L ａm and n are each independently 0 (zero) or 1. B or L ａ Is A １ C or L ｂ is B or L ａ A １ at a site different from the site that binds to A １ is bonded to.

[0019] As described above, when the chemical structure of the compound of this embodiment is viewed macroscopically, the chelating moiety (in general formula (1), symbol A １ It is preferred that the first atomic group (represented by symbol B in general formula (1)) containing the albumin binding moiety and the second atomic group (represented by symbol C in general formula (1)) containing the binding moiety to the PSMA molecule are linearly arranged via the chelating moiety.

[0020] In general formula (1), A １ Between and B, and A １ and C may be indirectly bonded to each other via a linker structure, or may be directly bonded to each other without a linker structure. １ Between and B, and A １ When there is a linker structure between each of C and C, the linker structures may be the same or different. The linker structure will be described in detail later.

[0021] The compound of the present invention, when radiolabeled, is a compound having a structure in which A in the formula (1) is a compound having a structure in which A ... １ has a cyclic structure having two or more nitrogen atoms, and each nitrogen atom is connected via two or more adjacent carbon atoms, or １ has a chain structure, and the chain structure preferably has two or more nitrogen atoms, and each nitrogen atom is connected via two or more adjacent carbon atoms.

[0022] In the formula (1), A １When A has a cyclic structure, the skeleton of the cyclic structure may be composed of only nitrogen atoms and carbon atoms, or may be composed of oxygen atoms in addition to nitrogen atoms and carbon atoms. The bonds between carbon atoms in the cyclic structure may be chain-like or may form a cyclic structure. １ has a chain structure, the bonds between carbon atoms in the chain structure may be interrupted by a nitrogen atom. The bonds between carbon atoms in the chain structure may be linear or may form a cyclic structure.

[0023] In addition, in the formula (1), A １ When A has a cyclic structure or a chain structure, １ has a nitrogen-bonded atomic group directly bonded to a nitrogen atom constituting the cyclic structure or the chain structure. Specific examples of the nitrogen-bonded atomic group 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-shaped. Furthermore, in the formula (1), A １ has a cyclic structure or a chain structure, B is A １ and C binds to any site of A that is different from the binding site of B. １ B is bonded to any site of L ａ via or L ａ When B is bonded to the nitrogen-bonding group without an intervening group, C is ａ via or L ａ It is preferable that the nitrogen atom is bonded to a site other than the nitrogen-bonding atomic group to which the nitrogen atom is bonded without an intervening bond.

[0024] Specifically, in the formula (1), the symbol A １The chelating moiety capable of coordinating with a radioactive metal represented by the formula (A1) 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 formula (A1). That is, 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 formula (A1). These structures can be appropriately selected depending on the type of radioactive metal described below. Regardless of the structure of the chelating moiety, improved accumulation in target tissues expressing PSMA and reduced accumulation in non-target tissues, particularly the kidney, are both achieved.

[0025] In the formula (1), symbol A １ Examples of the chelating moiety represented by the formula (I) include, but are not limited to, structures derived from the following compounds:

[0026] <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-tetratetraacetic acid (DOTAGA)

[0027] <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)

[0028] <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-pentaazacyclopentadodecane-N,N',N",N'",N""-pentaacetic acid (PEPA)

[0029] <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) 6-(1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-N,N'-,methyl)picolinic acid (H2macropa) 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-isothiacyanatophenethyl)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)

[0030] <NOTA or its derivatives> ・2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid (NOTA)

[0031]

[0032] In formula (A1), R 11 , R 12 , R 13 and R 14are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ５ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ , -(CHCOOH)(CH ２ ) ｐ COOH, and p is an integer of 0 to 3.

[0033] In formula (A2), R 21 , R 22 , R 23 and R 24 are each independently a carboxy group or a carboxyalkyl group having 2 or 3 carbon atoms.

[0034] In formula (A3), R 31 , R 32 , R 33 and R 34 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R 35 is a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0035] In formula (A4), R 41 , R 42 , R 43 and R 44 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R 45 is a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0036] In formula (A5), R 48 and R 49 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0037] In formula (A6), R 51 , R 52 , R 53 , R 54 and R 55 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0038] In formula (A7), R 61 , R 62 , R 63 , R 64 , R 65 and R 66 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom; R 67 is a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0039]

[0040] In formula (A8), R 71 , R 72 and R 73 are each independently an atomic group having a hydrogen atom and 2 to 10 carbon atoms, which may contain a nitrogen atom or an oxygen atom.

[0041] In formula (A9), R 81 and R 82 are each independently 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 is the oxygen atom (=O) of a hydroxyl group or a carbonyl group, and R 83 and R 84 is a substituted or unsubstituted pyridinyl group, and R 85 and R 86 are each independently -COO-R ａ and R ａ is an alkyl group having 1 to 5 carbon atoms.

[0042] Specific examples of the structure represented by formula (A1) include structures represented by the following formulae (A1-1) to (A1-7).

[0043]

[0044]

[0045]

[0046] Specific examples of the structure represented by formula (A2) include structures represented by the following formulae (A2-1) and (A2-2).

[0047]

[0048] Specific examples of the structure represented by formula (A3) include structures represented by the following formulae (A3-1) to (A3-7).

[0049]

[0050]

[0051] Specific examples of the structure represented by formula (A4) include structures represented by the following formulae (A4-1) and (A4-2).

[0052]

[0053] Specific examples of the structure represented by formula (A5) include structures represented by the following formulae (A5-1) to (A5-3).

[0054]

[0055] A specific example of the structure represented by formula (A6) is a structure represented by the following formula (A6-1).

[0056]

[0057] Specific examples of the structure represented by formula (A7) include structures represented by the following formulae (A7-1) and (A7-2).

[0058]

[0059] Specific examples of the structure represented by formula (A8) include structures represented by the following formulae (A8-1) to (A8-3).

[0060]

[0061] Specific examples of the structure represented by formula (A9) include structures represented by the following formulae (A9-1) to (A9-4).

[0062]

[0063] Another embodiment of the compound of the present invention will be described below. This embodiment will be described focusing on the differences from the embodiments described above, and the explanations for the embodiments described above will be applied appropriately to the points not specifically described.

[0064] In another embodiment, when viewed macroscopically, the chemical structure of the compound of the present invention is such that a chelating moiety is bonded in a branched manner between a first atomic group comprising an albumin binding moiety and a second atomic group comprising a binding moiety to a PSMA molecule. Specifically, the first atomic group comprising an albumin binding moiety and the second atomic group comprising a binding moiety to a PSMA molecule are preferably bonded in a branched manner via a linker structure bonded to the chelating moiety. Such a compound is preferably represented by the following general formula (2):

[0065]

[0066] In formula (2), A ２ A is a chelating moiety capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding moiety, and C is an atomic group containing a binding moiety to a PSMA molecule. ２ is Neunpa or Octapa or a derivative thereof. ｃ is the linker structure. ２ When is Octapa, L ｃ contains a polyethylene glycol structure.

[0067] Furthermore, from the viewpoint of achieving high levels of both improved accumulation in target tissues expressing PSMA and reduced accumulation in non-target tissues, particularly the kidney, when the compound is radiolabeled, a compound represented by the formula (2) containing A ２ has a chain structure, and the chain structure preferably has two or more nitrogen atoms, and each nitrogen atom is connected via two or more adjacent carbon atoms.

[0068] In the formula (2), A ２ When A has a chain structure, the bond between carbon atoms in the chain structure may be interrupted by a nitrogen atom. The bond between carbon atoms in the chain structure may be a chain or may form a cyclic structure. ２ As the compound, a compound represented by the above formula (A3) or formula (A4) or a derivative thereof is more preferable.

[0069] Matters applicable to each of the above-described embodiments will be described below. Unless otherwise specified, the following description is appropriately applied to the description of general formula (1) and general formula (2), and can also be adopted in appropriate combination.

[0070] In formula (1) or (2), the moiety represented by the symbol B is an atomic group having an affinity for albumin, preferably serum albumin, more preferably human serum albumin, and including an albumin-binding moiety, which is a chemical structure capable of reversibly binding to albumin. When the compound of the present invention contains such a structure, when the compound is labeled with a radioactive metal and administered to a living body, it can increase retention in blood and reduce accumulation in the kidney.

[0071] Specifically, a compound having an albumin-binding moiety in its molecule easily binds to albumin in the blood, and the compound bound to albumin is no longer subjected to glomerular filtration in the kidney, thereby reducing transfer and excretion into the kidney and urine and improving retention in the blood, which results in reduced accumulation in the kidney, a normal tissue, and further enhancing transfer of the compound to target tissues such as tumor tissues expressing PSMA.

[0072] When the compound represented by formula (1) is used, the distance between the albumin binding site and the binding site with the PSMA molecule can be appropriately secured, so that both the affinity for albumin and the affinity for the PSMA molecule can be achieved. In particular, since the albumin binding site is located at one structural end of the compound of the present invention and the binding site with the PSMA molecule is located at the other structural end of the compound of the present invention, the distance between the albumin binding site and the binding site with the PSMA molecule can be sufficiently secured, which is further advantageous in that it can achieve both the affinity for albumin and the affinity for the PSMA molecule at a high level.

[0073] Instead, when the compound represented by the formula (2) is used, L ｃ The linker structure represented by the formula (2) ensures an appropriate distance between the albumin binding site and the PSMA molecule binding site, thereby achieving both affinity for albumin and affinity for the PSMA molecule. ｃ By adopting a structure containing a polyethylene glycol group and not containing a cyclohexyl group or a naphthyl group as the linker structure represented by the formula (I), it is possible to ensure an appropriate distance between the albumin binding site and the binding site with the PSMA molecule, and it is further advantageous in that it is possible to achieve a high level of both affinity for albumin and affinity for the PSMA molecule.

[0074] In the formula (1) or (2), examples of the structure of the albumin binding moiety 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, and derivatives thereof, and structures derived from one or more of the structures described in WO 2005 / 117984, WO 2010 / 127336, and WO 2010 / 172844. Additionally or alternatively, an antibody or peptide capable of binding to albumin (for example, the peptides described in WO 2007 / 106120) can also be used as the albumin binding moiety.

[0075] Among these, from the viewpoint of obtaining a compound that can be used in living organisms and from the viewpoint of reducing unintended accumulation in normal organs such as the kidneys, it is preferable to use, as the structure of the albumin binding moiety, one or more of substituted or unsubstituted phenylbutyric acid, Evans blue, and derivatives thereof, or an antibody or peptide capable of binding to albumin.

[0076] Substituted or unsubstituted phenylbutyric acid applicable as the albumin binding moiety includes, for example, a structure represented by the following formula (B1).

[0077]

[0078] In formula (B1), R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, and the portion indicated by the wavy line is a bonding portion to other structures. In formula (B1), R is preferably a hydrogen atom, an iodine atom, a bromine atom, or a methyl group.

[0079] Examples of Evans blue and its derivatives that can be used as the albumin binding moiety include those having the structure represented by the following formula (B2).

[0080]

[0081] In formula (B2), R b1 Or R b11 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, or a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, and the portion indicated by the wavy line is a bonding portion to another structure. b1 and R b4 are all methyl groups, and R b2 and R b3 and R b5 Or R b11 are preferably all hydrogen atoms.

[0082] The antibody capable of binding to albumin may be an immunoglobulin of the class IgG, IgA, IgM, IgD, or IgE, as long as it has affinity for albumin, or an antibody fragment (e.g., a Fab fragment). From the viewpoint of reducing accumulation in unintended tissues such as the liver, when an antibody capable of binding to albumin is used as the albumin-binding moiety, it is preferable to use a Fab fragment with a low molecular weight.

[0083] Examples of peptides capable of binding to albumin include peptides containing the sequences disclosed in WO 2007 / 106120, and more specifically, peptides containing the following peptide sequences, but are not limited to these sequences: In the following peptide sequences, amino acids are represented by single letters, with the N-terminus on the left side of the page and the C-terminus on the right side of the page. LCLRDWGCLW (SEQ ID NO: 1) DICLPRWGCLWW (SEQ ID NO: 2) MEDICLPRWGCLWGD (SEQ ID NO: 3) QRLMEDICLPRWGCLWEDDE (SEQ ID NO: 4) QGLIGDICLPRWGCLWGRSV (SEQ ID NO: 5) QGLIGDICLPRWGCLWGRSVK (SEQ ID NO: 6) EDICLPRWGCLWEDD (SEQ ID NO: 7) RLMEDICLPRWGCLWEDD (SEQ ID NO: 8) MEDICLPRWGCLWEDD (SEQ ID NO: 9) MEDICLPRWGCLWED (SEQ ID NO: 10) RLMEDICLARWGCLWEDD (SEQ ID NO: 11) EVRSFCTRWPAEKSCKPLRG (SEQ ID NO: 12) RAPESFVCYWETICFERSEQ (SEQ ID NO: 13)

[0084] In formula (1) or (2), the binding moiety with a PSMA molecule, represented by the symbol C, is an atomic group containing a binding moiety with a PSMA molecule, which has an affinity for a PSMA molecule expressed in tissues that cause diseases such as cancer, and has a chemical structure that allows it to reversibly bind to the PSMA molecule. Because the compound of the present invention contains such a structure, when it is labeled with a radioactive metal and administered to a living body, it can be efficiently accumulated in tissues that are the target of treatment or diagnosis, thereby improving the efficiency of treatment or diagnosis.

[0085] PSMA is a membrane-bound protein whose expression is particularly elevated in prostate cancer.The expression level of PSMA in normal tissues, including the prostate, is low, but the expression level of PSMA increases as the malignancy of prostate cancer increases.Therefore, PSMA is one of the useful target molecules in the present invention, and is particularly useful as a target for the diagnosis and treatment of prostate cancer.

[0086] Cancers that express PSMA molecules include, for example, prostate cancer, which may be primary or metastatic.

[0087] The chemical structure at the binding site to the PSMA molecule can be appropriately selected depending on the target tissue and the amount of PSMA molecules expressed in the tissue. Specifically, a structure having affinity for the PSMA molecule can be used as the binding site to the PSMA molecule. Examples of the structure having affinity for the PSMA molecule include one or more of a low molecular weight compound, a peptide, an antibody, and an antibody fragment such as a Fab fragment.

[0088] In the above formula (1) or (2), the binding site to the PSMA molecule preferably has a structure represented by the following formula (C1), or is an antibody or peptide capable of binding to the PSMA molecule. When the compound of the present invention contains such a structure, when it is labeled with a radioactive metal and administered, it can be efficiently accumulated in the tissue to be treated or diagnosed, thereby improving the efficiency of treatment or diagnosis.

[0089]

[0090] In formula (C1), a and b are each independently an integer of 1 to 7. In formula (C1), the portion indicated by the wavy line is A1 or L in formula (1). a , or L in formula (2) c This is the connecting part.

[0091] The antibody capable of binding to a PSMA molecule may be an immunoglobulin of the IgG, IgA, IgM, IgD, or IgE class, or an antibody fragment (e.g., a Fab fragment), as long as it has affinity for the PSMA molecule. From the viewpoint of reducing accumulation in unintended tissues such as the liver, when an antibody capable of binding to a PSMA molecule is used as a binding moiety for the PSMA molecule, it is preferable to use a Fab fragment with a low molecular weight.

[0092] When the compound of the present invention has the structure of formula (1), it is more preferable that the compound has a structure represented by the following general formula (1S), and it is also more preferable that the compound has a structure represented by the following general formula (1T). Such a structure provides a compound with a sufficient number of heteroatoms capable of coordinating a radiometal, thereby enhancing the efficiency of complex formation when coordinating a radiometal to the compound of the present invention. In addition, the degree of freedom of molecular movement at the albumin binding site and the binding site with the PSMA molecule is increased, thereby achieving a high level of affinity for albumin and affinity for the PSMA molecule. Furthermore, unintended accumulation in normal tissues such as the liver and kidneys is reduced.

[0093]

[0094] In formula (1S) and formula (1T), A １ are each independently a chelating moiety capable of coordinating with a radioactive metal ion. In formula (1S), C is an atomic group containing a binding site to a PSMA molecule. In formulas (1S) and (1T), L ａ In formula (1S) and formula (1T), L ｂ Is L ａ In formula (1S) and formula (1T), m and n are each independently 0 (zero) or 1. In formula (1S) and formula (1T), the same explanation as in formula (B1) above applies as appropriate. In formula (1S) and formula (1T), when n is 1, L ａ Is A １ In formula (1S) and formula (1T), when n is 0, the carbon atom of the carbonyl group bonded to the phenyl alkyl group is １ In formula (1S) and formula (1T), when m is 1, C or L ｂ Is, L ａ A １ at a site different from the site that binds to A １ In formula (1S) and formula (1T), when m is 0, C or a nitrogen atom is bonded to A １at a site different from the site that binds to A １ is bonded to.

[0095] When the compound of the present invention has the structure of formula (1) above, it is more preferable that the compound have a structure represented by the following general formula (3). Such a structure ensures that the compound has a sufficient number of heteroatoms capable of coordinating a radiometal, thereby enhancing the efficiency of complex formation when coordinating a radiometal to the compound of the present invention. In addition, the degree of freedom of molecular movement at the albumin binding site and the binding site with the PSMA molecule is increased, thereby achieving a high level of affinity for both albumin and PSMA molecule. Furthermore, unintended accumulation in normal tissues such as the liver and kidneys is reduced.

[0096]

[0097] In formula (3), R B1 and R B2 one of which is an atomic group containing an albumin binding site, and the other is a hydrogen atom, a hydroxyl group, or a carboxyl group; R C1 and R C2 One of these is an atomic group that contains a bond to the PSMA molecule, and the other is a hydrogen atom, a hydroxyl group, or a carboxyl group. B1 is an atomic group containing the albumin binding site, and R C1 is an atomic group that contains the bond to the PSMA molecule, and R B2 and R C2 Preferably, both of R B2 is an atomic group containing the albumin binding site, and R C2 is an atomic group that contains the bond to the PSMA molecule, and R B1 and R C1and are preferably both hydrogen atoms or each independently a carboxyalkyl group having 1 to 5 carbon atoms. In any of the above-described embodiments, it is preferred that the albumin binding moiety is located at one structural end of the compound and the binding moiety to the PSMA molecule is located at the other structural end of the compound, so that when the chemical structure of the compound of the present invention is viewed macroscopically, the chelating moiety, the albumin binding moiety, and the binding moiety to the PSMA molecule are arranged in a substantially linear fashion.

[0098] In particular, in formula (3), the atomic group containing the albumin binding moiety is preferably an atomic group containing the structure represented by formula (B1) or formula (B2) described above as the albumin binding moiety. Specific examples of such chemical structures are shown in the following formulas (3-1) to (3-4). In the following formulas (3-1) and (3-2), L １ are each independently an alkyl group containing a carboxy group and having 1 to 8 carbon atoms. In the following formulas (3-3) and (3-4), g is each independently an integer of 1 to 5, and h is 0 or 1.

[0099] In addition, in the following formulas (3-1) to (3-4), R, R b1 Or R b11 Line R C1 and R C2 The explanations for the above formulas (B1) and (B2) and formula (3) are applied independently as appropriate to the explanations for R. That is, R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, and preferably R is a hydrogen atom, an iodine atom, a bromine atom, or a methyl group. b1 Or R b11 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms, or a substituted or unsubstituted alkoxy group having from 1 to 6 carbon atoms, and preferably R b1 and R b4 are all methyl groups, and R b2 and R b3 and R b5 Or R b11 It is preferable that all of R are hydrogen atoms. C1 and RC2 One of the groups is an atomic group that contains a bond to the PSMA molecule, and the other is a hydrogen atom, a hydroxyl group, or a carboxyalkyl group having 1 to 5 carbon atoms.

[0100]

[0101]

[0102] The compounds of the present invention having the structures related to the above formula (1) and formula (3) can be produced, for example, by the methods and synthetic routes described in the examples below.

[0103] When the compound of the present invention has a structure represented by the above formula (2), it is more preferable that, in formula (2), B is represented by the above formula (B1) and C is represented by the above formula (C1). Specifically, it is more preferable that the compound has a structure represented by the following formula (2S). Such a structure provides a compound with a sufficient number of heteroatoms capable of coordinating a radiometal, thereby improving the efficiency of complex formation when coordinating a radiometal to the compound of the present invention. In addition, the degree of freedom of molecular movement at the albumin binding site and the binding site with the PSMA molecule is increased, thereby achieving high levels of affinity for albumin and affinity for the PSMA molecule. Furthermore, unintended accumulation in normal tissues such as the liver and kidneys is reduced. Furthermore, the production time required for complex formation is shortened, further improving the production efficiency and radiochemical yield of the radiolabeled compound.

[0104]

[0105] In formula (2S), A ２ is Neunpa or Octapa or a derivative thereof. ｃ is a linker structure. In formula (2S), R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms. In formula (2S), a and b are each independently an integer of 1 to 7. In formula (2S), A ２ When is Octapa, L ｃ contains a polyethylene glycol structure.

[0106] The compounds of the present invention having structures related to the above formula (2) and formula (2S) can be produced, for example, by the methods and synthetic routes described in the examples below.

[0107] The compound of the present invention, preferably dissolved in an aqueous liquid such as a solvent or buffer solution, can be reacted with a radioactive metal ion to coordinate the compound of each of the above embodiments with the radioactive metal ion, thereby obtaining a radiolabeled compound. This radiolabeled compound is a radioactive metal complex in which the chelating moiety of the compound is coordinated with the radioactive metal ion.

[0108] When a compound represented by formula (1) is used to obtain a radiolabeled compound, it is preferable that B in formula (1) has a structure represented by formula (B1) above. Specifically, it is more preferable to use a compound represented by formula (1S) to obtain a radiolabeled compound. This can increase the efficiency of complex formation.

[0109] 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, 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.

[0110] 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.

[0111] In obtaining a radiolabeled compound, the order of addition of the compound and the radioactive metal source does not matter 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 simultaneously added to a reaction vessel containing a solvent and reacted.

[0112] 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, physiological saline, or a buffer solution such as sodium acetate buffer, ammonium acetate buffer, phosphate buffer, phosphate-buffered physiological saline, Tris buffer, HEPES buffer, or tetramethylammonium acetate buffer. The reaction temperature can be, for example, room temperature (25°C), or can be heated.

[0113] The radioactive metal source may be, for example, a solution in which radioactive metal ions are dispersed in a solvent mainly composed of water.

[0114] 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.

[0115] 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.

[0116] The radioactive metal coordinated in the radioactively labeled compound in an ionic state can be 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, the following radioactive metal nuclides are preferred from the viewpoint of commercial applicability and improving complex formation ability: 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, 212Pb, 212 Bi, 213 Bi, 225 Ac or 227 It is preferable to use Th. 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.

[0117] 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, and 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 is preferably used, and more preferably 64 Cu, 67 Cu, 89 Sr, 90 Y, 177 Lu, 186 Re or 188 Re is used, more preferably 90 Y is used.

[0118] 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 preferable 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. Examples of nuclides that emit gamma rays through gamma decay include: 68 Ga, 99m Tc or 201 Tl is preferably used.

[0119] When the radioactive metals coordinated in an ionic state to the radioactive metal complex are selected based on the ionic radius, radioactive metals having an ionic radius of about 70 to 130 pm include: 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.

[0120] For example, when a radioactively labeled 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 radioactive metal. 89 When Zr 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) and (A4), and more preferably a compound having a chelate moiety with a structure represented by the formula (A1). 68 Ga or 111 When 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).

[0121] The bond between the chelating moiety and the atomic group containing the albumin-binding moiety may be such that the chelating moiety and the albumin-binding moiety are directly bonded without the linker structure described below, or the chelating moiety and the atomic group containing the albumin-binding moiety are indirectly bonded via the linker structure described below. Similarly, the bond between the chelating moiety and the atomic group containing the PSMA molecule-binding moiety may be such that the chelating moiety and the PSMA molecule-binding moiety are directly bonded without the linker structure described below, or the chelating moiety and the atomic group containing the albumin-binding moiety are indirectly bonded via the linker structure described below. In either the "direct" or "indirect" embodiment described above, bonding via an amide bond is preferred from the viewpoint of achieving both ease of synthesis and stability of the chemical structure.

[0122] L in formula (1) ａ Or L ｂ or L in formula (2) ｃ The linker structures represented by the formula (I) are preferably structures derived from compounds capable of independently forming an amide bond or an ether bond. Specific examples thereof include structures derived from L- or D-amino acids, such as acidic amino acids such as glutamic acid and aspartic acid, and basic amino acids such as lysine, dicarboxylic acids such as oxalic acid and malonic acid, diamines such as ethylenediamine, polyethylene glycol groups, and amino acids having a cyclic aliphatic group containing 5 to 10 carbon atoms or an aromatic group containing 6 to 14 carbon atoms in the structure. These may be used alone, or multiple groups may be linked together via an amide bond or an ether bond. Furthermore, the above-mentioned structures may each independently be unsubstituted or substituted with various substituents. When the above-mentioned linker structure contains a structure derived from an amino acid or the like, for example, for the purpose of controlling dynamics in the body, peptide linkers described in WO 2017 / 150549, WO 2019 / 065774, WO 2019 / 221269, WO 2020 / 075746, WO 2020 / 145227, WO 2020 / 145228, etc. can be used.

[0123] When the linker structure contains a structure derived from ethylene glycol, it is also preferable that the linker structure is indirectly bonded via a linker structure represented by the following formula (P): This structure is derived from ethylene glycol, and in formula (P), k is preferably an integer of 2 or more and 10 or less, more preferably an integer of 2 or more and 8 or less, and even more preferably an integer of 2 or more and 5 or less.

[0124]

[0125] These linker structures may be composed of a single type of linker structure, or may be composed of a single type of linker structure repeated or a combination of multiple types of linker structures, which may be bonded in a linear or branched chain.

[0126] In particular, when the compound represented by formula (2) is used, L ｃ The linker structure in (1) preferably has a polyethylene glycol structure represented by formula (P) and does not contain a cyclohexyl group or a naphthyl group. Such a structure allows the chemical structure to move easily and ensures an appropriate distance between the albumin binding site and the binding site to the PSMA molecule, thereby effectively achieving both affinity for albumin and affinity for the PSMA molecule.

[0127] In other embodiments where the chelating moiety and the albumin binding moiety are "indirectly" bound, or where the chelating moiety and the binding moiety to the PSMA molecule are "indirectly" bound, they may be linked by known coupling methods, for example, by click reaction. Structures bound by these methods are also encompassed by the linker structure of this specification. Hereinafter, an example will be described in which click reaction is used to bond the chelating moiety and the binding moiety to the PSMA molecule. In this case, the chelating moiety and the binding moiety to the PSMA molecule each have a click-reactive atomic group, and these atomic groups react with each other to bond the chelating moiety and the binding moiety to the PSMA molecule. In other words, the reaction is carried out between a first atomic group in the chelating moiety and a second atomic group in the binding moiety to the PSMA molecule.

[0128] In the present invention, the combination of click-reactive atomic groups is appropriately selected depending on the type of click reaction, and examples include a combination of an alkyne and an azide, and a combination of a 1,2,4,5-tetrazine and an alkene. These atomic groups may be any combination, as long as the first atomic group has one of the aforementioned atomic groups and the second atomic group has an atomic group that is a combination of the first atomic groups. From the viewpoint of achieving both stability of the bond between the chelating moiety and the PSMA molecule and improved binding efficiency, it is preferable that the first atomic group be an alkyne and the second atomic group be an azide, or that the first atomic group be a 1,2,4,5-tetrazine and the second atomic group be an alkene. Specific examples of click reactions using such combinations of atomic groups include the Huisgen cycloaddition reaction and the inverse electron demand Diels-Alder reaction.

[0129] Specific examples of combinations of atomic groups capable of Click reaction include, as shown in the following formulas, a combination of an atomic group containing dibenzylcyclooctyne (DBCO) as the alkyne of the first atomic group (formula (11a)) and an atomic group containing an azide group as the azide of the second atomic group (formula (12a)), or a combination of an atomic group containing 1,2,4,5-tetrazine as the first atomic group (formula (11b)) and an atomic group containing trans-cyclooctene (TCO) as the alkene of the second atomic group (formula (12b)).

[0130]

[0131] (In formula (11a), R １ represents a chelate moiety, and in formula (12a), R ２ indicates the binding site with the PSMA molecule.)

[0132]

[0133] (In formula (11b), R ３ and R ４ one of which represents a chelating moiety or a binding moiety to the PSMA molecule, and the other represents a hydrogen atom, a methyl group, a phenyl group, or a pyridyl group; and in formula (12b), R ５ indicates a chelating moiety or a binding moiety to a PSMA molecule.

[0134] In the present invention, when the binding moiety between the chelating moiety and the PSMA molecule is bonded by a click reaction, the order of addition is not important as long as the click reaction can proceed. For example, one of the chelating moiety and the binding moiety with the PSMA molecule may be added to a reaction vessel containing a solvent, and then the other may be added and reacted, or one of the chelating moiety and the binding moiety with the PSMA molecule may be dispersed in a solvent and the other may be added to the dispersion and reacted. Alternatively, they may be added simultaneously to a reaction vessel containing a solvent and reacted.

[0135] In each of the above-mentioned embodiments, examples of substituents that may be substituted in each atomic group, each structure, and each chemical structure of the compound and radiolabeled compound include halogen atoms, saturated or unsaturated alkyl groups, hydroxy groups, aldehyde groups, carboxy groups, acyl groups, amino groups, nitro groups, ester groups, isothiocyanate groups, thioxy groups, cyano groups, amide groups, imide groups, phosphate groups, phenyl groups, benzyl groups, pyridyl groups, naphthyl groups, etc. These substituents may be used alone or in combination of two or more types of substituents.

[0136] Although the present invention has been described above based on its preferred embodiments, the present invention is not limited to the above-described embodiments. For example, in the above-described embodiments, compounds having one chelating moiety, one albumin-binding moiety, and one PSMA-binding moiety have been described. However, as long as the present invention is achieved, at least one of the albumin-binding moiety and the PSMA-binding moiety may have multiple sites in one chemical structure.

[0137] The present invention will be described in more detail below with reference to the following examples. However, the scope of the present invention is not limited to these examples. In the following examples, unless otherwise specified, all NMR analyses were performed using a JEOL JNM-AL400 FT-NMR instrument, with tetramethylsilane (TMS) as the internal standard and the TMS resonance set to 0.00 ppm. All chemical shifts are in ppm on the delta scale (δ), and signal fine splittings are indicated using abbreviations (s: singlet, d: doublet, t: triplet, m: multiplet, br: broad). Mass spectrometry was performed using an LCMS 2020 (Shimadzu Corporation) for MS and an LCMS-IT-TOF (Shimadzu Corporation) for HRMS.

[0138] [Examples 1-1 to 1-4 and Comparative Examples 1-1 to 1-3] In these examples, two types of compounds (PSMA-DA1 and PSMA-DB) targeting PSMA were synthesized. 111 In ions, 90 Y ions or 225 Radiolabeled compounds were obtained, each coordinated with an Ac ion. Details are provided below. The PSMA-DA1 used in Examples 1-1 to 1-4 has a chemical structure containing a PSMA binding moiety and an albumin binding moiety, linearly arranged via a chelating moiety, as shown in the general formula (1) above. In PSMA-DA1, the chelating moiety and the PSMA binding moiety are directly bonded via an amide bond, and the chelating moiety and the atomic group containing the albumin binding moiety are indirectly bonded via a lysine-derived linker structure. The PSMA-DB used in Comparative Examples 1-1 to 1-3 contains a chelating moiety and a PSMA binding moiety in its structure, but does not contain an albumin binding moiety.

[0139] Examples 1-1 to 1-4 The synthetic routes in Examples 1-1 to 1-4 are outlined below as synthetic routes (V-1) and (V-2).

[0140] [Rule 26, 30.05.2022]

[0141] [Rule 26, 30.05.2022]

[0142] (1) Synthesis of PSMA-DA1 (Compound 1) Compound 1 was synthesized in three steps from 1,4,7,10-tetraazacyclododecane according to the method described in Chem Commun. 2008, 28, 3248-3250. Compound 1 (20 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and methyl-N ６ 1-(4-(4-iodophenyl)butanoyl)-L-lysinate (11 mg, 0.0254 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (7.0 mg, 0.037 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (5.0 mg, 0.037 mmol), and triethylamine (5 μL, 0.036 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Thereafter, (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexane-2-yl)ureido)pentanediate (13 mg, 0.0267 mmol), EDC hydrochloride (7.0 mg, 0.037 mmol), HOAt (5.0 mg, 0.037 mmol), and triethylamine (5 μL, 0.036 mmol) were added, and the mixture was stirred at room temperature for 72 hours. After removing the solvent, 6 N hydrochloric acid (3 mL) was added to the residue, and the mixture was stirred at 40°C for 24 hours. The mixture was purified by reverse-phase HPLC under the following conditions to obtain the target compound (PSMA-DA1). The yield and MS were as follows:

[0143] Purification conditions: Cosmosil 5C １８ -AR-II column (10 x 250 mm), mobile phase: MeCN / H ２ O / trifluoroacetic acid (TFA) [10 / 90 / 0.1 (0 min) to 100 / 0 / 0.1 (90 min)], flow rate: 4 mL / min. Yield: 1.0 mg (yield: 3%, calculated from the amount of PSMA-DA1 obtained relative to the amount of Compound 1). MS (ESI): m / z 1250.5 [M+H] ＋ .

[0144] (2)１１１ In labeling (Example 1-1) [ １１１ In]InCl ３ The reaction mixture was then purified by reversed-phase HPLC under the following conditions to obtain the desired radiolabeled compound ([ １１１ The radioactivity of the radiolabeled compound obtained was measured using a curiemeter, and the compound used in the reaction was [ １１１ In]InCl ３ The percentage of the radioactivity in the solution was taken as the radiochemical yield (%). A portion of the HPLC fraction of the radiolabeled compound was analyzed under the same HPLC conditions as those for purification, and the radiochemical purity (%) was calculated as the percentage of the area value of the radiolabeled compound relative to the area values ​​of all detected peaks. The radiochemical yield was 61-90%, and the radiochemical purity was 95% or higher.

[0145] 111 Purification conditions for In labeling: Cosmosil 5C １８ -PAQ column (4.6 x 250 mm), mobile phase: MeCN / H ２ O / TFA [20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min) or 5 / 95 / 0.1 (0 to 10 min), 5 / 95 / 0.1 (10 min) to 35 / 65 / 0.1 (40 min)], flow rate: 1 mL / min.

[0146] A compound in which PSMA-DA1 is coordinated with non-radioactive In can be prepared, for example, by the following method. The obtained In complex was used to identify the HPLC retention time of the radiolabeled compound. PSMA-DA1 (1 mg) and anhydrous indium(III) chloride (2 mg) were dissolved in dimethyl sulfoxide (DMSO) (100 μL), and 2-(N-morpholino)ethanesulfonic acid buffer (0.1 M, pH 5.6, 900 μL) was added. The reaction solution was stirred at 60°C for 12 hours, and then the solution was purified by reverse-phase HPLC using the following method to obtain a compound with the following MS. Purification conditions: Cosmosil 5C １８ ​-AR-II column (10 x 250 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 minutes) to 100 / 0 / 0.1 (90 minutes)], flow rate: 4 mL / min. MS (ESI): m / z1362.4 [M+H] ＋ .

[0147] (3) ９０ Y Labeling (Example 1-2) [ 90 Y]YCl ３ The solution (65-118 MBq, 10 μL) and a DMSO solution of PSMA-DA1 (1 mM, 10 μL) were added and left to stand at 90°C for 30 minutes. The reaction solution was then purified by reverse-phase HPLC under the following conditions to obtain the desired radiolabeled compound ([ ９０ The radiochemical yield was measured in the same manner as in Example 1-1. The HPLC conditions used for the analysis of radiochemical purity are as follows: ９０ The purification conditions for Y labeling were used. As a result, the radiochemical yield was 49-79%, and the radiochemical purity was 95% or more.

[0148] ９０ Purification conditions for Y labeling: Cosmosil 5C １８ -PAQ column (4.6 x 250 mm), mobile phase: MeCN / H ２ O / TFA [20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min) or 5 / 95 / 0.1 (0 to 10 min), 5 / 95 / 0.1 (10 min) to 35 / 65 / 0.1 (40 min)], flow rate: 1 mL / min.

[0149] (4) ２２５ Ac labeling (Example 1-3) ２２５ Ac]AcCl ３ To the 0.2 M hydrochloric acid solution (1.5 MBq, 10 μL) of the above, 0.1 M acetic acid-ammonium acetate buffer (pH 5.5, 170 μL) and a DMSO solution of PSMA-DA1 (2.0 mM, 10 μL) were added, and the mixture was left to stand at 70°C for 1 hour. ２ 0 (800 μL) was added and the mixture was passed through an Oasis HLB Light column. ２ ​After passing 10 mL of ethanol through the column, 70% EtOH (0.5 mL) was passed through the column to obtain a purified solution. The purified solution was evaporated to dryness by heating, and then 158 mM acetic acid-sodium acetate buffer (pH 6.5) containing 5% ethanol was added to obtain the target radiolabeled compound ([ ２２５ A dosing solution of [Ac]Ac-PSMA-DA1) was obtained. The radiochemical yield was measured by the following method. The radioactivity of the obtained radiolabeled compound was measured by a gamma ray spectrometer, and the [Ac-PSMA-DA1]Ac solution used in the reaction was ２２５ Ac]AcCl ３ The percentage of radioactivity in the solution was taken as the radiochemical yield (%). The radiochemical purity of the obtained radiolabeled compound was measured by the following method. That is, a portion of the solution of the radiolabeled compound was analyzed by TLC (iTLC-SG, mobile phase: MeCN / H ２ The radiochemical purity (%) was calculated as the percentage of the area value of the radiolabeled compound relative to the area values ​​of all detected peaks. As a result, the radiochemical yield was 49% and the radiochemical purity was 87%.

[0150] (5) ８９ Zr Labeling (Examples 1-4) A Type I Plus vial (2R) (manufactured by SCHOTT) was filled with [ ８９ Zr]Zr(Ox) ２ A 1.0 M hydrochloric acid solution (2.2 MBq, 10 μL) of the above was dispensed, heated to 110°C, and the solvent was distilled off under an Ar stream for approximately 40 minutes. 0.1 mol / L hydrochloric acid (100 μL), 300 mM gentisic acid-0.78 M acetic acid-sodium acetate buffer (pH 5.5, 50 μL), PSMA-DA1-DMSO solution (2 mM, 75 μL), and DMSO (75 μL) were added to the vial, and the mixture was left to stand at 70°C for 1 hour to obtain the desired radiolabeled compound ([ ８９ The radiochemical purity of the radiolabeled compound was measured in the same manner as in Example 1-3. As a result, the radiochemical purity was 96%.

[0151] Comparative Examples 1-1 to 2-3 The synthetic routes in Comparative Examples 1-1 to 2-3 are outlined below as synthetic routes (VI-1) and (VI-2).

[0152] [Rule 26, 30.05.2022]

[0153] [Rule 26, 30.05.2022]

[0154] (1) Synthesis of PSMA-DB Compound 1 (35 mg, 0.045 mmol), synthesized in the same manner as in Examples 1-1 to 1-4, was dissolved in DMF (2 mL), and (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanediate (22 mg, 0.045 mmol), EDC hydrochloride (10 mg, 0.052 mmol), HOAt (7.0 mg, 0.051 mmol), and triethylamine (7 μL, 0.050 mmol) were added, followed by stirring at room temperature for 24 hours. Then, aniline (5 μL, 0.055 mmol), EDC hydrochloride (10 mg, 0.052 mmol), HOAt (7.0 mg, 0.051 mmol), and triethylamine (7 μL, 0.050 mmol) were added, and the mixture was stirred at room temperature for 24 hours. After removing the solvent, the residue was treated with TFA (1.8 mL), triisopropylsilane (100 μL), and H ２ 0 (100 μL) was added and stirred at room temperature for 24 hours. After removing the solvent, the residue was purified by reverse-phase HPLC under the following conditions to obtain the target compound (PSMA-DB). The yield and MS were as follows:

[0155] Purification conditions: Cosmosil 5C １８ -AR-II column (10 x 250 mm), mobile phase: MeCN / H ２ O / TFA [5 / 95 / 0.1 (0-10 min), 5 / 95 / 0.1 (10 min) - 35 / 65 / 0.1 (40 min)], flow rate: 4 mL / min. Yield: 5.0 mg (yield: 12%, calculated from the amount of PSMA-DB obtained relative to the amount of Compound 1). MS (ESI) m / z 925.3 [M+H] ＋ .

[0156] (2) 111 In Labeling (Comparative Example 1-1) The target radiolabeled compound ([１１１ [In]In-PSMA-DB) was obtained. The radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used for the purification and measurement of radiochemical purity were as follows. As a result, the radiochemical yield was 61 to 90%, and the radiochemical purity was 95% or more.

[0157] A compound in which PSMA-DB is coordinated with non-radioactive In can be produced, for example, by the following method. The obtained In complex was used to identify the HPLC retention time of the radiolabeled compound. ２ To a solution of 2000kJ / MeCN / TFA (49.95 / 49.95 / 0.1, 300 μL) was added anhydrous indium(III) chloride (10 equivalents). After stirring at room temperature for 18 hours, the solution was purified by reversed-phase HPLC. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [5 / 95 / 0.1 (0 to 10 minutes), 5 / 95 / 0.1 (10 minutes) to 35 / 65 / 0.1 (40 minutes)], flow rate: 1 mL / min.

[0158] (3) ９０ Y Labeling (Comparative Example 1-2) The target radiolabeled compound ([ ９０ [Y]Y-PSMA-DB) was obtained. The radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The radiochemical purity was measured under the HPLC conditions shown in the purification conditions for the compound in which PSMA-DB is coordinated with non-radioactive In. As a result, the radiochemical yield was 49 to 79%, and the radiochemical purity was 95% or more.

[0159] (4) ２２５ Ac Labeling (Comparative Example 1-3) The target radiolabeled compound ([ ２２５The radiochemical yield and radiochemical purity were measured in the same manner as described in Examples 1-3. The radiochemical yield was 48% and the radiochemical purity was 83%.

[0160] <Evaluation of stability in plasma> Mouse plasma (200 μL) was 111 In]In-PSMA-DA1 (370 kBq) or [ ９０ A solution of [Y]Y-PSMA-DA1 (3.7 MBq) in saline (20 μL) was added and allowed to stand at 37°C for 24 hours (n=3). Then, MeCN (200 μL) was added and the mixture was centrifuged at 10,000 × g for 5 minutes. The supernatant was filtered, and the filtrate was analyzed by reverse-phase HPLC under the following conditions. (Analysis conditions: Cosmosil 5C １８ -PAQ column (4.6 x 250 mm), mobile phase: MeCN / H ２ O / TFA [20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min)], flow rate: 1 mL / min. As a result, 95% or more of each labeled compound was stably present in mouse plasma even after standing at 37°C for 24 hours.

[0161] <Binding evaluation using cultured cells> LNCaP cells (PSMA-positive, human prostate cancer) and PC-3 cells (PSMA-negative, human prostate cancer) were used. These cells were purchased from American Type Culture Collection and DS Biomedical, respectively. Each cell was cultured in RPMI 1640 medium (manufactured by Nacalai Tesque) containing antibiotics (penicillin and streptomycin) and 10% heat-inactivated fetal bovine serum at 37°C and 5% CO ２ were cultured under

[0162] LNCaP cells and PC-3 cells were cultured at 4.0 × 10 ５ The cells were seeded in a 12-well plate at 1000 cells / well and incubated at 37°C, 5% CO ２ The plate was left standing for 48 hours under the following conditions. １１１ In]In-PSMA-DA1 or [ １１１An assay medium (RPMI 1640 medium containing 0.5% FBS) solution (1 mL) containing [In]In-PSMA-DB (37 kBq) was added to the plate. After that, the plate was incubated at 37°C, 5% CO ２ In the inhibition experiment, the culture medium was removed and the １１１ In]In-PSMA-DA1 or [ １１１ A solution of [In]In-PSMA-DB (37 kBq) and 2-(phosphonomethyl)pentanediol (2-PMPA) (PSMA inhibitor, final concentration 100 μM) in assay medium (1 mL) was added. The plate was then incubated at 37°C, 5% CO ２ The wells were then left to stand for 1 hour under reduced pressure. After removing the assay medium, each well was washed with assay medium (1 mL) containing neither radiolabeled compound nor 2-PMPA, and the cells were lysed with 1 N aqueous sodium hydroxide solution (200 μL x 2). The radioactivity of the assay medium and cell lysate was measured using a gamma counter. Separately, the total protein concentration in the cell lysate was calculated using a BCA Protein Assay Kit (Thermo Fisher Scientific). The percentage of sample radioactivity relative to the amount of added radioactivity (% ID) was divided by the total protein amount (% ID / mg protein) for each sample. Data are expressed as mean ± standard deviation. A significant difference test was performed using Student's t-test and one-way analysis of variance (ANOVA) test with Dunnett's post-hoc test, with p<0.05 being considered to indicate a significant difference.

[0163] The results of the evaluation of binding to cultured cells are shown in Figure 1. A higher value indicates a greater amount of radiolabeled compound present and a higher accumulation of the compound. １１１ In]In-PSMA-DA1 and [ １１１ In]In-PSMA-DB showed higher binding to LNCaP cells compared to PC-3 cells, and this binding was significantly reduced by the addition of an excess amount of a PSMA inhibitor (2-PMPA). １１１ In]In-PSMA-DA1 and [ １１１It was shown that In]In-PSMA-DB specifically binds to cells with high PSMA expression.

[0164] <Evaluation of binding to albumin> １１１ In]In-PSMA-DA1 or [ １１１ A PBS solution of [In]In-PSMA-DB (37 kBq, 50 μL) was added to 200 μL of PBS, mouse plasma, human plasma, or a PBS solution of human serum albumin (HSA) (45 mg / mL), and the mixture was allowed to stand at 37°C for 10 minutes. The reaction mixture was then loaded onto a spin column (Sephadex G-100, Cytiva) and centrifuged at 1500 × g for 2 minutes at 4°C. After separation, the radioactivity of the column and eluate were measured using a gamma counter. Data are expressed as mean ± standard deviation. Significance tests were performed using Student's t-test and one-way analysis of variance (ANOVA) test with Dunnett's post-hoc test, with p<0.05 considered significant.

[0165] The results of the albumin binding evaluation are shown in Figure 2. The higher the value, the stronger the binding ability to albumin. When the compound to be evaluated binds to albumin and forms a complex, it passes through the column due to the increase in molecular size, but when it does not bind to albumin, it is retained in the gel inside the column. １１１ In]In-PSMA-DA1 and [ １１１ When [In]In-PSMA-DB was allowed to stand in PBS and then applied to the column, no significant radioactivity was observed in the eluate. On the other hand, when it was allowed to stand in mouse plasma, human plasma, and HSA solution, [ １１１ In] compared to In-PSMA-DB １１１ The radioactivity in the eluate of In]In-PSMA-DA1 was significantly higher, １１１ It was shown that [In]In-PSMA-DA1 binds to plasma albumin.

[0166] <Evaluation of radioactivity distribution in the body using LNCaP or PC-3 tumor-bearing mice> Animal experiments were conducted in accordance with the guidelines of the Kyoto University Animal Experiment Committee. ｓｃｉｄ Mice were purchased from CLEA Japan, Inc. The animals were housed under a 12-hour / 12-hour day / night cycle and were provided with food and water ad libitum. LNCaP cells (1.0 × 10 cells) were cultured in a mixture of PBS and Corning Life Sciences Matrigel (1:1, 150 μL). ７ cells / mouse) or PC-3 cells (1.0 × 10 ７ The cells were suspended and subcutaneously implanted into the right shoulder of mice under isoflurane anesthesia. The mice were then kept for 40 to 60 days. １１１ In]In-PSMA-DA1, or [ １１１ A saline solution of [In]In-PSMA-DB (185 kBq, 100 μL) was administered via the tail vein (n = 3 for each group). Mice were euthanized 1, 4, 24, 48, 96, and 192 hours after administration. Blood and organs were then collected, and organ mass and radioactivity were measured. The percentage of radioactivity (%ID) relative to the injected dose was divided by the blood mass or organ mass (g) and expressed as %ID / g. A higher %ID / g value indicates a higher amount of radiolabeled compound present and higher accumulation of the compound in target organs.

[0167] LNCaP tumor-implanted mice and [ １１１ The results (mean ± standard deviation, n=3 for each) for In]In-PSMA-DA1 are shown in Table 1 below and Figure 3. １１１ The results for [In]In-PSMA-DB (mean ± standard deviation, n=3 for each) are shown in Table 2 below and Figure 3. １１１ In]In-PSMA-DA1 showed high accumulation in LNCaP tumors (9.41-12.6% ID / g 1-24 hours after administration). It also showed retention in the blood (14.0% ID / g 24 hours after administration), and the tumor / kidney ratio exceeded 1 48 hours after administration. １１１In] In-PSMA-DB at all time points １１１ In]In-PSMA-DA1 showed lower tumor accumulation and a lower tumor / kidney ratio than In-PSMA-DA1. １１１ In]In-PSMA-DA1 has high accumulation in tumors with high PSMA expression, and １１１ It was revealed that it has superior biodistribution compared to [In]In-PSMA-DB.

[0168]

[0169]

[0170] PC-3 tumor-implanted mice and [ １１１ The results (mean ± standard deviation, n=3 for each) for PC-3 tumor-bearing mice and [In]In-PSMA-DA1 are shown in Table 3 below. １１１ The results for [In]In-PSMA-DB (mean ± standard deviation, n=3 for each) are shown in Table 4 below. １１１ In]In-PSMA-DA1 and [ １１１ The accumulation of both [In]In-PSMA-DB in PC-3 tumors was lower than that in LNCaP tumors at the same time points, indicating that both radiolabeled compounds selectively accumulate in PSMA-positive tumors.

[0171]

[0172]

[0173] <SPECT / CT using LNCaP tumor-implanted mice> LNCaP tumor-implanted mice prepared by the method described above were subjected to [ １１１ In]In-PSMA-DA1 or [ １１１A saline solution of [In]In-PSMA-DB (1.9-3.0 MBq, 150 μL) was administered via the tail vein. 24 and 48 hours after administration, SPECT / CT was performed using a Gamma Medica-Ideas FX3300 preclinical imaging system. Under isoflurane anesthesia, imaging was performed using a 1.0 mm pinhole collimator with a rotation radius of 35 mm, a projection time of 70 seconds, and 32 projections. After SPECT, CT (tube voltage: 60 kV, tube current: 350 μA) was performed. Image reconstruction of the SPECT projection data was performed using the three-dimensional ordered subset expectation maximization method (8 subsets, 5 iterations).

[0174] The results of SPECT / CT are shown in Figure 4. In the figure, the area indicated by the arrow is the location of the tumor, and the area indicated by the circle is the location of the kidney. The higher the SUV, the higher the radioactivity accumulation. １１１ SPECT / CT imaging using In]In-PSMA-DA1 showed significant radioactivity accumulation in the LNCaP tumor (arrow in the figure) 24 and 48 hours after administration. High radioactivity accumulation was also observed in the kidney (circle in the figure), but 48 hours after administration, the radioactivity signal was at the same level as in the tumor. １１１ SPECT / CT imaging using In]In-PSMA-DB also showed radioactivity accumulation in the LNCaP tumor (arrow in the figure), but the accumulation was lower than in the kidney (circle in the figure). １１１ In]In-PSMA-DA1 can clearly visualize tumors with high PSMA expression by SPECT, and １１１ In]In-PSMA-DB.

[0175] < ９０ Evaluation of tumor growth inhibition by Y-labeled compounds> ９０ Y]Y-PSMA-DA1 (3.7 MBq) or [ ９０A saline solution (100 μL) of [Y]Y-PSMA-DB (3.7 MBq) was administered via the tail vein to LNCaP tumor-bearing mice (n = 7). As a control, 100 μL of saline was administered via the tail vein to LNCaP tumor-bearing mice (n = 7). ９０ After administration of the Y-labeled compound, tumor volume and body weight were measured three times per week. Tumor volume was calculated as follows: (tumor volume) = [(long side) × (short side) ２ / 2] was calculated based on the formula. ９０ The tumor volume on the day administration of the Y-labeled compound started was [ ９０ Y] Y-PSMA-DA1, [ ９０ Y]Y-PSMA-DB and saline-treated groups were 63.1 ± 8.7, 66.1 ± 30.7, and 66.7 ± 25.7 mm ３ It was.

[0176] The results of this evaluation are shown in Figure 5. ９０ Y]Y-PSMA-DA1 and [ ９０ When [Y]Y-PSMA-DB was administered, significant differences in tumor volume were observed 9 days and 33 days after administration compared to the saline administration group. ９０ Y]Y-PSMA-DB compared to [ ９０ Y]Y-PSMA-DA1 was observed to have a tendency to suppress tumor growth. ９０ Administration of [Y]Y-PSMA-DA1 caused a slight decrease in the body weight of the mice, but this subsequently recovered to a value equivalent to that of the saline-administered group.

[0177] < 225 Evaluation of tumor growth inhibition by Ac-labeled compounds> ２２５ Ac]Ac-PSMA-DA1 (20 kBq) or [ ２２５ [Ac]Ac-PSMA-DB (20 kBq) was dissolved in 100 μL of 5% ethanol-containing acetate buffer (158 mM, pH 6.5) and administered via the tail vein to mice bearing LNCaP tumors (n = 6 or 5). As a control, 100 μL of 5% ethanol-containing acetate buffer (158 mM, pH 6.5) was administered via the tail vein to mice bearing LNCaP tumors (n = 4). ２２５After administration of Ac-labeled compounds, tumor volume and body weight were measured twice a week. ２２５ The tumor volume on the day of starting administration of Ac-labeled compound was [ ２２５ Ac] Ac-PSMA-DA1, [ ２２５ Ac]Ac-PSMA-DB, and 5% ethanol-containing acetate buffer groups had 75.3 ± 26.0, 80.6 ± 20.8, and 91.1 ± 15.9 mm ３ It was.

[0178] The results of this evaluation are shown in Figure 6. ２２５ Ac]Ac-PSMA-DA1 and [ ２２５ When [Ac]Ac-PSMA-DB was administered, tumor growth was significantly suppressed compared to the saline administration group. ２２５ In the group administered Ac-PSMA-DA1, tumor growth was minimal, and continued growth suppression was observed up to 6 weeks after administration. ２２５ The weight loss thought to be the effect of administration of [Ac]Ac-PSMA-DA1 was transient. ２２５ The weight loss, which was thought to be the effect of administration of Ac]Ac-PSMA-DB, was temporarily accelerated, but no recovery was observed thereafter.

[0179] Example 2 In this example, a compound (PtDA) was synthesized that contains (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid (the structure of the above formula (C1) where a is 2 and b is 4) as a binding moiety for PSMA, and uses a click reaction between an azide group and dibenzylcyclooctyne (DBCO) to bond the chelating moiety to the binding moiety for PSMA. Next, these compounds were treated with a radioactive metal. １１１ Radiolabeled compounds with coordinated In ions were obtained. The synthetic routes are outlined below as synthetic routes (VIII-1) to (VIII-4). The compound used in Example 2 contains a chelating moiety, a PSMA binding moiety, and an albumin binding moiety in its structure. １１１There are two synthetic routes for coordinating with In ions (see synthetic route (VIII-4)), but the radiolabeled compound obtained by either route is the same. In PtDA, the chelating moiety and the binding site for the PSMA molecule are indirectly bound via a chemical structure derived from a click reaction and a polyethylene glycol group, and the chelating moiety and the atomic group containing the albumin binding site are indirectly bound via a linker structure derived from lysine.

[0180]

[0181]

[0182]

[0183]

[0184] <Synthesis of Compound 71> N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６ -[(4-methylphenyl)diphenylmethyl]-L-lysine (1000 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), and the solution was mixed with tert-butyl trichloroacetimidate (699.5 mg, 3.2 mmol) and BF ３ ・OEt ２ (25 μL) was added. The reaction solution was stirred at room temperature for 42 hours. After removing the solvent, the residue was ２ The mixture was washed with 20 mL of ethyl acetate (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (ethyl acetate / hexane). The yield, NMR spectrum, and MS were as follows:

[0185] Yield: 569 mg (yield: 52%, N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６ (Calculated from the amount of substance of the obtained compound 71 relative to the amount of substance of -[(4-methylphenyl)diphenylmethyl]-L-lysine).１ H-NMR (400MHz, CDCl ３ ) δ7.69 (d, J=7.3Hz, 2H), 7.56 (d, J=7.8Hz, 2H), 7.45 (d, J=7.8Hz, 4H), 7.33 (d, J=8.2Hz, 4H), 7.23 (m, 6H), 7.13 (m, 2H), 7.04 (d, J=7.8Hz, 2H), 5.39 (d, J=8.2Hz, 1H), 4.35 (d, J=6.9Hz, 2H), 4.25 (m, 1H), 4.18 (t, J=6.9Hz, 1H), 2. 26 (s, 3H), 2.12 (m, 2H), 1.77 (m, 1H), 1.59 (m, 1H), 1.49 (m, 4H), 1.44 (s, 9H). １３ C-NMR (100MHz, CDCl ３ ) δ171.6, 155.7, 146.3 (2C), 143.7 (2C), 143.2, 141.1 (2C), 135.4, 128.4-128.3 (8C), 127.6-127.5 (6C), 126.9 (2C), 126.0 (2C), 125.0 (2C), 119.8 (2C), 81.7, 70.5, 66.7, 60.2, 47.1, 43.2, 32.7, 30.4, 27.8 (3C), 22.8, 20.7. HRMS (ESI): m / z681.3677 [M+H] ＋ .

[0186] Synthesis of Compound 72: Compound 71 (569 mg, 0.84 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA) (100 μL), triisopropylsilane (250 μL), and dichloromethane (4.65 mL) and stirred at room temperature for 6 hours. After removing the solvent, the residue was purified by medium-pressure column chromatography (methanol / chloroform). The yield, NMR spectrum, and MS were as follows:

[0187] Yield: 355 mg (yield: 100%, calculated from the amount of substance of the obtained compound 72 relative to the amount of substance of the compound 71). １ H-NMR (400MHz, CDCl ３) δ7.71 (d, J=7.6Hz, 2H), 7.56 (d, J=7.1Hz, 2H), 7.35 (t, J=7.6Hz, 2H), 7.27 (t, J=7.6Hz, 2H), 5.72 (d, J=8.0Hz, 1 H), 4.33 (d, J=7.1Hz, 2H), 4.16 (t, J=6.6Hz, 2H), 3.38 (s, 2H), 1.77-1.56 (m, 4H), 1.43 (s, 9H), 1.27-1.13 (m, 2H). １３ C-NMR (100MHz, CDCl ３ ) δ171.5, 156.2, 143.6 (2C), 141.1 (2C), 127.6 (2C), 127.0 (2C), 125.0 (2C), 119.8 (2C), 82.3, 66.9, 54.1, 50.0, 46.9, 39.5, 31.1, 27.7 (3C), 26.8, 22.1. HRMS (ESI): m / z425.2437 [M+H] ＋ .

[0188] <Synthesis of Compound 73> 4-(4-iodophenyl)butanoic acid (364 mg, 1.25 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (320 mg, 1.7 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (228 mg, 1.7 mmol) were added, followed by stirring at 0°C for 15 minutes. Thereafter, compound 72 (355 mg, 0.84 mmol) and triethylamine (169 mg, 1.7 mmol) were added, followed by stirring at 0°C. After 15 hours, the reaction solution was ２ The mixture was washed with 20 mL of ethyl acetate (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (ethyl acetate / hexane). The yield, NMR spectrum, and MS were as follows:

[0189] Yield: 226 mg (yield: 39%, calculated from the amount of substance of the obtained compound 73 relative to the amount of substance of the compound 72). １ H-NMR (400MHz, CDCl ３) δ7.73 (d, J = 7.3Hz, 2H), 7.60-7.50 (m, 6H), 7.37 (t, J = 7.3Hz, 2H) , 7.28 (t, J = 7.3Hz, 2H), 6.83 (d, J = 8.2Hz, 2H), 4.38-4.27 (m, 2H), 4.25-4.16 (m, 2H), 3.21-3.14 (m, 2H), 2.48 (m, 2H), 2.08 (t, J=7.3Hz, 2H), 1.91-1.84 (m, 2H), 1.73-1.57 (m, 2H), 1.47-1.29 (m, 13H). １３ C-NMR (100MHz, CDCl ３ ) δ172.8, 171.5, 156.0, 143.5 (2C), 141.0-140.9 (3C), 137.1 (2C), 130.3 (2C), 127.5 (2C), 126.9 (2C), 1 24.9 (2C), 119.8 (2C), 90.8, 82.0, 66.8, 53.9, 46.9, 38.9, 35.4, 34.4, 32.1, 28.6, 27.9 (3C), 26.7, 22.2. HRMS (ESI): m / z697.2130 [M+H] ＋ .

[0190] <Synthesis of Compound 74> Piperidine (1 mL) was added to a solution of Compound 73 in DMF (4 mL). After stirring at room temperature for 2 hours, the solution was ２ The mixture was washed with 20 mL of ethyl acetate (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). The yield, NMR spectrum, and MS were as follows:

[0191] Yield: 133 mg (yield: 87%, calculated from the amount of substance of the obtained compound 74 relative to the amount of substance of the compound 73). １ H-NMR (400MHz, CDCl ３) δ7.58 (d, J=8.2Hz, 2H), 6.92 (d, J=8.2Hz, 2H), 3.31-3.27 (m, 1H), 3.23 (m, 2H), 2.58 (m, 2H), 2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.74-1.65 (m, 2H), 1.56-1.48 (m, 2H), 1.44 (s, 9H), 1.43-1.40 (m, 2H). １３ C-NMR (100MHz, CDCl ３ ) δ175.2, 172.3, 141.1, 137.3 (2C), 130.5 (2C), 90.9, 80.9, 54.7, 39.1, 35.6, 34.6, 34.3, 29.2, 28.0 (3C), 26.8, 22.9. HRMS (ESI): m / z475.1453 [M+H] ＋ .

[0192] <Synthesis of Compound 75> Compound 75 was synthesized in three steps from 1,4,7,10-tetraazacyclododecane in the same manner as in the above example (Chem Commun. 2008, 28, 3248-3250).

[0193] <Synthesis of Compound 76> N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU) (176 mg, 0.41 mmol) was added to a solution of compound 75 (317 mg, 0.41 mmol) in DMF (2 mL), and the mixture was stirred at 0°C for 15 minutes. N,N-Diisopropylethylamine (DIPEA) (53 mg, 0.41 mmol) was added to the reaction solution, and the mixture was stirred at 0°C for an additional 15 minutes, after which compound 74 (163 mg, 0.34 mmol) was added. After stirring at room temperature for 12 hours, the solution was purified by reverse-phase HPLC under the following conditions. The yield and MS were as follows: Purification conditions: Cosmosil 5C １８ -AR-II column (20 x 250 mm), mobile phase: MeCN / H ２O / TFA [30 / 70 / 0.1 (0 min) - 90 / 10 / 0.1 (40 min)], flow rate: 5 mL / min. Yield: 229 mg (55%, calculated from the amount of compound 76 obtained relative to the amount of compound 75). HRMS (ESI) m / z 1229.6182 [M+H] ＋ .

[0194] <Synthesis of Compound 77> COMU (147 mg, 0.34 mmol) was added to a solution of Compound 76 (106 mg, 0.086 mmol) in DMF (0.6 mL), and the mixture was stirred at 0°C for 15 minutes. DIPEA (89 mg, 0.69 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for another 15 minutes. Then, dibenzocyclooctyneamine (ADIBO-NH ２ After stirring at room temperature for 12 hours, the solution was purified by reversed-phase HPLC under the following conditions. The yield and MS were as follows. Purification conditions: Cosmosil 5C １８ -AR-II column (20 x 250 mm), mobile phase: MeCN / H ２ O / TFA [20 / 80 / 0.1 (0 min) - 90 / 10 / 0.1 (35 min)], flow rate: 5 mL / min. Yield: 51 mg (40%, calculated from the amount of compound 77 relative to the amount of compound 76). HRMS (ESI): m / z 1487.7351 [M+H] ＋ .

[0195] <Synthesis of Compound 78 (ADA)> COMU (70 mg, 0.16 mmol) was added to a solution of Compound 76 (50 mg, 0.041 mmol) in MeCN (0.4 mL) and stirred at 0°C for 15 minutes. DIPEA (89 mg, 0.69 mmol) was added to the reaction solution, and the mixture was stirred at 0°C for another 15 minutes, after which N-hydroxysuccinimide (19 mg, 0.16 mmol) was added. After stirring at room temperature for 24 hours, the solution was ２The mixture was washed with 100 mL of ethyl acetate and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and half of the residue was dissolved in a TFA / thioanisole / triisopropylsilane mixture (95 / 3 / 2, 2 mL) and stirred at room temperature for 11 hours. After removing the solvent, the residue was dissolved in DMF (0.4 mL) and triethylamine (10 μL) to give ADIBO-NH ２ (6.2 mg, 0.023 mmol) was added. The reaction solution was stirred at room temperature for 24 hours, and then the solution was purified by reversed-phase HPLC under the following conditions. The yield and MS were as follows. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) - 90 / 10 / 0.1 (40 min)], flow rate: 1 mL / min. Yield: 6.7 mg (yield: 27%, calculated from the amount of compound 78 obtained relative to the amount of compound 76). HRMS (ESI): m / z 1207.4213 [M+H] ＋ .

[0196] <Synthesis of Compound 7A> (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexane-2-yl)ureido)pentanediate (31 mg, 0.064 mmol) was dissolved in DMF (0.5 mL), and 2,5-dioxopyrrolidine-1-yl 1-azido-3,6,9,12-tetraoxapentadecan-15-oate (25 mg, 0.064 mmol) was added. After stirring at room temperature for 12 hours, the solution was purified by reverse-phase HPLC under the following conditions. The yield, NMR spectrum, and MS were as follows.

[0197] Purification conditions: Cosmosil 5C １８ -AR-II column (10 x 250 mm), mobile phase: MeCN / H ２O / TFA [30 / 70 / 0.1 (0 min) to 90 / 10 / 0.1 (30 min)], flow rate: 4 mL / min. Yield: 35 mg (yield: 72%, calculated from the amount of compound 7A obtained relative to the amount of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanediate). １ H-NMR (400MHz, CDCl ３ ) δ4.26-4.23 (m, 2H), 3.75 (t, J=5.2Hz, 2H), 3.69-3.61 (m, 14H), 3.41 (t, J=5.2Hz, 2H), 3.38-3.16 (m, 2H), 2.59 (t, J=5. 2Hz, 2H), 2.34 (dt, J = 2.3, 7.5Hz, 2H), 2.11-1.60 (m, 4H), 1.54 (t, J = 7.0Hz, 2H), 1.48-1.40 (m, 27H), 1.39-1.26 (m, 2H). １３ C-NMR (100MHz, CDCl ３ ) δ174.3 (2C), 172.8 (2C), 158.4, 82.7, 82.4, 81.2, 70.4 (2C), 70.3, 70.1, 70.0 (2C), 69.9, 66.8, 53.7, 53.3, 50.5, 39.2, 35.8, 31.5, 31.3, 28.2, 27.9 (3C), 27.8 (7C), 21.9. HRMS (ESI): m / z761.4656 [M+H] ＋ .

[0198] <Synthesis of Compound 7B> Compound 7A (23 mg, 0.030 mmol) was dissolved in TFA (950 μL) and triisopropylsilane (50 μL) and stirred at room temperature for 4 hours. After removing the solvent, the residue was purified by reversed-phase HPLC under the following conditions. The yield, NMR spectrum, and MS were as follows. Purification conditions: Cosmosil 5C １８ -AR-II column (10 x 250 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 40 / 60 / 0.1 (30 min)], flow rate: 4 mL / min. Yield: 11 mg (yield: 63%, calculated from the amount of compound 7B obtained relative to the amount of compound 7A).１ H-NMR (400MHz, CDCl ３ ) δ7.52 (s, 1H), 6.37 (s, 2H), 4.39 (s, 1H), 4.31 (s, 1H), 3.66 (m, 16H), 3.40 (s, 2H), 2.53-1.23 (m, 14H). HRMS (ESI): 593.2779 [M+H] ＋ .

[0199] Synthesis of Compound 7C (PtDA) Compound 77 (20 mg, 0.013 mmol) was dissolved in DMF (0.6 mL), and Compound 7A (35 mg, 0.046 mmol) was added. After stirring at room temperature for 12 hours, the solvent was removed. The residue was treated with TFA (1.9 mL), thioanisole (60 μL), triisopropylsilane (20 μL), and H ２ 0 (20 μL) was added and stirred at room temperature for 10 hours. After removing the solvent, the residue was purified by reversed-phase HPLC under the following conditions. The yield and MS were as follows. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) - 90 / 10 / 0.1 (40 min)], flow rate: 1 mL / min. Yield: 1.0 mg (4.2%, calculated from the amount of compound 7C (PtDA) relative to the amount of compound 77). HRMS (ESI): m / z 900.3488 [M+2H] ２＋ .

[0200] <By Route A [ １１１ Synthesis of In]In-ADA> In 2-(N-morpholino)ethanesulfonic acid (MES) buffer solution (0.1 M, pH 5.7, 100 μL) １１１ In]InCl ３ The solution (9.2 MBq, 100 μL) and a dimethyl sulfoxide (DMSO) solution of compound 78 (0.60 mM, 7 μL) were added and left to stand at 90° C. for 5 minutes. The reaction solution was then purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２O / TFA [10 / 90 / 0.1 (0 min) to 70 / 30 / 0.1 (30 min)], flow rate: 1 mL / min. The radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used for measuring the radiochemical purity were the same as the purification conditions described above. The radiochemical conversion rate ([ １１１ In]InCl ３ for radioactivity of １１１ The radioactivity of In-ADA and the radiochemical yield are shown in Table 5 below.

[0201] <By Route A [ １１１ Synthesis of In]In-PtDA> Phosphate buffered saline (PBS) / DMSO mixture (9 / 1, 200 μL) or DMSO (200 μL) was added to [ １１１ [In]In-ADA (0.80 MBq) was added, and then compound 7B (0.2 mg) was further added. After standing at 37°C for 10 or 30 minutes, the reaction solution was purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 70 / 30 / 0.1 (30 min)], flow rate: 1 mL / min. The radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used for measuring the radiochemical purity were the same as the purification conditions described above. The radiochemical conversion rate ([ １１１ In]In-ADA radioactivity [ １１１ The radioactivity of In]In-PtDA) and radiochemical yield are shown in Table 5 below.

[0202] <By Route B １１１ Synthesis of In]In-PtDA> In MES buffer (0.1 M, pH 5.7, 150 μL) １１１ In]InCl ３ The solution (2.1 MBq, 100 μL) and a DMSO solution of compound 7C (0.56 mM, 2 μL) were added and left to stand at 90°C for 5 minutes. The reaction solution was then purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８-AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 70 / 30 / 0.1 (30 min)], flow rate: 1 mL / min. The radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used for measuring the radiochemical purity were the same as the purification conditions described above. The radiochemical purity ([ １１１ In]InCl ３ for radioactivity of １１１ The radioactivity of In]In-PtDA) and radiochemical yield are shown in Table 5 below.

[0203]

[0204] In-ADA and In-PtDA coordinated with non-radioactive In can be prepared by the following method. The obtained In complex was used to identify the HPLC retention time of the radiolabeled compound. <Synthesis of non-radioactive In-ADA> Compound 78 (1 equivalent) was dissolved in acetate buffer (1.0 M, pH 5.0, 100 μL), and indium(III) chloride anhydrate (10 equivalents) was added. The reaction solution was stirred at 90°C for 5 minutes, and then the solution was purified by reversed-phase HPLC. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 30.1 (0 minutes) to 90 / 10 / 0.1 (40 minutes)], flow rate: 1 mL / min. MS (ESI): m / z1319.3 [M+H] ＋ .

[0205] <Synthesis of non-radioactive In-PtDA> Compound 7C (0.5 mg, 1.25 mmol) was dehydrated with H ２ Anhydrous indium(III) chloride (0.62 mg, 2.8 μmol) was added to a solution of 200 Mg / MeCN / TFA (49.95 / 49.95 / 0.1, 300 μL). After stirring at room temperature for 18 hours, the solution was purified by reversed-phase HPLC. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２O / TFA [10 / 90 / 0.1 (0 min) - 90 / 10 / 0.1 (40 min)], flow rate: 1 mL / min. Yield: 0.05 mg (yield: 9.4%, calculated from the amount of non-radioactive In-PtDA obtained relative to the amount of compound 7C). HRMS (ESI): m / z 956.2893 [M+2H] ２＋ .

[0206] <Evaluation of partition coefficient> A mixture of PBS (pH 7.4, 3 mL) and 1-octanol (3 mL) was added with [ １１１ [In]In-PtDA (111 kBq) was added, dispersed by vortexing for 2 minutes, and then centrifuged at 4000 × g for 5 minutes. 1 mL was collected from the 1-octanol layer and the PBS layer, and the radioactivity of each layer was measured using a gamma counter (n = 3). The calculation formula was "(Partition coefficient) = Log １０ [(Radioactivity [kBq] in the 1-octanol layer) / (Radioactivity [kBq] in the PBS layer)] was used. As a result, １１１ The Log P of In]In-PtDA was −3.08±0.02.

[0207] <Evaluation of Plasma Stability> Mouse plasma (200 μL) was １１１ A solution of [In]In-PtDA (259 kBq) in physiological saline (20 μL) was added and left to stand at 37°C for 24 hours (n=3). MeCN (400 μL) was added and centrifuged at 10,000 × g for 5 minutes. The supernatant was filtered, and the filtrate was analyzed by reverse-phase HPLC under the following conditions. Analysis conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 70 / 30 / 0.1 (30 min)], flow rate: 1 mL / min. As a result, as shown in Figure 7, １１１ In]In-PtDA remained stable at 95% or more in mouse plasma even after standing at 37°C for 24 hours.

[0208] <Binding evaluation using cultured cell lines> LNCaP cells and PC-3 cells were cultured in the same manner as in Example 1-1 above, and a cell binding experiment was carried out. １１１Evaluation was carried out using the same experimental procedures and statistical methods as in Example 1-1, except that 0.5% FBS-containing RPMI1640 medium (1 mL) containing In]In-PtDA (37 kBq) was used.

[0209] The results are shown in Figure 8. １１１ In]In-PtDA showed higher binding affinity to LNCaP cells (15% ID / mg protein) compared to PC-3 cells (0.15% ID / mg protein), and the binding was significantly reduced (0.36% ID / mg protein) by the addition of an excess amount of PSMA inhibitor (2-PMPA). １１１ In]In-PtDA was shown to specifically bind to PSMA-positive cells.

[0210] <Evaluation of binding to albumin> As in Example 1-1 above, binding to albumin was evaluated using PBS, mouse plasma, human plasma, and human albumin. １１１ The evaluation was carried out using the same experimental procedures and statistical methods as in Example 1-1, except that a PBS solution of In]In-PtDA (37 kBq, 50 μL) was used.

[0211] The results are shown in Figure 9. １１１ When [In]In-PtDA was placed in PBS and then applied to the column, little radioactivity was detected in the eluate (6.9%). On the other hand, when placed in mouse plasma, human plasma, and human albumin solution, high levels of radioactivity were observed in the eluate (67.2, 79.0, and 92.4%, respectively). １１１ It has been shown that [In]In-PtDA binds to plasma albumin.

[0212] <Evaluation of Internal Radioactivity Distribution Using LNCaP Tumor-Borne Mice> LNCaP tumor-borne mice were prepared in the same manner as in Example 1-1, and [ １１１A saline solution of [In]In-PtDA (241 kBq / 100 μL) was administered via the tail vein (n=3), and the mice were euthanized 1, 24, and 48 hours after administration. Blood and organs were then collected, and organ mass and radioactivity were measured. The percentage of radioactivity (%ID) relative to the injected dose was divided by the blood mass or organ mass (g) and expressed as %ID / g. A higher %ID / g value indicates a higher amount of radiolabeled compound present and higher accumulation of the compound in target organs.

[0213] LNCaP tumor-implanted mice and [ １１１ The results for [In]In-PtDA (mean ± standard deviation, n=3 for each) are shown in Table 6 below. １１１ In]In-PtDA showed high accumulation in LNCaP tumors (16.0 and 18.7% ID / g at 24 and 48 hours after administration, respectively) and retention in the blood (6.33-19.8% ID / g at 1-48 hours after administration). Furthermore, kidney accumulation at 1 hour after administration was 37.2% ID / g. This is a radiolabeled compound known to target PSMA. １１１ In]In-PSMA-I&T (kidney: 191% ID / g), and [ ６８ This was significantly lower than [Ga]Ga-PSMA-11 (kidney: 139% ID / g) (e.g., EJNMMI Res, 2012, 2, 23, J Nucl Med, 2017, 58, 235-242).

[0214]

[0215] <SPECT / CT evaluation using tumor-implanted mice> Male CB17 / IcrJcl-Prkdc mice were bred in the same manner as in Example 1-1. ｓｃｉｄ Mice were cultured with LNCaP cells (1.0 × 10 cells) in a mixture of PBS and Matrigel (1:1, 150 μL). ７ PC-3 cells (1.0 × 10 cells / mouse) were suspended and subcutaneously implanted into the right shoulder of mice under isoflurane anesthesia. In addition, the same mice were treated with PC-3 cells (1.0 × 10 cells / mouse) in a mixture of PBS and Matrigel (1:1, 150 μL). ７A suspension of LNCaP cells (1000 cells / mouse) was subcutaneously implanted into the left shoulder of mice under isoflurane anesthesia. The mice were then kept for 40 to 60 days. In this way, tumor-bearing mice were obtained in which LNCaP cells and PC-3 cells were simultaneously implanted into one mouse.

[0216] Next, the tumor-implanted mice were treated with [ １１１ A saline solution of [In]In-PtDA (2.7 MBq, 100 μL) was administered via the tail vein. SPECT / CT was performed 24 and 48 hours after administration using a Gamma Medica-Ideas FX3300 preclinical imaging system. Images were acquired under isoflurane anesthesia using a 1.0 mm pinhole collimator with a 35 mm rotation radius, 70 seconds projection time, and 32 projections. After SPECT, CT (tube voltage: 60 kV, tube current: 350 μA) was performed. Image reconstruction of the SPECT projection data was performed using the three-dimensional ordered subset expectation maximization method (8 subsets, 5 iterations).

[0217] The results of SPECT / CT are shown in Figure 10. The higher the SUV, the higher the radioactivity accumulation. １１１ SPECT / CT imaging using In]In-PtDA showed high radioactivity accumulation in the LNCaP tumor 24 and 48 hours after administration, but almost no radioactivity signal was observed in the PC-3 tumor. １１１ It was shown that [In]In-PtDA allows clear visualization of PSMA-positive tumors.

[0218] [Examples 3-1 to 3-3 and Comparative Examples 2-1 to 2-2] In these examples, compounds targeting PSMA were synthesized. １１１A radiolabeled compound coordinated with In ions was obtained. The synthetic routes are outlined below as synthetic routes (X-1) to (X-3). The compounds (Octapa-2, Octapa-3, and Neunpa-2) used in Examples 3-1 to 3-3 have a chemical structure in which a chelating moiety, a binding moiety for PSMA molecules, and an albumin binding moiety are each linked in a branched manner via a linker structure, as shown in the general formula (2) above. The compounds (Octapa-1 and Neunpa-1) used in Comparative Examples 2-1 and 2-2 have a chelating moiety and a binding moiety for PSMA molecules, but do not have an albumin binding moiety in their structures.

[0219] [Rule 26, 30.05.2022]

[0220] [Rule 26, 30.05.2022]

[0310]

[0221] [Rule 26, 30.05.2022]

[0222] <Synthesis of Compound 101> L-phenylalanine amide (985 mg, 6.0 mmol) was dissolved in tetrahydrofuran (THF) (20 mL), and LiAlH ４ A solution of (1139 mg, 30 mmol) in THF (10 mL) was slowly added at 0° C. The reaction mixture was stirred at 60° C. for 24 hours, and then H ２ O (1.2 mL), 15% aqueous sodium hydroxide (1.2 mL), and H ２0 (3.6 mL) was added sequentially. After stirring at room temperature for 1 hour, the mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. Concentrated sulfuric acid (5 mL) was added to the residue, followed by a mixture of concentrated nitric acid (400 μL) and concentrated sulfuric acid (400 μL). After stirring at room temperature for 5 hours, the mixture was neutralized and extracted with chloroform (50 mL x 3). The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 830 mg (yield: 71%, calculated from the amount of compound 101 obtained relative to the amount of L-phenylalaninamide). MS (ESI) m / z: 196.1 [M+H] ＋ .

[0223] <Synthesis of Compound 102> Compound 102 was synthesized in three steps from compound 101 according to a previously reported method (J Am Chem Soc. 2013, 135, 12707-12721, J Chem Soc Dalt Trans. 2014, 43, 7176-7190).

[0224] <Synthesis of Compound 103> Compound 102 (288 mg, 0.36 mmol) was dissolved in methanol (5 mL), and palladium on carbon (30 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours, then filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 150 mg (yield: 54%, calculated from the amount of compound 103 obtained relative to the amount of compound 102). １ H-NMR (400MHz, CDCl ３ ) δ7.82 (d, J = 6.9Hz, 2H), 7.70-7.60 (m, 4H), 6.86 (d, J = 7.6Hz, 2H), 6.54 (d, J = 7.6Hz, 2H), 4.07 (m, 5H), 3 .40-3.23 (m, 5H), 2.91-2.89 (m, 2H), 2.73-2.69 (m, 1H), 2.53-2.50 (m, 2H), 1.62 (s, 18H), 1.40 (s, 18H). MS (ESI) m / z: 806.4 [M+H] ＋ .

[0225] <Synthesis of Compound 104> Compound 104 was synthesized according to a previously reported method (Bioconjug. Chem. 2017, 28, 2145-2159).

[0226] <Synthesis of Compound 105> To a solution of compound 104 (729 mg, 1.17 mmol) in MeCN (40 mL), t-butyl bromoacetate (396 μL, 2.69 mmol) and sodium carbonate (285 mg, 2.69 mmol) were added, and the mixture was stirred at 60°C for 24 hours. After returning to room temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (hexane / ethyl acetate). Yield: 566 mg (yield: 57%, calculated from the amount of compound 105 obtained relative to the amount of compound 104). １ H-NMR (400MHz, CDCl ３ ) δ8.14 (d, J=8.7Hz, 2H), 8.05-8.02 (m, 2H), 7.71-7.67 (m, 4H), 7.62-7.58 (m, 2H), 7.37 (d, J = 8.7 Hz, 2H), 4.08 (s, 4H), 3.41 (t, J = 7.0Hz, 4H), 2.86-2.77 (m, 8H), 1.34 (s, 18H). MS (ESI) m / z: 851.2 [M+H] ＋ .

[0227] Synthesis of Compound 106 Thiophenol (253 μL, 1.53 mmol) and potassium carbonate (212 mg, 1.53 mmol) were added to a solution of Compound 105 (566 mg, 0.67 mmol) in THF (20 mL), and the mixture was stirred at 50° C. for 50 hours. After returning to room temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 213 mg (yield: 66%, calculated from the amount of compound 106 obtained relative to the amount of compound 105). １ H-NMR (400MHz, CDCl ３ ) δ8.14 (d, J=8.2Hz, 2H), 7.42-7.37 (m, 2H), 3.26 (s, 4H), 2.91-2.65 (m, 12H), 1.47 (s, 18H). MS (ESI) m / z: 481.3 [M+H] ＋ .

[0228] <Synthesis of Compound 107> t-Butyl-6-(bromomethyl)picolinate (264 mg, 0.97 mmol) and sodium carbonate (103 mg, 0.97 mmol) were added to a solution of Compound 106 (213 mg, 0.44 mmol) in N,N-dimethylformamide (DMF) (15 mL), and the mixture was stirred at 60°C for 24 hours. After returning to room temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 224 mg (yield: 60%, calculated from the amount of compound 107 obtained relative to the amount of compound 106). １ H-NMR (400MHz, CDCl ３ ) δ8.06 (d, J = 8.5Hz, 2H), 7.88-7.86 (m, 2H), 7.75-7.73 (m, 4H), 7.23 (d, J = 8.7Hz , 2H), 3.99 (s, 4H), 3.30 (s, 4H), 2.74-2.63 (m, 12H), 1.62 (s, 18H), 1.45 (s, 18H). MS (ESI) m / z: 863.5 [M+H] ＋ .

[0229] <Synthesis of Compound 108> A reaction similar to that for the synthesis of Compound 103 was carried out to obtain 50.7 mg (yield 23%, calculated from the amount of compound 108 obtained relative to the amount of compound 107) of Compound 108 from Compound 107. １ H-NMR (400MHz, CDCl ３ ) δ7.86 (d, J=7.1Hz, 2H), 7.78-7.72 (m, 4H), 6.85 (d, J=8.2, 2H), 6.56 (d, J=8.2, 2H), 4.00 (s, 4H), 3.32 (s, 4H), 2.76-2.55 (m, 12H), 1.62 (s, 18H), 1.44 (s, 18H). MS (ESI) m / z: 833.4 [M+H] ＋ .

[0230] Synthesis of Compound 109: Compound 103 (56.6 mg, 0.073 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (28.8 mg, 0.15 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (20.4 mg, 0.15 mmol), and triethylamine (21 μL, 0.15 mmol) were added to a solution of 6-(Fmoc-amino)hexanoic acid (31.1 mg, 0.088 mmol) in dichloromethane (7 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 30.2 mg (37%, calculated from the amount of compound 109 obtained relative to the amount of compound 103). HRMS (ESI) m / z: 1111.6170 [M+H] ＋ .

[0231] Synthesis of Compound 110: A reaction similar to that for the synthesis of Compound 109 was carried out to obtain 17.7 mg of Compound 110 (yield 25%, calculated from the amount of Compound 110 relative to the amount of Compound 108) from Compound 108. HRMS (ESI) m / z: 1168.6372 [M+H] ＋ .

[0232] <Synthesis of Compound 111> Compound 109 (30.2 mg, 0.027 mmol) was dissolved in a mixture of piperidine (1 mL) and DMF (4 mL) and stirred at room temperature for 2.5 hours. Ethyl acetate and H ２ After adding 0, the organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and then THF (5 mL) was added to the residue. Succinic anhydride (11 mg, 0.11 mmol) and N,N-diisopropylethylamine (DIPEA) (19 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 9.7 mg (37%, calculated from the amount of compound 111 obtained relative to the amount of compound 109). HRMS (ESI) m / z: 989.5600 [M+H] ＋ .

[0233] Synthesis of Compound 112: The same reaction as in the synthesis of Compound 111 was carried out to obtain 17.7 mg (yield 95%) of Compound 112 from Compound 110. HRMS (ESI) m / z: 1046.6139 [M+H] ＋ .

[0234] <Synthesis of Compound 113> To a solution of compound 111 (6.2 mg, 6.3 μmol) in dichloromethane (5 mL), (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexane-2-yl)ureido)pentanediate (6.2 mg, 13 μmol), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU) (5.0 mg, 13 μmol), and DIPEA (10 μL, 0.57 μmol) were added, and the mixture was stirred at room temperature for 26 hours. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 4.5 mg (yield: 49%, calculated from the amount of compound 113 obtained relative to the amount of compound 111). HRMS (ESI) m / z: 729.9404 [M+2H] ＋ .

[0235] Synthesis of Compound 114 To a solution of compound 112 (19.3 mg, 0.018 mmol) in dichloromethane (5 mL) were added (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanediate (17.6 mg, 0.036 mmol), EDC hydrochloride (6.9 mg, 0.036 mmol), HOAt (4.9 mg, 0.036 mmol), and triethylamine (5 μL, 0.036 mmol). The reaction mixture was stirred at room temperature for 6 hours, and then the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 15.6 mg (yield: 57%, calculated from the amount of compound 114 obtained relative to the amount of compound 112). HRMS (ESI) m / z: 758.4704 [M+2H] ＋ .

[0236] <Synthesis of Compound 115 (Octapa-1)> Compound 113 (11.4 mg, 7.8 μmol) was dissolved in trifluoroacetic acid (TFA) / H ２ The residue was dissolved in a mixture of 2 mL of 2H O / triisopropylsilane (95 / 2.5 / 2.5, 2 mL) and stirred at room temperature for 3 hours. After removing the solvent, the residue was purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) - 30 / 70 / 0.1 (30 min)], flow rate: 1 mL / min. Yield: 2.2 mg (yield: 27%, calculated from the amount of compound 115 obtained relative to the amount of compound 113). HRMS (ESI) m / z: 1066.4325 [M+H] ＋ .

[0237] Synthesis of Compound 116 (Neunpa-1) The same reaction as in the synthesis of Compound 115 was carried out to obtain 1.8 mg (43% yield) of Compound 116 from Compound 114. HRMS (ESI) m / z: 1123.4924 [M+H] ＋ .

[0238] <Synthesis of Compound 117> N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６ Compound 103 (42.3 mg, 0.055 mmol), EDC hydrochloride (21.1 mg, 0.11 mmol), HOAt (15.0 mg, 0.11 mmol), and triethylamine (15 μL, 0.11 mmol) were added to a solution of -[(4-methylphenyl)diphenylmethyl]-L-lysine (40.9 mg, 0.065 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 69.3 mg (91%, N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６(Calculated from the amount of substance of the obtained compound 117 relative to the amount of substance of -[(4-methylphenyl)diphenylmethyl]-L-lysine). HRMS (ESI) m / z: 1382.7418 [M+H] ＋ .

[0239] Synthesis of Compound 118: The same reaction as in the synthesis of Compound 117 was carried out to obtain 123 mg of Compound 118 (77% yield, calculated from the amount of Compound 118 relative to the amount of Compound 108) from Compound 108. HRMS (ESI) m / z: 1439.8029 [M+H] ＋ .

[0240] <Synthesis of Compound 119> Compound 117 (115 mg, 0.083 mmol) was dissolved in a mixture of piperidine (1 mL) and DMF (4 mL) and stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and H ２ After adding O, the organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (5 mL). 4-(4-iodophenyl)butanoic acid (49.3 mg, 0.17 mmol), EDC hydrochloride (32.6 mg, 0.17 mmol), HOAt (23.1 mg, 0.17 mmol), and triethylamine (20 μL, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 7 hours, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 62.4 mg (52%, calculated from the amount of compound 119 obtained relative to the amount of compound 117). HRMS (ESI) m / z: 1432.6529 [M+H] ＋ .

[0241] Synthesis of Compound 120: A reaction similar to that for the synthesis of Compound 119 was carried out to obtain 84.2 mg of Compound 120 (yield 66%, calculated from the amount of Compound 120 relative to the amount of Compound 118) from Compound 118. HRMS (ESI) m / z: 1489.7260 [M+H] ＋ .

[0242] Synthesis of Compound 121: Compound 119 (62.4 mg, 0.044 mmol) was dissolved in 1% TFA-containing dichloromethane (5 mL) and stirred at room temperature for 2 hours. After removing the solvent, the residue was dissolved in THF (5 mL), and succinic anhydride (8.1 mg, 0.088 mmol) and DIPEA (15 μL, 0.088 mmol) were added. The solution was stirred at room temperature for 4 hours, and the solvent was then removed. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 65 mg (100%, calculated from the amount of compound 121 obtained relative to the amount of compound 119). HRMS (ESI) m / z: 1276.5478 [M+H] ＋ .

[0243] Synthesis of Compound 122: The same reaction as in the synthesis of Compound 121 was carried out to obtain 39.1 mg of Compound 122 (yield 35%, calculated from the amount of Compound 122 relative to the amount of Compound 120) from Compound 120. HRMS (ESI) m / z: 1333.5464 [M+H] ＋ .

[0244] <Synthesis of Compound 123> To a solution of compound 121 (65 mg, 0.051 mmol) in dichloromethane (5 mL) were added (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanediate (37.3 mg, 0.077 mmol), EDC hydrochloride (19.2 mg, 0.10 mmol), HOAt (13.6 mg, 0.10 mmol), and triethylamine (15 μL, 0.10 mmol). The reaction mixture was stirred at room temperature for 5 hours, and then the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 54.3 mg (yield: 61%, calculated from the amount of compound 123 relative to the amount of compound 121). HRMS (ESI) m / z: 873.4248 [M+2H] ＋ .

[0245] Synthesis of Compound 124: The same reaction as in the synthesis of Compound 123 was carried out to obtain 22.3 mg of Compound 124 (yield 25%, calculated from the amount of Compound 124 relative to the amount of Compound 122) from Compound 122. HRMS (ESI) m / z: 902.4312 [M+2H] ＋ .

[0246] <Synthesis of Compound 125 (Octapa-2)> Compound 123 (9.6 mg, 6.6 μmol) was dissolved in TFA / H ２ The residue was dissolved in a mixture of 0 / triisopropylsilane (95 / 2.5 / 2.5, 1 mL) and stirred at room temperature for 2 hours. After removing the solvent, the residue was purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min)], flow rate: 1 mL / min. Yield: 1.3 mg (yield: 17%, calculated from the amount of compound 125 relative to the amount of compound 123). HRMS (ESI) m / z: 677.2144 [M+2H] ＋ .

[0247] Synthesis of Compound 126 (Neunpa-2) The same reaction as in the synthesis of Compound 125 was carried out to obtain 2.0 mg of Compound 126 (47% yield, calculated from the amount of Compound 126 relative to the amount of Compound 124) from Compound 124. HRMS (ESI) m / z: 705.74021 [M+2H] ＋ .

[0248] <Synthesis of Compound 127> N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６ A solution of -[(4-methylphenyl)diphenylmethyl]-L-lysine (625 mg, 1.0 mmol) in dichloromethane (20 mL) was added with tert-butyl trichloroacetimidate (437 mg, 2.0 mmol) and BF ３ ・OEt ２(20 μL, 0.16 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure. The residue was purified by medium pressure column chromatography (hexane / ethyl acetate). Yield: 322 mg (47%, N ２ -[(9H-fluoren-9-ylmethoxy)carbonyl]-N ６ (Calculated from the amount of substance of the obtained compound 127 relative to the amount of substance of -[(4-methylphenyl)diphenylmethyl]-L-lysine). １ H-NMR (400MHz, CDCl ３ ) δ7.71-7.69 (m, 2H), 7.56 (d, J = 7.2Hz, 2H), 7.46 (d, J = 8.1Hz, 4H), 7.35-7.3 0 (m, 4H), 7.26-7.21 (m, 6H), 7.15-7.11 (m, 2H), 7.04 (d, J = 8.1Hz, 2H), 5.38 ( d, J = 8.7Hz, 1H), 4.35 (d, J = 6.4Hz, 2H), 4.28-4.23 (m, 1H), 4.18 (t, J = 7.5Hz, 1H), 2.26 (s, 3H), 2.12-2.11 (m, 2H), 1.81-1.75 (m, 1H), 1.59-1.44 (m, 14H). MS (ESI) m / z: 681.4 [M+H] ＋ .

[0249] Synthesis of Compound 128 Compound 127 (200 mg, 0.47 mmol) was dissolved in 5% TFA-containing dichloromethane (10 mL) and stirred at room temperature for 3 hours. After removing the solvent, the residue was purified by medium-pressure column chromatography (methanol / chloroform). The resulting amine was dissolved in DMF (10 mL), and 4-(4-iodophenyl)butanoic acid (273 mg, 0.94 mmol), EDC hydrochloride (180 mg, 0.94 mmol), HOAt (123 mg, 0.94 mmol), and triethylamine (130 μL, 0.94 mmol) were added. The reaction mixture was stirred overnight at room temperature, and then the mixture was diluted with ethyl acetate and H ２ O was added. The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform).

[0250] Yield: 161 mg (yield: 50%, calculated from the amount of substance of the obtained compound 128 relative to the amount of substance of the compound 127). １ H-NMR (400MHz, CDCl ３ ) δ7.76 (d, J=7.5Hz, 2H), 7.60-7.53 (m, 4H), 7.39 (t, J=7.5Hz, 2H), 7.30 (t, J=7.5Hz, 2H), 6.92-6.86 (m, 2H), 4.40 -4.09 (m, 4H), 3.27-3.19 (m, 2H), 2.52 (t, J = 7.8Hz, 2H), 1.93-1.80 (m, 3H), 1.71-1.62 (m, 1H), 1.52-1.36 (m, 13H). MS (ESI) m / z: 697.2 [M+H] ＋ .

[0251] <Synthesis of Compound 129> Compound 128 (473 mg, 0.68 mmol) was dissolved in a mixture of piperidine (2 mL) and DMF (8 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and H ２ After adding 2H2O, the organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). The resulting amine was dissolved in DMF (10 mL), and 3,6,9-trioxaundecanediol acid (91.1 mg, 0.41 mmol), EDC hydrochloride (78.6 mg, 0.41 mmol), HOAt (55.8 mg, 0.41 mmol), and triethylamine (57 μL, 0.41 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours, and then the mixture was diluted with ethyl acetate and H2O. ２ O was added. The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform).

[0252] Yield: 87.9 mg (yield: 37%, calculated from the amount of substance of the obtained compound 129 relative to the amount of substance of the compound 128). １ H-NMR (400MHz, CD ３OD) δ7.58 (d, J=8.7Hz, 2H), 6.96 (d, J=7.5, 2H) 4.41-4.29 (m, 2H), 4.0 9-4.02 (m, 2H), 3.85-3.73 (m, 8H), 3.60 (q, J=7.2Hz, 2H), 3.35 (s, 2H) , 3.10 (t, J=4.0Hz, 2H), 2.55 (t, J=7.5Hz, 2H), 2.16-2.14 (m, 2H), 1.8 9-1.81 (m, 2H), 1.41 (s, 9H), 1.32-1.27 (m, 3H), 1.18 (t, J = 7.0Hz, 2H). MS (ESI) m / z: 701.2 [M+Na] ＋ .

[0253] <Synthesis of Compound 130> Compound 117 (400 mg, 0.29 mmol) was dissolved in a mixture of piperidine (1 mL) and DMF (4 mL) and stirred at room temperature for 2.5 hours. Ethyl acetate and H ２ After adding 2H2O, the organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). The resulting amine was dissolved in DMF (10 mL), and compound 129 (170 mg, 0.25 mmol), EDC hydrochloride (95.9 mg, 0.50 mmol), HOAt (68.1 mg, 0.50 mmol), and triethylamine (69 μL, 0.50 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and then the mixture was diluted with ethyl acetate and H2O. ２ O was added. The organic layer was dried over sodium sulfide and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 272 mg (yield: 60%, calculated from the amount of compound 130 obtained relative to the amount of compound 117). HRMS (ESI) m / z: 911.4302 [M+2H] ＋ .

[0254] Synthesis of Compound 131: Compound 130 (272 mg, 0.15 mmol) was dissolved in 1% TFA-containing dichloromethane (3 mL) and stirred at room temperature for 1.5 hours. After removing the solvent, the residue was dissolved in THF (5 mL), and succinic anhydride (30 mg, 0.30 mmol) and DIPEA (52 μL, 0.30 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. The residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 230 mg (92%, calculated from the amount of compound 131 obtained relative to the amount of compound 130). HRMS (ESI) m / z: 832.8701 [M+2H] ＋ .

[0255] <Synthesis of Compound 132> To a solution of compound 131 (186 mg, 0.11 mmol) in dichloromethane (5 mL), (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanediate (63.4 mg, 0.13 mmol), HBTU (83.4 mg, 0.22 mmol), and DIPEA (38 μL, 0.22 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure column chromatography (methanol / chloroform). Yield: 80.4 mg (yield: 34%, calculated from the amount of compound 132 obtained relative to the amount of compound 131). HRMS (ESI) m / z: 1068.0419 [M+2H] ＋ .

[0256] <Synthesis of Compound 133 (Octapa-3)> Compound 132 (10 mg, 4.7 μmol) was dissolved in TFA / H ２ The residue was dissolved in a mixture of 2.5MgO / triisopropylsilane (95 / 2.5 / 2.5, 2 mL) and stirred at room temperature overnight. After removing the solvent, the residue was purified by reversed-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２O / TFA [20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min)], flow rate: 1 mL / min. Yield: 2.3 mg (yield: 29%, calculated from the amount of compound 133 obtained relative to the amount of compound 132). HRMS (ESI) m / z: 843.2900 [M+2H] ＋ .

[0257] < １１１ Preparation of Radioactively Labeled Compounds by In Labeling (Examples 3-1 to 3-2, Comparative Example 2-1)> Three types of Octapa derivatives (Octapa-1 to -3) were each dissolved in acetate buffer (pH 5.5, 10 mM, 350 μL) [ １１１ In]InCl ３ The solution (100 μL) was mixed, and an aqueous solution (<10% DMSO, 10 μM, 50 μL) of the labeled precursor (compound 115, 25, or 33) was added. After standing at room temperature for 15 minutes, the reaction solution was purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -MS-II column (4.6 × 150 mm), mobile phase: MeCN / acetate buffer (pH 4.5, 10 mM) [10 / 90 (0 min) to 30 / 70 (30 min) or 20 / 80 (0 min) to 50 / 50 (30 min)], flow rate: 1 mL / min. Radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used for measuring radiochemical purity were the same as those for the purification described above.

[0258] As a result, the following three types of radiolabeled compounds were obtained with radiochemical yields of 55 to 93% and radiochemical purities of 99% or more. １１１ In]In-Octapa-1 Example 3-1: [ １１１ In]In-Octapa-2 Example 3-2: [ １１１ In] In-Octapa-3

[0259] < １１１ Preparation of Radioactively Labeled Compounds by In Labeling (Example 3-3, Comparative Example 2-2)> Two types of Neunpa derivatives (Neunpa-1 and -2) were dissolved in acetate buffer (pH 4.0, 10 mM, 350 μL) [ １１１ In]InCl ３The solution (100 μL) was mixed, and an aqueous solution of the labeled precursor (compound 116 or 26) (<10% DMSO, 10 μM, 50 μL) was added. After standing at room temperature for 15 minutes, the reaction solution was purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 30 / 70 / 0.1 (30 min) or 20 / 80 / 0.1 (0 min) to 50 / 50 / 0.1 (30 min)], flow rate: 1 mL / min. Radiochemical yield and radiochemical purity were measured in the same manner as described in Example 1-1. The HPLC conditions used to measure the radiochemical purity were the same as those for the purification described above.

[0260] As a result, the following two types of radiolabeled compounds were obtained with a radiochemical yield of 55 to 93% and a radiochemical purity of 99% or more. １１１ In]In-Neunpa-1 Example 3-3: [ １１１ In] In-Neunpa-2

[0261] <Binding evaluation using cultured cells> LNCaP cells and PC-3 cells cultured in the same manner as in Example 1-1 above were each cultured at 4.0 × 10 ５ The cells were seeded in a 12-well plate at 1000 cells / well and incubated at 37°C, 5% CO ２ The plate was then left to stand for 48 hours under a 5% CO atmosphere. The culture medium was removed, and 1 mL of an assay medium (RPMI 1640 medium containing 0.5% FBS) solution containing the radiolabeled compounds of Examples 3-1 to 3-3 or Comparative Examples 2-1 to 2-2 (37 kBq each) was added. Thereafter, the plate was placed at 37°C, 5% CO ２ For the inhibition experiment, the culture medium was removed, and then 1 mL of assay medium containing the radiolabeled compound and 2-(phosphonomethyl)pentanediol (2-PMPA) (PSMA inhibitor, final concentration 100 μM) was added. The plate was then incubated at 37°C, 5% CO ２The wells were then left to stand for 1 hour under reduced pressure. After removing the assay medium, each well was washed with assay medium (1 mL), and the cells were lysed with 1 N aqueous sodium hydroxide solution (200 μL x 2). The radioactivity of each cell lysate was measured using a gamma counter. Separately, the total protein concentration in the cell lysate was calculated using a BCA Protein Assay Kit manufactured by Thermo Fisher Scientific. The percentage of radioactivity in the sample relative to the amount of added radioactivity (%ID) was divided by the total protein amount (%ID / mg protein) for each sample. Data are expressed as mean ± standard deviation. A significant difference test was performed using Student's t-test and one-way analysis of variance (ANOVA) test with Dunnett's post-hoc test, with p<0.05 being considered to indicate a significant difference.

[0262] The results of the evaluation of binding to cultured cells are shown in Figure 11. Higher values ​​indicate greater amounts of radiolabeled compound present and higher accumulation of the compound. The radiolabeled compounds of Examples 3-1 to 3-3 and Comparative Examples 2-1 and 2-2 exhibited higher binding affinity to PSMA-positive LNCaP cells compared to PSMA-negative PC-3 cells, and this binding was significantly reduced by the addition of an excess amount of a PSMA inhibitor (2-PMPA). Thus, the radiolabeled compounds of each Example and Comparative Example were shown to specifically bind to PSMA-positive cells.

[0263] <Evaluation of binding to albumin> Binding to albumin was evaluated using PBS and human albumin in the same manner as in the above examples. The evaluation was carried out using the same experimental procedures and statistical methods as in Example 1-1, except that PBS solutions (37 kBq, 50 μL each) of the radiolabeled compounds of Examples 3-1 to 3-3 and Comparative Examples 2-1 to 2-2 were used.

[0264] The results are shown in Figure 12. Examples 3-1 to 3-3 ([ １１１ In] In-Octapa-2, [ １１１ In]In-Octapa-3 and [ １１１The radioactivity ratio of the eluate in the HSA solution using [In]In-Neunpa-2) was significantly higher than the radioactivity ratio of the eluate in PBS. １１１ In]In-Octapa-1 and [ １１１ The radioactivity percentage of the eluate in the HSA solution of [In]In-Neunpa-1) was low, similar to that in the case of PBS. These results demonstrate that the compounds and radiolabeled compounds used in Examples 3-1 to 3-3 have the ability to bind to albumin.

[0265] <Evaluation of Internal Radioactivity Distribution Using Tumor-Borne Mice> LNCaP tumor-bearing mice were prepared in the same manner as in Example 1-1, and a saline solution (259 kBq / 100 μL each) of each radiolabeled compound of Examples 3-1 to 3-3 or Comparative Examples 2-1 to 2-2 was administered via the tail vein (n=2 to 3). 1, 4, 24, 48, 96, and 192 hours after administration, the mice were euthanized. Blood and organs were then collected, and the organ mass and radioactivity were measured. The percentage of radioactivity (%ID) relative to the injected dose was divided by the blood mass or organ mass (g) and expressed as %ID / g. A higher %ID / g value indicates a higher amount of radiolabeled compound present and higher accumulation of the compound in the target organ.

[0266] The results (mean ± standard deviation, n = 2 to 3 for each) of the LNCaP tumor-implanted mice and each radiolabeled compound are shown in Tables 7 to 11 below and FIG. 13. It was confirmed that each of the radiolabeled compounds in Examples 3-1 to 3-3 had high blood retention and tumor accumulation, while exhibiting reduced kidney accumulation to a similar extent compared to those in Comparative Examples 2-1 and 2-2. This is indicative of the results of Example 3-1 ([ １１１ In]In-Octapa-2), Example 3-2 ([ １１１ In]In-Octapa-3) and Example 3-3 ([ １１１ This was particularly evident in [In]In-Neunpa-2).

[0267] Comparative Example 2-1 ([ １１１ In]In-Octapa-1; mean ± standard deviation, n = 3 for each, n = 2 for 192 time points only).

[0268]

[0269] Example 3-1 ([ １１１ In]In-Octapa-2; mean ± standard deviation, each n = 3).

[0270]

[0271] Example 3-2 ([ １１１ In]In-Octapa-3; mean ± standard deviation, each n = 3).

[0272]

[0273] Comparative Example 2-2 ([ １１１ In]In-Neunpa-1; mean ± standard deviation, n = 3 for each, n = 2 for 192 time points only).

[0274]

[0275] Example 3-3 ([ １１１ In] In-Neunpa-2; mean ± standard deviation, each n = 3).

[0276]

[0277] <SPECT / CT evaluation using tumor-implanted mice> Mice were obtained by simultaneous transplantation of tumors of LNCaP cells and PC-3 cells in the same manner as in Example 2, and then the mice were subjected to the SPECT / CT evaluation using the tumor-implanted mice in Example 3-1 ([ １１１ A saline solution (7.3 MBq, 150 μL) of [In]In-Octapa-2 was administered via the tail vein. 24 hours after administration, SPECT / CT was performed in the same manner as in Example 2, and the obtained images were reconstructed.

[0278] The results of SPECT / CT are shown in Figure 14. １１１ SPECT / CT imaging using In]In-Octapa-2 showed high radioactivity accumulation in the LNCaP tumor (solid arrow in the figure) 24 hours after administration, but almost no radioactivity signal was observed in the PC-3 tumor (broken arrow in the figure). Radioactivity accumulation was also observed in the kidney (circle in the figure). From these results, １１１It was shown that [In]In-Octapa-2 can clearly visualize tumors with high PSMA expression.

[0279] Examples 4-1 to 4-2 In Examples 4-1 to 4-2, a compound (PSMA-NAT-DA1) was synthesized that contains (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid (a structure in which a is 2 and b is 4 in the above formula (C1)) as a binding moiety to the PSMA molecule, and has a chemical structure that contains a binding moiety to the PSMA molecule and an albumin binding moiety in a linear arrangement via a chelating moiety, as shown in the above general formula (1). Next, a radioactive metal was added to PSMA-NAT-DA1. １１１ In ions or ２２５ Radiolabeled compounds were obtained, each coordinated with an Ac ion. Details are shown below. PSMA-NAT-DA1 contains a chelating moiety, a binding moiety for the PSMA molecule, and an albumin-binding moiety in its structure. In PSMA-NAT-DA1, the chelating moiety and the binding moiety for the PSMA molecule are indirectly bound via chemical structures derived from trans-4-aminocyclohexane-1-carboxylic acid and naphthylglycine, and the chelating moiety and the atomic group containing the albumin-binding moiety are indirectly bound via a linker structure derived from lysine.

[0280] The synthetic routes in Examples 4-1 and 4-2 are outlined below.

[0281] [Rule 26, 30.05.2022]

[0282] [Rule 26, 30.05.2022]

[0283] (1) Synthesis of PSMA-NAT-DA1 PSMA-NAT-DA1 was synthesized according to the following procedure.

[0284] <Synthesis of Compounds 202 and 203> Compound 1 was synthesized in the same manner as described in Example 1-1. Compound 202 was synthesized in four steps from N2-[(9H-fluoren-9-ylmethoxy)carbonyl]-N6-[(4-methylphenyl)diphenylmethyl]-L-lysine according to a previously reported method (Chem Commun. 2021, 57, 6432-6435). To a solution of compound 1 (131 mg, 0.17 mmol) in N,N-dimethylformamide (DMF) (0.4 mL), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU) (72.4 mg, 0.17 mmol) and N,N-diisopropylethylamine (DIPEA) (95 μL, 0.17 mmol) were added under ice-cooling and stirred for 15 minutes. Compound 202 (66.8 mg, 0.14 mmol) was added, and the mixture was stirred at room temperature for 5 days. The solution was purified by reverse-phase HPLC to obtain compound 203. Purification conditions: Cosmosil 5C １８ -AR-II column (10 x 250 mm), mobile phase: MeCN / H ２ O [3 / 7 (0 minutes) to 9 / 1 (60 minutes)], flow rate: 5 mL / min. MS (ESI): m / z1230 [M+H] ＋ .

[0285] <Synthesis of Compound 204> Compound 204 was obtained in nine steps from Fmoc-Lys(ivDde)-OH with reference to a previously reported method (J. Med. Chem. 2016, 59, 1761-1775, Mol. Pharm. 2018, 15, 3502-3511). In the chemical formula of compound 204, the chemical structure represented by the symbol Gp indicates a resin.

[0286] Synthesis of Compound 205: Compound 203 (49.6 mg, 0.044 mmol), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU) (16.7 mg, 0.44 mmol), and DIPEA (188 μL, 0.44 mmol) were added to resin-bound compound 204, and the mixture was shaken overnight in DMF. After washing with DMF, the mixture was washed with trifluoroacetic acid (TFA) / triisopropylsilane / H ２ 0 (95:2.5:2.5, 2 mL) was added and the mixture was shaken for 3 hours. The solution was then purified by reversed-phase HPLC under the following conditions to obtain the target compound 205 (PSMA-NAT-DA1). Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 250 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 min) to 90 / 10 / 0.1 (40 min)], flow rate: 5 mL / min. Yield: 11 mg (16%, calculated from the amount of compound 205 obtained relative to the amount of compound 203). MS (ESI) m / z: MS (ESI) m / z 793 [M+2H] ２＋ .

[0287] (2) 111 In labeling (Example 4-1) The desired radiolabeled compound ([ １１１ In]In-PSMA-NAT-DA1) was obtained.

[0288] 2-morpholinoethanesulfonic acid buffer solution (0.1 M, pH 5.7, 150 μL) １１１ In]InCl ３ The solution (3.7 MBq, 100 μL) and a dimethyl sulfoxide solution of Compound 205 (1 μg / μL, 5 μL) were added, and the mixture was left to stand at 90° C. for 30 minutes. Thereafter, the reaction solution was purified by reversed-phase HPLC to obtain the radiolabeled compound ([ １１１ In]In-PSMA-NAT-DA1) was obtained.

[0289] [Rule 26, 30.05.2022]

[0290] The obtained １１１The radiochemical purity of [In]In-PSMA-NAT-DA1 was determined by the following method: １１１ A portion of the HPLC fraction of In]In-PSMA-NAT-DA1 was analyzed again under the following HPLC conditions, and the [ １１１ The percentage of the area value of [In]In-PSMA-NAT-DA1 was defined as the radiochemical purity (%).

[0291] The radiochemical yield was measured in the same manner as described in Example 1-1. The HPLC conditions used to measure the radiochemical purity are shown below. As a result, the radiochemical yield was 9% and the radiochemical purity was 95% or more. When the same synthesis was carried out again, the radiochemical yield improved to 60%. Purification conditions: Cosmosil 5C １８ -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H ２ O / TFA [10 / 90 / 0.1 (0 minutes) to 90 / 10 / 0.1 (40 minutes)], flow rate: 1 mL / min.

[0292] (3) ２２５ Ac Labeling (Example 4-2) The desired radiolabeled compound ([ ２２５ Ac]Ac-PSMA-NAT-DA1).

[0293] [Replenishment based on Rule 26 30.05.2022] The solution was dispensed into 1.5 mL Protein LoBind Tubes (manufactured by EPPENDORF) [ ２２５ Ac]AcCl ３ To a 0.2 mol / L hydrochloric acid solution (1.0 MBq, 20 μL) of the above, 0.1 M acetic acid-ammonium acetate buffer (pH 5.5, 170 μL) and a DMSO solution of PSMA-NAT-DA1 (2.0 mM / L, 10 μL) were added, and the mixture was left to stand at 70°C for 1 hour. ２ 0 (0.8 mL) was added, and the solution was passed through an Oasis HLB Light column. ２ After passing 10 mL of ethanol through the column, 70% EtOH (0.5 mL) was passed through the column to obtain the desired radiolabeled compound ([ ２２５ Ac]Ac-PSMA-NAT-DA1) 70% ethanol solution was obtained.

[0294] The radiochemical yield was measured by the following method. The radioactivity of the obtained radiolabeled compound was measured by a gamma ray spectrometer. ２２５ Ac]AcCl ３ The percentage of the radioactivity in the solution was taken as the radiochemical yield (%).

[0295] The radiochemical purity of the obtained radiolabeled compound was measured by the following method. A portion of the solution of the radiolabeled compound was purified by TLC (iTLC-SG, mobile phase: H ２ The radiochemical purity (%) was calculated as the percentage of the area value of the radiolabeled compound relative to the area values ​​of all detected peaks. As a result, the radiochemical yield was 35% and the radiochemical purity was 86%.

[0296] <Binding evaluation using cultured cells> LNCaP cells and PC-3 cells cultured in the same manner as in Example 1-1 above were each cultured at 4.0 × 10 ５ The cells were seeded in a 12-well plate at 1000 cells / well and incubated at 37°C, 5% CO ２ The plate was left standing for 48 hours under the following conditions. １１１ An assay medium (RPMI 1640 medium containing 0.5% FBS) solution (1 mL) containing [In]In-PSMA-NAT-DA1 (8.5 kBq) was added to the plate. Then, the plate was incubated at 37°C, 5% CO ２ In the inhibition experiment, the culture medium was removed and the １１１ A solution of [In]In-PSMA-NAT-DA1 (37 kBq) and 2-(phosphonomethyl)pentanediol (2-PMPA) (PSMA inhibitor, final concentration 100 μM) in assay medium (1 mL) was added. The plate was then incubated at 37°C, 5% CO ２ The mixture was left standing under reduced pressure for 1 hour.

[0297] After removing the assay medium, each well was washed with assay medium (1 mL) containing neither radiolabeled compound nor 2-PMPA, and the cells were lysed with 1 N aqueous sodium hydroxide solution (200 μL × 2). The radioactivity of the assay medium and cell lysate was measured using a gamma counter. Separately, the total protein concentration in the cell lysate was calculated using a BCA Protein Assay Kit manufactured by Thermo Fisher Scientific. The percentage of the radioactivity in the sample relative to the amount of added radioactivity (% ID) was divided by the total protein amount (% ID / mg protein) for each sample. Data are expressed as mean ± standard deviation. A significant difference test was performed using Student's t-test and one-way analysis of variance (ANOVA) test with Dunnett's post-hoc test, with p<0.05 being considered to indicate a significant difference.

[0298] The results of the evaluation of binding to cultured cells are shown in Figure 15. A higher value indicates a greater amount of radiolabeled compound present and a higher accumulation of the compound. １１１ In]In-PSMA-NAT-DA1 showed higher binding affinity to LNCaP cells compared to PC-3 cells, and this binding was significantly reduced by the addition of an excess amount of a PSMA inhibitor (2-PMPA). １１１ It was shown that In]In-PSMA-NAT-DA1 specifically binds to cells with high PSMA expression.

[0299] <Evaluation of binding to albumin> １１１A solution of [In]In-PSMA-NAT-DA1 in phosphate-buffered saline (PBS) (37 kBq, 50 μL) was added to 200 μL of a PBS solution of human serum albumin (HSA) (45 mg / mL), mouse plasma, human plasma, or PBS, and the mixture was allowed to stand at 37°C for 10 minutes. The reaction mixture was then loaded onto a spin column (Sephadex G-50, Cytiva) and centrifuged at 1500 × g for 2 minutes at 4°C. After separation, the radioactivity of the column and eluate was measured using a gamma counter. Data are expressed as mean ± standard deviation. A significant difference test was performed using Student's t-test and one-way analysis of variance (ANOVA) test with Dunnett's post-hoc test, with p<0.05 being considered to indicate a significant difference.

[0300] The results of the evaluation of binding to albumin are shown in Figure 16. A higher value indicates a higher binding affinity to albumin. When the compound to be evaluated binds to albumin and forms a complex, it passes through the column due to the increase in molecular size, but when it does not bind to albumin, it is thought to be retained in the gel inside the column. １１１ When [In]In-PSMA-NAT-DA1 was allowed to stand in PBS and then applied to the column, no significant radioactivity was observed in the eluate. On the other hand, when it was allowed to stand in mouse plasma, human plasma, and HSA solution, [ １１１ The radioactivity in the eluate of In]In-PSMA-NAT-DA1 was significantly higher, １１１ These results suggest that [In]In-PSMA-NAT-DA1 binds to plasma albumin.

[0301] <Evaluation of radioactivity distribution in the body using LNCaP or PC-3 tumor-bearing mice> Animal experiments were conducted in accordance with the guidelines of the Kyoto University Animal Experiment Committee. ｓｃｉｄ Mice were purchased from CLEA Japan, Inc. The animals were housed under a 12-hour / 12-hour day / night cycle and were provided with food and water ad libitum. LNCaP cells (4.3 × 10 cells) were cultured in a mixture of PBS and Corning Life Sciences Matrigel (1:1, 150 μL). ６cells / mouse) or PC-3 cells (3.3 × 10 ６ cells / mouse) were suspended and, under isoflurane anesthesia, CB17 / IcrJcl-Prkdc ｓｃｉｄ The tumor was subcutaneously implanted into the right shoulder of the mice. The mice were then housed for 40 to 60 days. １１１ A saline solution of [In]In-PSMA-NAT-DA1 (259 kBq, 100 μL) was administered via the tail vein (n = 3 for each). Mice were euthanized 1, 4, 24, 48, 96, and 192 hours after administration. Blood and organs were then collected, and their weights and radioactivity were measured.

[0302] LNCaP tumor-implanted mice １１１ In]In-PSMA-NAT-DA1 was administered, and the pharmacokinetics (% ID / g) was evaluated. The results are shown in Table 12 (mean ± standard deviation, n = 3).

[0303]

[0304] [ １１１ In]In-PSMA-NAT-DA1 showed high accumulation in LNCaP tumors (23.0-131.6% ID / g 1-48 hours after administration). It also showed retention in the blood (12.3% ID / g 48 hours after administration), and the tumor / kidney ratio exceeded 1 24 hours after administration. These results suggest that [ １１１ It was revealed that In]In-PSMA-NAT-DA1 has high accumulation in tumors with high PSMA expression.

[0305] PC-3 tumor-implanted mice １１１ In]In-PSMA-NAT-DA1 was administered, and the pharmacokinetics (% ID / g) was evaluated. The results are shown in Table 13 (mean ± standard deviation, n = 3).

[0306]

[0307] [ １１１ The accumulation of [In]In-PSMA-NAT-DA1 in PC-3 tumors was significantly lower than that in LNCaP tumors at the same time point, demonstrating that the radiolabeled compound selectively accumulates in PSMA-positive tumors.

[0308] <SPECT / CT using LNCaP tumor-implanted mice> LNCaP tumor-implanted mice prepared by the method described above were subjected to [ １１１ A saline solution of [In]In-PSMA-NAT-DA1 (1.57-2.59 MBq, 150 μL) was administered via the tail vein. SPECT / CT was performed using a Gamma Medica-Ideas FX3300 preclinical imaging system 24, 48, and 96 hours after administration. Images were taken under isoflurane anesthesia using a 1.0 mm pinhole collimator with a 35 mm rotation radius, 70 seconds projection time, and 32 projections. After SPECT, CT (tube voltage: 60 kV, tube current: 350 μA) was performed. The SPECT projection data was subjected to image reconstruction using the three-dimensional ordered subset expectation maximization method (8 subsets, 5 iterations).

[0309] The results of SPECT / CT are shown in Figure 17. In the figure, the area indicated by the arrow is the location of the tumor, and the area indicated by the circle is the location of the kidney. The higher the SUV, the higher the radioactivity accumulation. In this SPECT / CT imaging, significant radioactivity accumulation was observed in the LNCaP tumor (arrow in the figure) 24 and 48 hours after administration. Radioactivity accumulation was also observed in the kidney (solid circle in the figure) 24 and 48 hours after administration, but was hardly detected 96 hours after administration (dashed circle in the figure). From these results, [ １１１ In]In-PSMA-NAT-DA1 can clearly visualize tumors with high PSMA expression by SPECT, and １１１ In]In-PSMA-DB.

Claims

1. A 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, wherein the first atomic group and the second atomic group are bound via the chelating moiety.

2. The compound according to claim 1, which is represented by the following general formula (1): (In formula (1), A １ is a chelating moiety capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding moiety, C is an atomic group containing a binding moiety to a PSMA molecule, and L ａ is a linker structure, and L ｂ Is L ａ m and n are each independently 0 or 1; B or L ａ A １ and C or L ｂ is B or L ａ A １ at a site different from the site that binds to A １ is bonded to 3. The compound according to claim 1 or 2, wherein in formula (1), C is represented by the following formula (C1): (In formula (C1), the portion indicated by the wavy line is A in formula (1). １ or L ｂ and a and b are each independently an integer of 1 or more and 7 or less.

4. In the formula (1), A １ has a cyclic structure, and the cyclic structure has two or more nitrogen atoms, and each nitrogen atom is connected via two or more adjacent carbon atoms, or １ has a chain structure having two or more nitrogen atoms, each nitrogen atom being connected via two or more adjacent carbon atoms, １ has a nitrogen-bonded atomic group directly bonded to a nitrogen atom constituting the cyclic structure or the chain structure, the nitrogen-bonded atomic group includes one or more of a carboxy group, a phosphate group, an amide group, a benzene ring, and a pyridine ring, and when B is bonded to the nitrogen-bonded atomic group, C is bonded to the nitrogen-bonded atomic group other than the atomic group to which B is bonded.

5. In the formula (1), A １ The compound according to any one of claims 1 to 4, wherein is DOTA, HOPO, Octapa, Macropa, or a derivative thereof.

6. The compound according to any one of claims 1 to 5, wherein in formula (1), the albumin binding moiety included in the first atomic group has a structure derived from one or more of gamma glutamic acid, substituted or unsubstituted phenylbutyric acid, lipid, hematin, bilirubin, clofibric acid, clofibrate, carotenoid, a compound having a steroid skeleton, a compound having an ibuprofen skeleton, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon having from 13 to 20 carbon atoms, cyanine dye, a dye having a sulfonic acid group, diazo dye, pentamethine cyanine dye, blue dextran, bromocresol green, Evans blue, and derivatives thereof, or is an antibody or peptide capable of binding to albumin.

7. The compound according to any one of claims 1 to 6, wherein in formula (1), the albumin binding moiety contained in the first atomic group has a structure represented by the following formula (B1) or (B2): (In formula (B1), R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, and the portion indicated by the wavy line is A in formula (1). １ or L ａ In formula (B2), R b1 Or R b11 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, and the portion indicated by the wavy line is A in the formula (1). １ or L ａ It is the bond between 8. A compound represented by the following general formula (2): (In formula (2), A ２ is a chelating moiety capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding moiety, and C is an atomic group containing a binding moiety to a PSMA molecule; ２ is Neunpa or Octapa or a derivative thereof, L ｃ is a linker structure, and A ２ When is Octapa, L ｃ contains a polyethylene glycol structure.) 9. The compound according to claim 8, wherein in formula (2), B is represented by the following formula (B1) and C is represented by the following formula (C1). (In formula (C1), the part indicated by the wavy line is L in formula (2) ｃ and a and b are each independently an integer of 1 or more and 7 or less.

10. A radiolabeled compound comprising the compound according to any one of claims 1 to 9 coordinated to a radioactive metal ion.

11. The radioactive metal is 68 Ga, 64 Cu, 67 Cu, 89 Zr, 90 Y, 99m Tc, 111 In, 177 Lu, 186 Re, 188 Re or 225 The radiolabeled compound of claim 10, which is Ac.

12. A radiopharmaceutical composition containing the radiolabeled compound according to claim 10 or 11 as an active ingredient.

13. A method for producing a radiolabeled compound, comprising coordinating the compound according to any one of claims 1 to 9 with a radioactive metal ion to obtain a radiolabeled compound.

14. A method for producing a radiolabeled compound according to claim 13, which uses the compound represented by the following general formula (1S): (In formula (1S), A １ is a chelating moiety capable of coordinating with a radioactive metal ion, C is an atomic group containing a binding site for a PSMA molecule, and L ａ is a linker structure, and L ｂ Is L ａ m and n are each independently 0 or 1; and R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms.

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