Compounds and radiolabeled compounds

Abstract

To provide compounds and radiolabeled compounds that can achieve both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly in the kidneys. [Solution] The compound of the present invention, when viewed macroscopically in terms of its chemical structure, has a chelate moiety located at the center of the structure, with an atomic group including an albumin binding moiety bonded to one side of the chelate moiety, and an atomic group including a target molecule binding moiety bonded to the other side of the chelate moiety. The chelate moiety may preferably be DOTA or a derivative thereof. The target molecule binding moiety may preferably have a structure that binds to a target molecule expressed in cancer tissue. The present invention also provides a radiolabeled compound in which the compound is coordinated to a radioactive metal ion.

Description

[Technical Field]

[0001] This invention relates to compounds and radiolabeled compounds. [Background technology]

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

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

[0004] Patent Document 2 describes a derivative having a structure derived from Evans blue as an albumin-binding site. This derivative has a chelate portion for chelating radioactive metals and a peptide or the like for binding to a target molecule in its structure, and is described as being usable as a radiotherapy agent and imaging agent.

[0005] Furthermore, Patent Document 3 describes a PSMA inhibitor that can bind to albumin. This inhibitor, like Patent Document 1, is also described as being able to target and bind to PSMA and be used for the detection and treatment of prostate cancer. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2019 / 075583 Brochure [Patent Document 2] International Publication No. 2017 / 196806 Pamphlet [Patent Document 3] International Publication No. 2018 / 098390 Brochure [Overview of the Initiative]

[0007] To improve specific accumulation in target tissues and sites, and reduce accumulation in non-target tissues and sites, controlling pharmacokinetics such as blood retention is crucial. One way to effectively control pharmacokinetics is to optimize the chemical structure. Generally, compounds with small molecular weights have poor blood retention, which can result in insufficient accumulation in target tissues or unintended accumulation in normal tissues. Furthermore, the compounds described in Patent Documents 1 to 3 show a high degree of nonspecific accumulation in the kidneys, indicating room for improvement in this respect.

[0008] Therefore, the present invention relates to compounds and radiolabeled compounds that can achieve both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly reduced accumulation in the kidneys.

[0009] The present invention provides a compound represented by the following general formula (1). [ka] (In formula (1), A is a chelate portion that can coordinate with a radioactive metal, B is an atomic group containing an albumin binding portion, and C is an atomic group containing a target molecule binding portion.) B is attached to any part of A, C is bound to A at a site different from the site where B is bound to A.

[0010] Furthermore, the present invention provides a radiolabeled compound in which an ion of a radioactive metal is coordinated to the aforementioned compound. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 is a graph showing the results of the internal radioactivity distribution experiment for the examples and comparative examples. [Figure 2] Figure 2 shows the SPECT / CT images in evaluation 5. [Figure 3] Figure 3 shows the SPECT / CT images in evaluation 6. [Figure 4] Figure 4 is a graph showing the results of cell binding experiments in Example 5-1 ([111In]In-PSMA-DA1) and Comparative Example 2-1 ([111In]In-PSMA-DB). [Figure 5] Figure 5 is a graph showing the results of albumin binding experiments with [111In]In-PSMA-DA1 and [111In]In-PSMA-DB. [Figure 6] Figure 6 is a graph showing the results of experiments on the distribution of radioactivity in the body using [111In]In-PSMA-DA1 and [111In]In-PSMA-DB. [Figure 7] Figure 7 shows SPECT / CT images of [111In]In-PSMA-DA1 and [111In]In-PSMA-DB. [Figure 8] Figure 8 is a graph showing the changes in tumor volume and mouse body weight in Example 5-2 ([90Y]Y-PSMA-DA1) and Comparative Example 2-2 ([90Y]Y-PSMA-DB). [Figure 9] Figure 9 is a graph showing the changes in tumor volume and mouse body weight in Example 5-3 ([225Ac]Ac-PSMA-DA1) and Comparative Example 2-3 ([225Ac]Ac-PSMA-DB). [Figure 10] Figure 10 is a graph showing the results of cell binding experiments with E4DA1 and E4D. [Figure 11] Figure 11 is a graph showing the results of experiments on the distribution of radioactivity within the body in E4DA1 and E4D. [Figure 12] Figure 12 shows SPECT / CT images from Example 6 ([111In]In-E4DA1) and Comparative Example 3 ([111In]IIn-E4D). [Figure 13] Figure 13 is an HPLC chart showing the results of plasma stability in Example 7 ([111In]In-PtDA). [Figure 14] Figure 14 is a graph showing the results of cell binding experiments with [111In]In-PtDA. [Figure 15] Figure 15 is a graph showing the results of albumin binding experiments with [111In]In-PtDA. [Figure 16] Figure 16 shows SPECT / CT images in [111In]In-PtDA. [Modes for carrying out the invention]

[0012] 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 "T~U[V]" is written (T and U are arbitrary numbers, and [V] is a unit), it means "T[V] or more and U[V] or less" unless otherwise specified. Also, if a chiral carbon atom is present in the structure, unless otherwise specified, it may be in an S configuration or an R configuration independently.

[0013] The compound of the present invention comprises, in its structure, a chelate portion capable of coordinating with radioactive metal ions, an atomic group containing an albumin-binding portion having a chemical structure capable of binding to albumin, and an atomic group containing a target molecule-binding portion having a chemical structure capable of binding to a target molecule. Having such a chemical structure, the radiolabeled compound obtained by coordinating radioactive metal ions to the compound of the present invention exhibits both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly the kidneys. The compound of the present invention is a precursor compound used for labeling with radioactive isotopes such as radioactive metals, i.e., preferably a labeling precursor. A description of radioactive metals will be given later.

[0014] The compound of the present invention is preferably represented by the following general formula (1). In other words, when the chemical structure of the compound is viewed macroscopically, it is preferable that the chelate portion (represented by the symbol A in general formula (1)) is located in the center of the structure, and that the atomic group containing the albumin binding portion (represented by the symbol B in general formula (1)) and the atomic group containing the target molecule binding portion (represented by the symbol C in general formula (1)) are arranged via the chelate portion.

[0015] Furthermore, it is more preferable that the atomic group containing the albumin binding site is bonded to one side of the chelate portion, and the atomic group containing the target molecule binding site is bonded to the other side of the chelate portion, and it is even more preferable that they are arranged substantially linearly. The "one side" and "other side" of the chelate portion refer to one side and the other side of the molecular structure when the molecular structure is virtually divided along the molecular symmetry plane of the chelate portion, and when the atomic group containing the albumin binding site and the target molecule binding site are in plane-symmetric positions, they are said to be "arranged substantially linearly".

[0016] [ka]

[0017] In formula (1), A is a chelate moiety capable of coordinating with radioactive metal ions, B is an atomic group containing an albumin binding moiety, and C is an atomic group containing a target molecule binding moiety. In formula (1), B is preferably bonded to any part of A. In formula (1), it is preferable that C is bound to A at a site different from the site where B is bound to A.

[0018] When the compound of the present invention is used as a radiolabeled compound, it is preferable that A in formula (1) has a cyclic structure, and that the cyclic structure has two or more nitrogen atoms, with each nitrogen atom being connected separated by two or more adjacent carbon atoms, from the viewpoint of achieving a high level of both improved accumulation in target tissue and reduced accumulation in non-target tissue, particularly the kidney.

[0019] If A has a cyclic structure, the cyclic structure may consist only of nitrogen atoms and carbon atoms, or it may contain 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 ring structure. Furthermore, if A has a chain-like structure, the bonds between carbon atoms in the chain-like structure may be broken by nitrogen atoms. The bonds between carbon atoms in the chain-like structure may be chain-like or may form a ring structure.

[0020] Furthermore, if A has a cyclic or chain-like structure, it is preferable that A has a nitrogen-bonding atomic group that is directly bonded to the nitrogen atoms constituting the cyclic or chain-like structure. Specific examples of the nitrogen-bonding atomic group include an atomic group containing one or more of the following: a carboxyl group, a phosphate group, an amide group, a benzene ring, and a pyridine ring, and it is even more preferable that the atomic group is in a chain-like structure. Furthermore, if A has a cyclic or chain structure, and B is bonded to any site on A, and C is bonded to any site on A different from the site on which B is bonded, then if B is bonded to the nitrogen-bonding atomic group described above, it is preferable that C is bonded to a site other than the nitrogen-bonding atomic group to which B is bonded.

[0021] Specifically, the chelate portion that can coordinate with the radioactive metal represented by the symbol A in formula (1) preferably has a structure derived from a compound represented by any one of the following formulas (A1) to (A9), and more preferably has a structure derived from a compound represented by the following formula (A1). In other words, the compound of the present invention is preferably a derivative of a compound represented by any one of the following formulas (A1) to (A9), and more preferably a derivative of a compound represented by the following formula (A1). These structures can be appropriately selected depending on the type of radioactive metal described later. Regardless of which structure the chelate portion has, it is possible to achieve both improved accumulation in target tissue and reduced accumulation in non-target tissues, particularly the kidney.

[0022] In formula (1), the chelate portion represented by the symbol A may be derived from, for example, the following compounds, but is not limited to these and is applicable. · 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(acetamidemethylene)phosphonic acid (DOTA-A-AMP) • Tetraazacyclododecanedimethanphosphonate (DO2P) α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetratetraacetic acid (DOTAGA) · 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) • 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid (TETPA) ·N,N',N”,N'”-Tetra(1,2-dihydro-1-hydroxy-2-oxopyridine-6-carbonyl)-1,5,10,14-tetraazatetradodecane(1,2-HOPO) · 1,4,7,10,13-Pentazacyclopentadodecane-N,N',N”,N'”,N””-Pentaacetate (PEPA) • Ethylenediaminetetraacetic acid (EDTA) ·6,6'-((ethane-1,2-diylbis((carboxymethyl)azandiyl))bis(methylene))dipicolinic acid (H4octapa) ·6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(-methylene))dipicolinic acid (H2bispa2) ·1,2-[{6-(carboxy)-pyridine-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)pyridine-2-yl]-methyl-1,2-diaminoethane (H6phospa) ·6,6'-(((((4-Isothiacyanate phenethyl)azandiyl)bis(ethane-2,1-diyl))bis((carboxymethyl)azandiyl))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) · 2-[4,7-Bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid (NOTA)

[0023]

Chem.

[0024] In formula (A1), R 11 , R 12 , R 13 and R 14 are each independently one of the groups consisting of -(CH2) p COOH, -(CH2) p C5H5N, -(CH2) p PO3H2, -(CH2) p CONH2, -(CHCOOH)(CH2) p COOH, and p is an integer from 0 to 3 inclusive.

[0025] 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.

[0026] 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 and optionally containing a nitrogen atom or an oxygen atom, and R 35 is a hydrogen atom, a carboxy group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0027] In formula (A4), R 41 , R 42 , R 43 and R 44 Each of these is an atomic group that independently has a hydrogen atom and 2 to 10 carbon atoms, and may also contain a nitrogen atom or an oxygen atom, R 45 This is a hydrogen atom, a carboxyl group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0028] In formula (A5), R 48 and R 49 Each of these is an atomic group that independently has a hydrogen atom and 2 to 10 carbon atoms, and may also contain a nitrogen atom or an oxygen atom.

[0029] In formula (A6), R 51 , R 52 , R 53 , R 54 and R 55 Each of these is an atomic group that independently has a hydrogen atom and 2 to 10 carbon atoms, and may also contain a nitrogen atom or an oxygen atom.

[0030] In formula (A7), R 61 , R 62 , R 63 , R 64 , R 65 and R 66 Each of these is an atomic group that independently has a hydrogen atom and 2 to 10 carbon atoms, and may also contain a nitrogen atom or an oxygen atom, R 67 This is a hydrogen atom, a carboxyl group, or a carboxyalkyl group having 2 or 3 carbon atoms.

[0031] [ka]

[0032] In formula (A8), R 71 , R 72 and R 73Each of these is an atomic group that independently has a hydrogen atom and 2 to 10 carbon atoms, and may also contain a nitrogen atom or an oxygen atom.

[0033] In formula (A9), R 81 and R 82 Each of these is independently an alkyl group having 1 to 5 carbon atoms, and the terminal end of the alkyl group may be substituted with a pyridyl group substituted with one or more carboxyl groups, R 87 R is a hydroxyl group or a carbonyl group, 83 and R 84 R is a substituted or unsubstituted pyridinyl group. 85 and R 86 These are, independently, -COO-R a And R a It is an alkyl group having 1 to 5 carbon atoms.

[0034] Specific structures represented by equation (A1) include, for example, the structures represented by the following equations (A1-1) to (A1-7).

[0035] [ka]

[0036] [ka]

[0037] [ka]

[0038] Examples of specific structures represented by equation (A2) include those represented by the following equations (A2-1) to (A2-2).

[0039] [ka]

[0040] Examples of specific structures represented by equation (A3) include those shown in equations (A3-1) to (A3-7) below.

[0041] [ka]

[0042] [ka]

[0043] Specific structures represented by equation (A4) include those shown in equations (A4-1) to (A4-2) below.

[0044] [ka]

[0045] Specific structures represented by equation (A5) include, for example, the structures represented by the following equations (A5-1) to (A5-3).

[0046] [ka]

[0047] A specific structure represented by equation (A6) is, for example, the structure represented by equation (A6-1) below.

[0048] [ka]

[0049] Specific structures represented by equation (A7) include, for example, the structures represented by the following equations (A7-1) to (A7-2).

[0050] [ka]

[0051] Specific structures represented by equation (A8) include, for example, the structures represented by the following equations (A8-1) to (A8-3).

[0052] [ka]

[0053] Specific structures represented by equation (A9) include, for example, the structures represented by the following equations (A9-1) to (A9-4).

[0054] [ka]

[0055] In formula (1), the part represented by the symbol B is an atomic group containing an albumin-binding site, which has an affinity for albumin, preferably serum albumin, and more preferably human serum albumin, and is a chemical structure that can reversibly bind to said albumin. The inclusion of such a structure in the compound of the present invention makes it possible to increase its retention in the blood while reducing its accumulation in the kidneys when the compound is labeled with a radioactive metal and administered to a living organism.

[0056] In detail, compounds containing an albumin-binding site in their molecule readily bind to albumin in the blood. Once bound to albumin, the compound is no longer subjected to glomerular filtration in the kidney, thus reducing its transfer to the kidneys and urine, and improving its retention in the blood. As a result, accumulation in normal tissues such as the kidneys decreases, further enhancing the transferability of the compound to target tissues such as tumor tissue. When a compound is used in which, when viewed macroscopically in terms of its chemical structure, the atomic group containing the albumin binding site and the atomic group containing the target molecule binding site are arranged via a chelate, an appropriate distance can be secured between the albumin binding site and the target molecule binding site, thereby achieving both affinity to albumin and affinity to the target molecule. In particular, since the albumin binding site is located at one structural end of the compound of the present invention and the target molecule binding site is located at the other structural end of the compound of the present invention, a sufficient distance can be secured between the albumin binding site and the target molecule binding site, which is even more advantageous in that it is possible to achieve a high level of both affinity to albumin and affinity to the target molecule.

[0057] In formula (1), the structure of the albumin-binding portion may be, for example, γ-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 hydrocarbons having 13 to 20 carbon atoms and being saturated or unsaturated, cyanine dyes, dyes having sulfonic acid groups, diazo dyes, pentamethine cyanine dyes, blue dextran, bromocresol green, and Evans blue and their derivatives, or structures derived from one or more of the structures described in International Publication No. 2005 / 117984, International Publication No. 2010 / 127336, or International Publication No. 2010 / 172844. In addition to or instead of the above, an antibody or peptide capable of binding to albumin (for example, the peptide described in International Publication No. 2007 / 106120) may be used as the albumin binding site.

[0058] Of these, from the viewpoint of obtaining compounds applicable to living organisms and reducing unintended accumulation in normal organs such as the kidneys, it is preferable to use one or more of substituted or unsubstituted phenylbutyrate, Evans blue, and their derivatives, or an antibody or peptide capable of binding to albumin, as the structure of the albumin-binding site.

[0059] Examples of substituted or unsubstituted phenylbutyric acid that can be used as an albumin binding site include the structure shown in formula (B1) below.

[0060] [ka]

[0061] 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 dashed line is a bond with another structure. In formula (B1), R is preferably a hydrogen atom, an iodine atom, a bromine atom, or a methyl group.

[0062] Examples of Evans blue and its derivatives that can be applied as albumin binding sites include the structure shown in the following formula (B2).

[0063] [ka]

[0064] In formula (B2), R b1 R b11 Each of these is 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 parts indicated by the dashed lines are bonding parts with other structures. In formula (B2), R b1 and R b4 Both are methyl groups, R b2 and R b3 R b5 R b11 Preferably, all of them are hydrogen atoms.

[0065] As an antibody capable of binding to albumin, immunoglobulins having classes of IgG, IgA, IgM, IgD and IgE may be used as long as they have an affinity for albumin, or antibody fragments (for example, Fab fragments) may be used. From the viewpoint of reducing accumulation in unintended tissues such as the liver, when using an antibody capable of binding to albumin as an albumin-binding portion, it is preferable to use a Fab fragment having a low molecular weight.

[0066] Examples of peptides capable of binding to albumin include peptides containing the sequences shown in WO 2007 / 106120 pamphlet, and specifically, peptides containing the following peptide sequences are included, but are not limited to these sequences. The following peptide sequences are shown in the single-letter notation of amino acids, with the left side of the paper being the N-terminus and the right side of the paper being the C-terminus. ·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)

[0067] In formula (1), the moiety represented by the symbol C is an atomic group containing a target molecule binding moiety having an affinity for a target molecule expressed in a tissue that causes diseases such as cancer and having a chemical structure capable of reversibly binding to the target molecule. When such a structure is included in the compound of the present invention and it is labeled with a radioactive metal and administered to a living body, it can be efficiently accumulated in a tissue to be treated or diagnosed, and the efficiency of treatment or diagnosis can be enhanced.

[0068] Examples of cancer include solid cancers such as brain tumor, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, large intestine cancer, small intestine cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, salivary gland cancer, glioma, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant melanoma, thyroid cancer, parathyroid cancer, nasal cancer, paranasal sinus cancer, bone tumor, angiofibroma, retinoblastoma, penile cancer, testicular cancer, and pediatric solid cancer, blood cancers such as malignant lymphoma, leukemia, and myeloma, sarcoma, and glioblastoma multiforme. These cancers may be primary or metastatic.

[0069] The chemical structure in the target molecule binding moiety can be appropriately selected according to the target tissue and the amount of the target molecule expressed in the tissue. Specifically, as the target molecule binding moiety, a molecule that is not highly expressed in normal tissues but is highly expressed in tissues that cause diseases such as cancer tissue can be used as the target molecule, and a structure having an affinity for the molecule can be adopted. Examples of the structure having an affinity for the target molecule include one or more of low molecular weight compounds, peptides, antibodies, and antibody fragments such as Fab fragments.

[0070] Examples of the target molecule include proteins, DNA, RNA, etc., and preferably a protein present on the cell membrane surface or penetrating the cell membrane. Specific examples of target molecules include tyrosine kinases such as HER2 and HER3, EPHA2, and KIT; proteins expressed on hematopoietic cells such as CD19, CD19A, CD20, CD22, CD27L, CD30, CD33A, CD38, CD56, CD70, CD74, CD79b, CD138, and SLAMF7; folate receptors such as FOLR1; tumor-associated Ca signaling transducers such as TROP2; carcinoembryonic antigen-associated cell adhesion molecules such as CEACAM5; ectonucleotide pyrophosphatases / phosphodiesterases such as ENPP3; and STE. Examples include metalloreductases such as AP1, epidermal growth factor receptors such as EGFR and EGFRvIII, cell adhesion molecules such as nectin 4, fibroblast growth factors such as FGFR2, phosphate transporters such as NaPi2b, endothelin receptors such as ETB1 and ETB2, zinc transporters such as LIV1A, carbonic anhydrases such as CA-IX, glucagon-like peptide receptors such as GLP-1 receptor, transmembrane glycoprotein NMB (gpNMB), prostate-specific membrane antigen (PSMA), mesothelin, guanylate cyclase C, and integrins.

[0071] When the compound of the present invention is used as a precursor for a compound used in the treatment or diagnosis of cancer, the structure of the target molecule binding site in formula (1) above may include, for example, a structure that binds to one of the target molecules of CA-IX, PSMA, or the GLP-1 receptor.

[0072] CA-IX is a membrane-bound protein whose expression is enhanced when cells are in a hypoxic state. For example, CA-IX expression is high in tissues with hypoxic regions, such as solid tumor tissue, while it is low in normal tissue. Therefore, CA-IX is one of the useful target molecules in this invention and is particularly useful as a target for the treatment and diagnosis of solid tumors.

[0073] PSMA is a membrane-bound protein whose expression is upregulated in prostate cancer. While PSMA is expressed at low levels in normal tissues, including the prostate, its expression increases as the malignancy of prostate cancer increases. Therefore, PSMA is one of the useful target molecules in this invention and is particularly useful as a target for the diagnosis and treatment of prostate cancer.

[0074] The GLP-1 receptor is a receptor for glucagon-like peptides, known as a type of incretin hormone secreted in the body. The GLP-1 receptor is known to be specifically expressed at higher levels in pancreatic cancer (particularly insulinoma) than in other normal tissues. Therefore, the GLP-1 receptor is also a useful target molecule in this invention and is particularly useful as a target for the diagnosis and treatment of pancreatic cancer.

[0075] In formula (1) above, the target molecule binding site preferably has a structure represented by any one of the following formulas (C1) to (C3), or is an antibody or peptide capable of binding to the target molecule. The inclusion of such a structure in the compound of the present invention allows for efficient accumulation in the tissue targeted for treatment or diagnosis when labeled with a radioactive metal and administered, thereby improving the efficiency of treatment or diagnosis.

[0076] In detail, formulas (C1) and (C2) below represent one form of the structure of the target molecule binding site that is preferably adopted when CA-IX is the target molecule. Furthermore, the following formula (C3) represents one form of the target molecule binding site structure that is preferably adopted when PSMA is the target molecule.

[0077] [ka]

[0078] In equation (C3), a and b are independent integers between 1 and 7. Also, in equations (C1) to (C3), the parts indicated by wavy lines are connections to other structures.

[0079] As antibodies capable of binding to the target molecule, immunoglobulins having the classes IgG, IgA, IgM, IgD, and IgE may be used, as long as they have affinity for the target molecule, or antibody fragments (e.g., Fab fragments) may be used. From the viewpoint of reducing unintended accumulation in tissues such as the liver, when using an antibody capable of binding to the target molecule as the target molecule binding site, it is preferable to use a Fab fragment with a low molecular weight.

[0080] Examples of peptides capable of binding to target molecules include, but are not limited to, peptides such as exendin-4, which has affinity for the GLP-1 receptor, or cyclic peptides such as cyclic RGD peptides (cRGD peptides), which have affinity for αvβ3 integrin and αvβ5 integrin.

[0081] The compounds of the present invention are more preferably having a structure represented by the following general formula (2). Having such a structure means that the compound has a sufficient number of heteroatoms capable of coordinating radioactive metals, thereby increasing the efficiency of complex formation when coordinating radioactive metals to the compound of the present invention. In addition, the degree of freedom of molecular movement at the albumin binding site and the target molecule binding site is increased, so that a high level of affinity for albumin and affinity for the target molecule can be achieved simultaneously. Furthermore, unintended accumulation in normal tissues such as the liver and kidneys is reduced.

[0082] [ka]

[0083] In formula (2), R B1 and R B2 One of them is an atomic group containing an albumin bond, 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 containing the target molecule binding site, and the other is a hydrogen atom, a hydroxyl group, or a carboxyl group. Of these, in equation (2), RB1 is an atomic group containing an albumin-binding moiety, and R C1 is an atomic group containing a target molecule-binding moiety, and R B2 and R C2 are both preferably hydroxyl groups. Alternatively, in formula (2), R B2 is an atomic group containing an albumin-binding moiety, and R C2 is an atomic group containing a target molecule-binding moiety, and R B1 and R C1 are both preferably hydrogen atoms or each independently a carboxyalkyl group having 1 to 5 carbon atoms. In any of the above-described embodiments, the albumin-binding moiety is disposed at one structural end of the compound, and the target molecule-binding moiety is disposed at the other structural end of the compound. Thus, when the chemical structure of the compound of the present invention is viewed macroscopically, it is preferable that the chelate moiety, the albumin-binding moiety, and the target molecule-binding moiety are arranged in a substantially linear manner.

[0084] In particular, in formula (2), the atomic group containing the albumin-binding moiety is preferably an atomic group containing a 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 (2-1) to (2-4). In the following formulas (2-1) and (2-2), L1 is each independently an alkyl group having 1 to 8 carbon atoms containing a carboxy group. In the following formulas (2-3) and (2-4), each independently, g is an integer of 1 to 5, and h is 0 or 1.

[0085] b1 to R b11 and R C1 and R C2 The descriptions regarding are each independently applicable to the above-described formulas (B1) and (B2), and formula (2) as appropriate. 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. R b1 R b11 Each of these is 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, preferably R b1 and R b4 Both are methyl groups, R b2 and R b3 R b5 R b11 Preferably, all of them are hydrogen atoms. R C1 and R C2 One of these is an atomic group containing a target molecule binding site, and the other is a hydrogen atom, a hydroxyl group, or a carboxyalkyl group having 1 to 5 carbon atoms.

[0086] [ka]

[0087] [ka]

[0088] Furthermore, in formula (2), the structure of formula (B1) is included as the albumin binding site, and specific examples of the chemical structure of the compound when CA-IX is the target molecule are shown in the following formulas (2a) to (2d). In formulas (2a) to (2d), R is independently a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, preferably a hydrogen atom, an iodine atom, a bromine atom, or a methyl group.

[0089] [ka]

[0090] [ka]

[0091] Furthermore, in formula (2), the structure of formula (B1) is included as the albumin binding site, and specific examples of the chemical structure of the compound when the GLP-1 receptor is the target molecule are shown in the following formulas (3a) to (3d). In formulas (3a) to (3d), R is independently a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, preferably a hydrogen atom, an iodine atom, a bromine atom, or a methyl group.

[0092] [ka]

[0093] [ka]

[0094] The compounds of the present invention having the above structures can be produced, for example, by the method described in the following reaction pathway (I) or (II), or by the method described in the examples below. In reaction pathways (I) and (II), R is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 5 carbon atoms, preferably R is a hydrogen atom, an iodine atom, a bromine atom, or a methyl group. In reaction pathway (II), "ALB" indicates the albumin binding site, and "Ligand" indicates the target molecule binding site.

[0095] [ka]

[0096] [ka]

[0097] The compounds of the present invention can be reacted with a radioactive metal, preferably in an aqueous solution such as a solvent or buffer, to obtain a radiolabeled compound, which is a radioactive metal complex. In this radiolabeled compound, the chelate portion of the compound is coordinated to the ions of the radioactive metal. From the viewpoint of increasing the efficiency of complex formation, it is preferable to use the radioactive metal reacted with the compound in the form of an ionizable radioactive metal compound, and more preferably in the form of a radioactive metal ion (hereinafter, these forms are collectively referred to as "radioactive metal source"). As a radioactive metal source, for example, a radioactive metal ion-containing solution in which radioactive metal ions are dissolved or dispersed in a solvent mainly composed of water can be used.

[0098] Furthermore, from the viewpoint of increasing the efficiency of complex formation with radioactive metals, regardless of the combination of the chelate portion in the compound and the radioactive metal, it is preferable to heat the compound and the radioactive metal during the complex formation reaction. By carrying out the reaction under such conditions, complex formation can proceed well even when using low-energy radiation that is difficult to detect or radioactive metal nuclides that emit alpha rays, so that the target radiolabeled compound can be obtained in high yield.

[0099] In obtaining a radiolabeled compound, the order in which the compound and the radioactive metal source are added does not matter, as long as complex formation between the compound and the radioactive metal ion is possible. For example, one of the compounds and the radioactive metal source may be added to a reaction vessel containing a solvent, followed by the other, or one of the compounds and the radioactive metal source may be dissolved in a solvent and then the other added to the solution and reacted. Alternatively, both may be added simultaneously to a reaction vessel containing a solvent and reacted.

[0100] The reaction conditions for obtaining the radiolabeled compound can be, for example, the following. The solvent used in this step may be, for example, water, physiological saline, or a buffer 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 may be, for example, room temperature (25°C), or it may be under heated conditions.

[0101] A radioactive metal source can be, for example, a solution in which radioactive metal ions are dispersed in a solvent mainly composed of water.

[0102] The amount of reaction solution in this process is not particularly limited, but from the viewpoint of practicality in the manufacturing process, 0.01 mL to 100 mL is realistic at the start of this process. Furthermore, from the viewpoint of yielding the desired radiolabeled compound, it is preferable that the concentrations of the compound and the radioactive metal ions in the reaction solution are independently 1 μmol / L to 100 μmol / L at the start of this process.

[0103] The resulting radiolabeled compound may be used as is, or it may be purified using a filtration filter, membrane filter, column packed with various packing materials, chromatography, etc. Furthermore, if necessary, in subsequent steps, a water-based solvent and other pharmaceutically acceptable components may be added to the radiolabeled compound to produce a radiopharmaceutical composition. A radiopharmaceutical composition can be produced, for example, by dissolving the radiolabeled compound produced by the above method in a water-based solvent that is approximately isotonic with living tissue. Radiopharmaceutical compositions are administered to living organisms orally, or parenterally (intravenously, subcutaneously, intraperitoneally, or intramuscularly) and are used for the treatment of diseases, the diagnosis of diseases, or the detection of lesions.

[0104] The radioactive metal coordinated in the radioactive labeling compound in an ionic state can use a metal nuclide that emits radiation such as alpha rays, beta rays, gamma rays, or a combination thereof. Examples of such radioactive metal nuclides include radioactive isotopes of alkali metals, alkaline earth metals, lanthanoids, actinoids, transition metals, or metals other than these metals. Among these, from the perspective of being commercially available and improving complex formation, as the nuclide of the radioactive metal, 44 Sc, 51 Cr, 57 Co, 58 Co, 60 Co, 59 Fe, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 89 Sr, 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 Bi, 213 Bi, 212 Pb, 227 Th or 225 Ac is preferably used. These radioactive metals can be produced according to conventional methods. These radionuclides are preferably obtained as a solution containing the radioactive metal in an ionized state.

[0105] When the radioactive labeling compound is used for the treatment of diseases, from the perspective of enhancing the therapeutic effect, it is preferable to use an alpha-ray-emitting nuclide or a beta - ray-emitting nuclide as the radioactive metal. The alpha-ray-emitting nuclide may be any nuclide that emits alpha rays during the decay process of the radioactive metal. Specifically, 212 Bi, 213 Bi,227 The or 225 Ac and the like are preferably used, more 227 The or 225 It is Ac, and more preferably Ac. 225 It is Ac. β - Radioactive radionuclides undergo the decay process of radioactive metals, including the β-emitting process. - Any radionuclide that emits radiation will suffice; in more detail, 60 Co, 59 Fe, 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 Bi, 213 Bi or 212 Pb and the like are preferably used, more 64 Cu, 67 Cu, 89 Sr or 90 Y is used, and more preferably 90 Y is used.

[0106] Furthermore, when using radiolabeled compounds for the purpose of diagnosing diseases or detecting lesions, from the perspective of improving diagnostic performance, β is used as the radioactive metal. + It is preferable to use a radioactive emission nuclide, an electron capture decay nuclide, or a gamma-ray emitting nuclide. + A radioactive emission nuclide can be any nuclide that emits positrons during the decay process of radioactive metals. 44 Sc, 58 Co, 68 Ga, 64 Cu or 89 Zr and the like are preferably used, more 64 Cu or 89 It is Zr. An electron-capture decay nuclide is any nuclide that emits Auger electrons or characteristic X-rays during the decay process of a radioactive metal.51 Cr, 57 Co, 58 Co, 67 Ga, 68 Ga, 64 Cu, 89 Zr, 111 In, 186 Re, 201 Tl or 197 Hg and the like are preferably used. A gamma-ray emitting nuclide can be any nuclide that emits gamma rays through gamma decay, and examples of nuclides that emit gamma rays through gamma decay include: 99m Tc, 68 Ga or 201 Tl is preferably used.

[0107] When selecting a radioactive metal coordinated in an ionic state to a radioactive metal complex based on its ionic radius, a radioactive metal with an ionic radius of approximately 70-130 pm is considered. 67 Ga, 68 Ga, 64 Cu, 67 Cu, 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 Bi, 213 Bi, 212 Pb, 225 Examples include Ac, which can preferably form a complex between the compound of the present invention having a chelate portion with the structure shown in formulas (A1) to (A9) and a radioactive metal ion.

[0108] For example, when using radiolabeled compounds for the purpose of treating diseases, as radioactive metals 225When Ac is used, the compound of the present invention preferably has a chelate portion with a structure represented by any of the above formulas (A1), (A3) to (A5), or (A7), and more preferably has a chelate portion with a structure represented by the above formula (A1). Also, as a radioactive metal 90 When Y is used, the compound of the present invention preferably has a chelate portion having a structure represented by any of the above formulas (A1) to (A3) or (A8), and more preferably has a chelate portion having a structure represented by the above formula (A1). Furthermore, when radiolabeled compounds are used for the purpose of diagnosing diseases or detecting lesions, as radioactive metals 89 When Zr is used, the compound of the present invention preferably has a chelate portion with a structure represented by any of the above formulas (A1), (A3), or (A4), and more preferably has a chelate portion with a structure represented by the above formula (A1). Also, as a radioactive metal 68 Ga or 111 When using In, the compound of the present invention preferably has a chelate portion having a structure represented by any of the above formulas (A1) to (A4) or (A9), and more preferably has a chelate portion having a structure represented by the above formula (A1).

[0109] The bond between the chelate portion and the atomic group containing the albumin binding portion may be a direct bond between the chelate portion and the albumin binding portion without the linker structure described later, or it may be an indirect bond between the chelate portion and the atomic group containing the albumin binding portion via the linker structure described later. Similarly, the bond between the chelate portion and the atomic group containing the target molecule binding portion may be a direct bond between the chelate portion and the target molecule binding portion without the linker structure described later, or it may be an indirect bond between the chelate portion and the atomic group containing the albumin binding portion via the linker structure described later. In either the "direct" or "indirect" manner described above, bonding via an amide bond is preferable from the viewpoint of achieving both ease of synthesis and stability of the chemical structure.

[0110] The linker structure is preferably derived from a compound capable of forming an amide bond. Specific examples include L- or D-form amino acids such as acidic amino acids like glutamic acid and aspartic acid, and basic amino acids like lysine; dicarboxylic acids such as oxalic acid and malonic acid; and diamines such as ethylenediamine. If the linker structure described above includes a structure derived from amino acids, etc., then, for example, peptide linkers described in International Publication No. 2017 / 150549, International Publication No. 2019 / 065774, International Publication No. 2019 / 221269, International Publication No. 2020 / 075746, International Publication No. 2020 / 145227, International Publication No. 2020 / 145228, etc., can be used for the purpose of controlling the dynamics in vivo.

[0111] Furthermore, if the linker structure described above includes a structure derived from ethylene glycol, it is also preferable that it is indirectly linked by the linker structure shown in the following formula (P). This structure is derived from ethylene glycol, and in formula (P), n is preferably an integer between 2 and 10, more preferably an integer between 2 and 8, and even more preferably an integer between 2 and 5.

[0112] [ka]

[0113] These linker structures may consist of one type of linker structure, or they may be formed by repeating one type of linker structure or by combining multiple types of linker structures, and these may be linked together in a linear or branched chain.

[0114] In the cases where the chelate portion and the albumin binding portion are "indirectly" bound, or where the chelate portion and the target molecule binding portion are "indirectly" bound, other embodiments may involve linking by known coupling methods, such as a click reaction. The following explanation will describe the case where a click reaction is used to link the chelate portion and the target molecule binding portion. In this case, the chelate portion and the target molecule binding portion each have click reaction-capable atomic groups, and these atomic groups react with each other to link the chelate portion and the target molecule binding portion. That is, the reaction takes place between the first atomic group of the chelate portion and the second atomic group of the target molecule binding portion.

[0115] In the present invention, appropriate combinations of click-reactive atomic groups are selected depending on the type of click reaction. Examples include combinations of alkynes and azides, and combinations of 1,2,4,5-tetrazine and alkenes. These atomic groups only need to have one of the above atomic groups as the first atomic group and a second atomic group that is a combination of the first atomic group. From the viewpoint of achieving both stability of the chelate and target molecule bonding sites and improved bonding efficiency, it is preferable that the first atomic group is an alkyne and the second atomic group is an azide, or that the first atomic group is 1,2,4,5-tetrazine and the second atomic group is an alkene. Specific examples of click reactions using such combinations of atomic groups include the Huisgen cycloaddition reaction and the reverse electron-demanded Diels-Alder reaction.

[0116] Specific examples of click-reaction-compatible atomic group combinations 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)).

[0117] [ka]

[0118] (In formula (11a), R1 represents the binding site to the chelating moiety, and in formula (12a), R2 represents the binding site to the target molecule.)

[0119] [ka]

[0120] (In formula (11b), one of R3 and R4 represents a binding site to the chelate or target molecule binding site, and the other represents a hydrogen atom, a methyl group, a phenyl group, or a pyridyl group; in formula (12b), R5 represents a binding site to the chelate or target molecule binding site.)

[0121] In the present invention, when the chelate portion and the target molecule binding portion are bonded by a click reaction, the order of addition does not matter as long as the click reaction can proceed. For example, one of the chelate portion and the target molecule binding portion may be added to a reaction vessel containing a solvent, and then the other may be added and reacted. Alternatively, one of the chelate portion and the target molecule binding portion may be dispersed in a solvent, and the other may be added and reacted. Or, they may be added simultaneously to a reaction vessel containing a solvent and reacted.

[0122] In each of the embodiments described above, examples of substituents that can be substituted in the chemical structures of A, B, and C, as well as the compound and the radiolabeled compound, include halogen atoms, saturated or unsaturated alkyl groups, hydroxyl groups, aldehyde groups, carboxyl 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, and the like. These substituents may be present individually or as a combination of two or more substituents.

[0123] Although the present invention has been described above based on its preferred embodiments, the present invention is not limited to the embodiments described above. For example, in each of the embodiments described above, compounds having one chelate portion, one albumin-binding portion, and one target molecule-binding portion have been described, but insofar as the present invention is achieved, at least one of the albumin-binding portion and the target molecule-binding portion may be present in multiple locations in a single chemical structure. [Examples]

[0124] The present invention will be described in more detail below with reference to examples. However, the scope of the present invention is not limited to these examples. In the following examples, unless otherwise specified, all NMR measurements were performed using a JEOL Ltd. JNM-AL400 FT-NMR spectrometer, with tetramethylsilane (TMS) as the internal standard and the TMS resonance set to 0.00 ppm. All chemical shifts are expressed in ppm on the delta scale (δ), and signal splitting is indicated using abbreviations (s: singlet, d: doublet, t: triplet, m: multiplet, br: broad). Furthermore, for mass spectrometry, LCMS 2020 (manufactured by Shimadzu Corporation) was used for MS, and LCMS-IT-TOF (manufactured by Shimadzu Corporation) was used for HRMS.

[0125] [Examples 1 to 4] In this example, as shown in formula (2a), compounds were synthesized using CA-IX as the target molecule, with R being an iodine atom (Example 1), a methyl group (Example 2), a bromine atom (Example 3), or a hydrogen atom (Example 4). Then, each compound was treated with a radioactive metal. 111 A radiolabeled compound with an In ion coordinated to it was obtained. The general reaction pathway in each example is shown below as reaction pathway (III).

[0126] [ka]

[0127] <Example 1> (1) Synthesis of compounds First, methyl N 6 -(4-(4-iodophenyl)butanoyl)-L-lignate (compound 1)) was synthesized by the following method.

[0128] Boc-Lys(OMe)-OH (118 mg, 0.40 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide (DMF), and 4-(4-iodophenyl)butyric acid (116 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (HOAt) (109 mg, 0.80 mmol), and triethylamine (150 μL, 1.1 mmol) were added to prepare the mixture. This mixture was stirred overnight at room temperature under an argon atmosphere, and then freeze-dried to obtain a residue. 2 mL of trifluoroacetic acid (TFA) was added to this residue, and the mixture was stirred at room temperature for 3 hours. After concentration, the residue was purified by medium-pressure silica gel chromatography (chloroform:methanol) to obtain 172 mg of the target product (100% yield) as a pale yellow oily substance.

[0129] Compound 1 1 H-NMR(400MHz,CDCl3)δ 7.57(d,J=8.4Hz,2H),6.91(d,J=8.0Hz,2H),4.03(s,1H),3.77(s,3H),3.20(s,2H),2.54(t ,J=7.6Hz,2H),2.18(t,J=7.4Hz,2H),1.98(s,2H),1.87(t,J=7.2Hz,2H),1.50-1.40(m,4H). Compound 1 13 C-NMR(100MHz, CDCl3)δ 173.9,170.0,141.1,137.2(2C),130.5(2C),90.9,53.1,52.8,38.7,35.4,34.5,29.6,28.4,27.0,21.7. MS(ESI)m / z C of compound 1 17 H 26 IN2O3, calculated value: 433.1; measured value: 433.1 ([M+H]+ ).

[0130] Next, the compound IS-DO2A-ALB1((S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-iodophenyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid) was synthesized by the following method.

[0131] Compound 1 (86 mg, 0.20 mmol) described above was dissolved in anhydrous DMF (5 mL), and then 2,2'-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (103 mg, 0.20 mmol), EDC·HCl (38 mg, 0.20 mmol), HOAt (27 mg, 0.20 mmol), and triethylamine (27 μL, 0.20 mmol) were added to prepare a mixture. This mixture was stirred at room temperature under an argon atmosphere for 24 hours. Subsequently, 6-(4-aminophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (59 mg, 0.20 mmol), EDC·HCl (38 mg, 0.20 mmol), HOAt (27 mg, 0.20 mmol), and triethylamine (27 μL, 0.20 mmol) were further added to the mixture, and the mixture was stirred for another 24 hours at room temperature under an argon atmosphere. After the reaction was complete, the mixture was freeze-dried to obtain a residue to which 6 N hydrochloric acid was slowly added under an ice bath, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated and purified by reverse-phase high-performance liquid chromatography (HPLC) under the following conditions to obtain the target compound (IS-DO2A-ALB1). The yield was 2.5 mg (1.2% yield).

[0132] HRMS(ESI)m / z C of IS-DO2A-ALB1 42 H 56 IN 11 NaO11 S2, Calculated value: 1104.2539; Measured value: 1104.2458 ([M+Na] + ).

[0133] HPLC purification conditions (1st time): Cosmosil 5C 18 - AR-II column (20 × 250 mm), mobile phase: MeCN / H2O / TFA [gradient of 15 / 85 / 0.1 (vol%, 0 min) to 45 / 55 / 0.1 (vol%, 60 min)], flow rate: 5 mL / min. HPLC purification conditions (2nd time): Cosmosil 5C 18 - AR-II column (4.6 × 150 mm), mobile phase: MeCN / H2O / TFA [gradient of 15 / 85 / 0.1 (vol%, 0 min) to 45 / 55 / 0.1 (vol%, 120 min)], flow rate: 1 mL / min.

[0134] (2) Synthesis of radiolabeled compounds Finally, as the target radiolabeled compound, [ 111 In]IS-DO2A-ALB1([ 111 In]Indium(III)(S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-iodophenyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid) was obtained.

[0135] As a radioactive metal to coordinate 111 In was used. Sodium acetate buffer (0.1 M, pH 4.6, 200 μL) and a radioactive metal source [ 111 Indium chloride (100 μL) was allowed to stand in a low-protein-adsorption tube (1.5 mL) at room temperature for 10 minutes. Then, DMSO solution of IS-DO2A-ALB1 (1 mM, 10 μL) was added to the buffer and mixed, and the reaction was carried out at 90°C for 30 minutes. Subsequently, the reaction mixture was purified by reverse-phase HPLC under the same conditions as above, and a radiolabeled compound in which a radioactive metal ion was coordinated to the compound was obtained.111 In]IS-DO2A-ALB1 was obtained. The radiochemical yield was 31%, and the radiochemical purity was over 99%.

[0136] <Example 2> (1) Synthesis of compounds Methyl N 6 -(4-(4-tolyl)butanoyl)-L-lignate (compound 2) was synthesized by the following method.

[0137] The reaction was carried out in the same manner as in Example 1, except that 4-(4-tolyl)butyric acid (71 mg, 0.40 mmol) was used instead of 4-(4-iodophenyl)butyric acid, and 128 mg (100% yield) of compound 2 was obtained as a pale yellow oily substance. Compound 2 1 H-NMR(400MHz,CDCl3)δ 8.58(s,2H),7.06(d,J=8.4Hz,2H),7.02(d,J=8.4Hz,2H),6.43(s,1H),4.02(t,J=6.0Hz,1H),3.73(s,1H),3.17(d,J=5.2 Hz,2H),2.54(t,J=7.6Hz,2H),2.29(s,3H),2.17(t,J=7.4Hz,2H),1.97(d,J=6.4Hz,2H),1.90-1.82(m,2H),1.48(br,4H). Compound 2 13 C-NMR(100MHz, CDCl3)δ 174.0,169.9,138.3,135.2,128.9(2C),128.1(2C),53.0,52.8,38.6,35.6,34.6,29.6,28.4,27.3,21.8,20.8. MS(ESI)m / z C of compound 2 18 H 29 N2O3, calculated value: 321.2; measured value: 321.2 ([M+H] + ).

[0138] Next, compound 2 was reacted and purified in the same manner as in Example 1 to synthesize IS-DO2A-ALB2((S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-tolyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid). The yield was 1.3 mg and 0.6%.

[0139] HRMS(ESI) of IS-DO2A-ALB2 m / z C 43 H 60 N 11 O 11 S2, Calculated value: 970.3910; Measured value: 970.3911 ([M+H] + ).

[0140] (2) Synthesis of radiolabeled compounds Using IS-DO2A-ALB2, the reaction and purification were carried out in the same manner as in Example 1, and a radiolabeled compound was obtained in which a radioactive metal ion was coordinated to the compound. 111 In]IS-DO2A-ALB2([ 111 In]Indium(III)(S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-tolyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid) was obtained. The radiochemical yield was 44%, and the radiochemical purity was over 99%.

[0141] <Example 3> (1) Synthesis of compounds Methyl N 6 -(4-(4-bromophenyl)butanoyl)-L-lignate (compound 3) was synthesized by the following method.

[0142] The reaction was carried out in the same manner as in Example 1, except that 4-(4-bromophenyl)butyric acid (97 mg, 0.40 mmol) was used instead of 4-(4-iodophenyl)butyric acid, and 154 mg (100% yield) of compound 3 was obtained as a pale yellow oily substance.

[0143] Compound 3 1 H-NMR(400MHz,CDCl3)δ 8.58(s,1H),7.36(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),6.58(t,J=5.6Hz,1H),4.02(t,J=6.4Hz,1H),3.74(s,3H) ,3.17(d,J=5.6Hz,2H),2.54(t,J=7.6Hz,2H),2.16(t,J=7.6Hz,2H),2.00(s,2H),1.89-1.84(m,2H),1.48(br,4H). Compound 3 13 C-NMR(100MHz, CDCl3)δ 173.9,170.0,140.5,131.2(2C),130.1(2C),119.5,53.0,52.9,38.7,35.4,34.4,29.6,28.4,27.0,21.7. MS(ESI)m / z C of compound 3 17 H 26 N2O3, calculated value: 385.1; measured value: 385.1 ([M+H] + ).

[0144] Next, compound 3 was reacted and purified in the same manner as in Example 1 to synthesize IS-DO2A-ALB3((S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-bromophenyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid). The yield was 3 mg and 1.5%.

[0145] HRMS(ESI) of IS-DO2A-ALB3 m / z C 42 H56 BrN 11 NaO 11 S2, Calculated value: 1056.2678; Measured value: 1056.2665 ([M+Na] + ).

[0146] (2) Synthesis of radiolabeled compounds Using IS-DO2A-ALB3, the reaction and purification were carried out in the same manner as in Example 1, and a radiolabeled compound in which a radioactive metal ion was coordinated to the compound was obtained. 111 In]IS-DO2A-ALB3([ 111 In]indium(III)(S)-2,2'-(4-(2-((1-carboxy-5-(4-(4-bromophenyl)butanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid) was obtained. The radiochemical yield was 32%, and the radiochemical purity was over 99%.

[0147] <Example 4> (1) Synthesis of compounds Methyl N 6 -(4-4-phenylbutanoyl)-L-lignate (compound 4) was synthesized by the following method.

[0148] The reaction was carried out in the same manner as in Example 1, except that 4-phenylbutyric acid (66 mg, 0.40 mmol) was used instead of 4-(4-iodophenyl)butyric acid, and 109 mg (89% yield) of compound 4 was obtained as a pale yellow oily substance.

[0149] Compound 4 1 H-NMR(400MHz,CDCl3)δ 8.53(s,2H),7.25-7.11(m,5H),6.74(t,1H),4.00(t,1H),3.69(s,1H),3.14(d,2H), 2.57(t,2H),2.15(t,2H),1.94(d,2H),1.97(d,2H),1.90-1.82(m,2H),1.45(br,4H). Compound 4 13 C-NMR(100MHz, CDCl3)δ 173.9,170.0,141.5,128.3(2C),128.2(2C),125.8,53.0,52.8,38.6,35.6,35.1,29.6,28.4,27.2,21.8. MS(ESI)m / z C of compound 4 17 H 27 N2O3, calculated value: 307.2; measured value: 307.2 ([M+H] + ).

[0150] Next, compound 4 was reacted and purified in the same manner as in Example 1 to synthesize IS-DO2A-ALB4((S)-2,2'-(4-(2-((1-carboxy-5-(4-phenylbutanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid). The yield was 3 mg and 1.7%.

[0151] HRMS(ESI) of IS-DO2A-ALB4 m / z C 42 H 58 N 11 O 11 S2, Calculated value: 956.3753; Measured value: 956.3760 ([M+H] + ).

[0152] (2) Synthesis of radiolabeled compounds Using IS-DO2A-ALB4, the reaction and purification were carried out in the same manner as in Example 1, and a radiolabeled compound was obtained in which a radioactive metal ion was coordinated to the compound. 111 In]IS-DO2A-ALB4([ 111In]Indium(III)(S)-2,2'-(4-(2-((1-carboxy-5-(4-phenylbutanamide)pentyl)amino)-2-oxoethyl)-10-(2-oxo-2-((4-(2-sulfamoylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)phenyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid) was obtained. The radiochemical yield was 44%, and the radiochemical purity was over 99%.

[0153] <Comparative Example 1> Using the method shown below, [ 111 In]DO3A-IS1 was synthesized. The general reaction pathway in this comparative example is shown as reaction pathway (IV).

[0154] [ka]

[0155] (1) Synthesis of compounds DO3A-IS1 was synthesized by the following method. Specifically, 2,2'-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (103 mg, 0.20 mmol) was dissolved in anhydrous DMF (4 mL), and then 6-(4-aminophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (59 mg, 0.20 mmol), EDC·HCl (38 mg, 0.20 mmol), HOAt (27 mg, 0.20 mmol), and triethylamine (27 μL, 0.20 mmol) were added to prepare a mixture. This mixture was stirred at room temperature under an argon atmosphere for 48 hours. After the reaction was complete, the mixture was freeze-dried to obtain a residue to which trifluoroacetic acid was slowly added under an ice bath, and the mixture was stirred at room temperature for 7 hours. Subsequently, the reaction mixture was concentrated and purified by reverse-phase HPLC under the following conditions to obtain the target compound (DO3A-IS1). The yield was 52 mg (19% yield). HPLC purification conditions (1st time): Cosmosil 5C 18- AR-II column (20 × 250 mm), mobile phase: MeCN / H2O / TFA [gradient of 10 / 90 / 0.1 (vol%), 5 min) to 25 / 75 / 0.1 (vol%), 75 min], flow rate: 5 mL / min. HPLC purification conditions (2nd time): Cosmosil 5C 18 - AR-II column (10 × 250 mm), mobile phase: MeCN / H2O / TFA [15 / 85 / 0.1 (vol%)], flow rate: 2.8 mL / min. NMR device used: JNM-ECS-400 (manufactured by JEOL Ltd.) DO3A-IS1 1 H-NMR(400MHz,DMSO-d6)δ 10.59(s,1H),8.81(s,1H),8.75(s,2H),7.86(d,2H,J=21.5Hz),7.65(d,2H,J=21.5Hz),3.9-4.1(br,16H),3.3-3.1(br,8H). DO3A-IS1 HRMS(ESI)m / z C 26 H 36 N9NaO9S2, calculated value: 682.2072; measured value: 682.2107 ([M+H] + ).

[0156] (2) Synthesis of radiolabeled compounds [ 111 In]DO3A-IS1 was obtained by the following method. Specifically, sodium acetate buffer (0.1M, pH 4.6, 200 μL) and a radioactive metal source [ 111 Indium chloride (100 μL) was allowed to stand in a low-protein-adsorption tube (1.5 mL) at room temperature for 10 minutes. Then, a DMSO solution of DO3A-IS1 (20 mM, 10 μL) was added to the buffer and mixed, and the reaction was carried out at 90°C for 30 minutes. Subsequently, the reaction mixture was purified by reverse-phase HPLC under the following conditions to obtain a radiolabeled compound in which a radioactive metal ion is coordinated to the compound. 111 In[DO3A-IS1] was obtained. The radiochemical yield was 76%, and the radiochemical purity was over 99%. HPLC purification conditions: Cosmosil 5C 18- AR-II column (4.6 × 150 mm), mobile phase: MeCN / H2O / TFA [gradient of 10 / 90 / 0.1 (vol%, 0 min) to 40 / 60 / 0.1 (vol%, 30 min)], flow rate: 0.6 mL / min.

[0157] <Evaluation 1: Distribution Coefficient> A mixture of PBS (3 mL, pH 7.4 (20°C)) and 1-octanol (3 mL) was mixed with the radiolabeled compound (740 kBq) of the example or comparative example, vortexed for 2 minutes, and then centrifuged at 4000 × g for 5 minutes. Subsequently, 1 mL was collected from the 1-octanol layer and 500 μL from the PBS layer, and the radioactivity of each layer was measured using a gamma counter (n=5). The formula for calculating the distribution coefficient is "log 10 The formula was calculated as [(1 - radioactivity of the octanol layer) / (radioactivity of the PBS layer × 2)]. The results are shown in Table 1 below, expressed as mean ± standard deviation (mean ± SD).

[0158] [Table 1]

[0159] <Evaluation 2: Cell binding inhibition experiment> In this evaluation, 111 In]IS-DO2A-ALB1~4 and [ 111 The coupling compatibility of In]DO3A-IS1 to CA-IX was evaluated. In detail, HT-29 cells (CA-IX high-expression cells, purchased from Dainippon Sumitomo Pharma Co., Ltd.) were placed in 4.0 × 10⁶ well plates. 5 Seeds were seeded individually per well with culture medium and incubated at 37°C for 24 hours under a 5% carbon dioxide atmosphere. Next, the culture medium was removed, and 1 mL of the culture medium (37 kBq / mL) containing the radiolabeled compound of Examples 1 to 4 or Comparative Example 1 was added to each well so that the acetazolamide concentration as an inhibitor was between 50,000 and 0.00512 nM. The cultures were then incubated at 37°C for 2 hours under a 5% carbon dioxide atmosphere. Samples containing the radiolabeled compound but without acetazolamide were also cultured under the same conditions. Each concentration group was performed with n=6. Next, the culture medium was removed, washed with PBS (1 mL), and the cells were lysed with 1 N sodium hydroxide aqueous solution (200 μL x 2) to obtain a cell lysate. The radioactivity in the cell lysate and the culture medium containing the radiolabeled compound were then measured using a gamma counter (model: Wallac 2470 Wizard, PerkinElmer, Massachusetts, USA). Separately, the total protein content (mg protein) in the cell lysate was quantified using the BCA method. The percentage of the sample's radioactivity relative to the added radioactivity (%ID) divided by the total protein content (%ID / mg protein) was calculated for each sample. Based on the percentage of radioactivity relative to total protein content (%ID / mg protein) for each acetazolamide concentration sample, with the acetazolamide-free sample's %ID / mg protein set as 100%, the 50% inhibitory concentration (IC) was determined using GraphPad Prism. 50 The mean ± standard deviation (mean ± SD) was calculated. The results are shown in Table 2 below.

[0160] [Table 2]

[0161] In this experiment, instead of changing the concentration range of the radiolabeled compound in Examples 1 to 4 or Comparative Example 1, the concentration range of the inhibitor was changed, so the calculated IC 50 A larger value indicates that a higher concentration of inhibitor is required to inhibit the binding of the radiolabeled compound to CA-IX. In other words, the calculated IC 50A larger value indicates a higher affinity between the radiolabeled compound and CA-IX. As shown in Table 1, the radiolabeled compounds of Examples 1 to 4, compared to those of Comparative Example 1, yielded the following calculated IC values. 50 The value is large. Therefore, it can be seen that the radiolabeled compounds of Examples 1 to 4 have a high affinity for the target molecule CA-IX.

[0162] <Evaluation 3: Experiment on in vivo radioactivity distribution in HT-29 tumor-bearing mice> Under 2% isoflurane anesthesia, HT-29 cells expressing CA-IX (5 × 10¹⁴ cells) were placed in the left shoulder of a 5-week-old male BALB / c nude mouse (purchased from Shimizu Experimental Materials Co., Ltd.). 6 A suspension of cells (per individual) was subcutaneously inoculated. The suspension consisted of a 1:1 volume mixture of HT-29 cells / DMEM medium (Thermo Fisher) and a matrix product (Geltrex®, Thermo Fisher). Subsequently, the subcutaneously inoculated mice were raised for 14 days in a room with a 12-hour day / night cycle, fed with normal feed and tap water, to obtain HT-29 tumor-bearing mice. Then, a saline solution of the radiolabeled compound from Examples 1 to 3 (259 kBq, 100 μL, containing 3 mg of ascorbic acid) or a saline solution of the radiolabeled compound from Comparative Example 1 (259 kBq, 100 μL, containing 1 mg of ascorbic acid) was administered to each mouse via the tail vein. The mice (n=5 in each group) were euthanized 1, 4, 8, 24, 48, 96, and 192 hours after administration, and blood, organs, and tumor sites were collected and their masses were measured. The radioactivity was also measured using a gamma counter. The degree of accumulation of radiolabeled compounds is expressed as the percentage of radioactivity relative to the injected dose (%ID) divided by the blood mass or organ mass (g) (%injected dose / g). A higher %ID / g value indicates a greater abundance of the radiolabeled compound and higher accumulation of the compound in the target organ. The results are shown in Figure 1.

[0163] As shown in Figure 1, the radiolabeled compounds of Examples 1 to 3 remain in the blood for a long period of time, indicating a long blood half-life. Furthermore, while the radiolabeled compounds of Examples 1 to 3 show little accumulation in the kidneys, they show high accumulation in tumors expressing CA-IX, indicating that they are particularly prone to specific accumulation in tumors due to the binding of the target molecule, CA-IX. In contrast, the radiolabeled compound of Comparative Example 1 showed very high accumulation in the kidneys compared to the results of each example, and consequently, poor accumulation in tumors. Therefore, the compounds of the present invention and radiolabeled compounds using the same can achieve both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly the kidneys.

[0164] <Evaluation 4: Experiment on in vivo radioactivity distribution in MDA-MB-231 tumor-bearing mice> Using the same method as in Evaluation 3, MDA-MB-231 cells (1 × 10⁶) with low CA-IX expression were placed in the left shoulder of 5-week-old male BALB / c nude mice. 7 MDA-MB-231 tumor-bearing mice were obtained by subcutaneous inoculation of a cell / mouse suspension. Then, a saline solution of the radiolabeled compound from Example 1 (40 kBq, 100 μL, containing 3 mg of ascorbic acid) was administered to each mouse via the tail vein. Twenty-four hours after administration, the mice (n=5 in each group) were euthanized, and blood, organs, and tumor sites were collected and their masses were measured. The radioactivity was also measured using a gamma counter. The degree of accumulation of radiolabeled compounds is expressed as %ID / g, which is the percentage of radioactivity relative to the injected dose (%ID) divided by the blood mass or organ mass (g). A higher %ID / g value indicates a greater abundance of the radiolabeled compound and higher accumulation of the compound in the target organ. The results are shown in Table 3 as mean ± standard deviation (n=5).

[0165] [Table 3]

[0166] As shown in Table 3, the accumulation of the radiolabeled compound in Example 1 in the MDA-MB-231 tumor was lower compared to the accumulation in the HT-29 tumor (10.73% ID / g) in Evaluation 3. Therefore, it can be seen that the radiolabeled compound accumulates more readily in tumors with high CA-IX expression.

[0167] <Evaluation 5: SPECT / CT in HT-29 tumor-bearing mice> After obtaining HT-29 tumor-bearing mice using the same method as in Evaluation 3, a saline solution of the radiolabeled compound from Example 1 (7.6-8.0 MBq, 150 μL, containing 3 mg of ascorbic acid) was administered via tail vein. SPECT / CT was performed 4, 24, and 48 hours after administration using a Gamma Medica-Ideas FX3300 pre-clinical imaging system. SPECT / CT was performed on tumor-bearing mice under 2% isoflurane anesthesia, with a rotation radius of 35 mm, projection time of 70 seconds, and 32 projections, using a 1.0 mm diameter pinhole collimator. After SPECT, CT (tube voltage: 60 kV, tube current: 350 μA) was performed under the same anesthesia. Image reconstruction of the SPECT projection data was performed using the 3D ordered subset expectation maximization method (8 subsets, 5 iterations). The results are shown in Figure 2. In Figure 2, the areas indicated by arrows are the locations of HT-29 tumors, and the areas indicated by circles are the locations of kidneys.

[0168] <Evaluation 6: SPECT / CT in MDA-MB-231 tumor-bearing mice> MDA-MB-231 tumor-bearing mice were obtained using the same method as in Evaluation 4, and then SPECT / CT was performed under the same conditions as in Evaluation 5. The results are shown in Figure 3. In Figure 3, the areas indicated by arrows are the locations of the MDA-MB-231 tumors, and the areas indicated by circles are the locations of the gastrointestinal tract.

[0169] As shown in Figures 2 and 3, the radioactivity signal of HT-29 tumors with high CA-IX expression (see Figure 2) is higher than that of MDA-MB-231 tumors (see Figure 3). Therefore, it can be seen that the radiolabeled compound of the present invention can clearly visualize tumors with high CA-IX expression.

[0170] [Examples 5-1 to 5-3, and Comparative Examples 2-1 to 2-3] In this example, two compounds (PSMA-DA1 and PSMA-DB) targeting PSMA were synthesized. Then, each compound was treated with a radioactive metal as 111 In ions, 90 Y ion or 225 Radiolabeled compounds were obtained by coordinating Ac ions to each compound. Details are shown below. The PSMA-DA1 used in Examples 5-1 to 5-3 contains a chelate, a target molecule binding, and an albumin binding site in its structure. The PSMA-DB used in Comparative Examples 2-1 to 2-3 contains a chelate and a target molecule binding site in its structure, but does not contain an albumin binding site.

[0171] <Examples 5-1 to 5-3> The general outlines of the reaction pathways in Examples 5-1 to 5-3 are shown below, designated as reaction pathways (V-1) and (V-2).

[0172] [ka]

[0173] [ka]

[0174] (1) Synthesis of PSMA-DA1 A precursor compound was obtained by synthesizing 1,4,7,10-tetraazacyclododecane in three steps according to the method described in Chem Commun. 2008, 28, 3248-3250. This precursor compound (20 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and methyl-N 6 -(4-(4-iodophenyl)butanoyl)-L-liginate (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. Subsequently, (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (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 then purified by reverse-phase HPLC under the following conditions to obtain the target compound (PSMA-DA1). The yield and MS results were as follows.

[0175] Purification conditions: Cosmosil 5C 18 - AR-II column (10 × 250 mm), mobile phase: MeCN / H2O / trifluoroacetic acid (TFA) [10 / 90 / 0.1 (0 min) ~ 100 / 0 / 0.1 (90 min)], flow rate: 4 mL / min. Yield: 1.0 mg (3%). MS(ESI)m / z1250.5[M+H] + .

[0176] (2) 111 In-type label (Example 5-1) Add to acetate buffer (0.1M, pH 5.5, 200 μL) [ 111In]InCl3 solution (3.7 MBq, 100 μL) and PSMA-DA1 DMSO solution (1 mM, 10 μL) were added and allowed to stand at 90°C for 30 minutes. Then the reaction mixture was purified by reverse-phase HPLC under the following conditions to obtain the target radiolabeled compound ([ 111 In]In-PSMA-DA1) was obtained. As a result, the radiochemical yield was 61-90%, and the radiochemical purity was over 95%.

[0177] 111 Purification conditions with In labeling: Cosmosil 5C 18 - PAQ column (4.6 × 250 mm), mobile phase: MeCN / H2O / TFA [20 / 80 / 0.1 (0 min) ~ 50 / 50 / 0.1 (30 min) or 5 / 95 / 0.1 (0 ~ 10 min), 5 / 95 / 0.1 (10 min) ~ 35 / 65 / 0.1 (40 min)], flow rate: 1 mL / min.

[0178] Furthermore, a compound in which PSMA-DA1 is coordinated to non-radioactive In can be produced, for example, by the following method. 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. After stirring the reaction mixture at 60°C for 12 hours, 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 250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) ~ 100 / 0 / 0.1 (90 minutes)], Flow rate: 4mL / min. MS(ESI):m / z1362.4[M+H] + .

[0179] (3) 90 Y-shaped sign (Example 5-2) Add to acetate buffer (0.1M, pH 5.5, 200 μL) [ 90YCl3 solution (65-118 MBq, 10 μL) and PSMA-DA1 DMSO solution (1 mM, 10 μL) were added and allowed to stand at 90°C for 30 minutes. Then the reaction mixture was purified by reverse-phase HPLC under the following conditions to obtain the target radiolabeled compound ([ 90 Y]Y-PSMA-DA1) was obtained. As a result, the radiochemical yield was 49-79%, and the radiochemical purity was over 95%.

[0180] 90 Purification conditions with Y labeling: Cosmosil 5C 18 - PAQ column (4.6 × 250 mm), mobile phase: MeCN / H2O / TFA [20 / 80 / 0.1 (0 min) ~ 50 / 50 / 0.1 (30 min) or 5 / 95 / 0.1 (0 ~ 10 min), 5 / 95 / 0.1 (10 min) ~ 35 / 65 / 0.1 (40 min)], flow rate: 1 mL / min.

[0181] (4) 225 Ac labeling (Example 5-3) [ 225 To a 0.2 M hydrochloric acid solution of Ac]AcCl3 (1.5 MBq, 10 μL), 0.1 M ammonium acetate buffer (pH 5.5, 170 μL) and a DMSO solution of PSMA-DA1 (2.0 M, 10 μL) were added, and the mixture was allowed to stand at 70°C for 1 hour. H2O (800 μL) was added to the reaction mixture and passed through an Oasis HLB Light column. After passing H2O (10 mL) through the column, 70% EtOH (0.5 mL) was passed through to obtain the target radiolabeled compound ([ 225 Ac[Ac-PSMA-DA1) was obtained. As a result, the radiochemical yield was 48-49%, and the radiochemical purity was 83-87%.

[0182] <Comparative Examples 2-1 to 2-3> The general outlines of the reaction pathways in Comparative Examples 2-1 to 2-3 are shown below as reaction pathways (VI-1) and (VI-2).

[0183] [ka]

[0184] [ka]

[0185] (1) Synthesis of PSMA-DB The precursor compound (35 mg, 0.045 mmol) synthesized in the same manner as in Example 5 was dissolved in DMF (2 mL), and (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (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, and the mixture was stirred at room temperature for 24 hours. After that, aniline (5 μL, 0.055 mmol) and EDC hydrochloride were added. (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, TFA (1.8 mL), triisopropylsilane (100 μL), and H2O (100 μL) were added to the residue, and the mixture was 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 results were as follows.

[0186] Purification conditions: Cosmosil 5C 18 -AR-II column (10 x 250mm), Mobile phase: MeCN / H2O / TFA [5 / 95 / 0.1 (0~10 minutes), 5 / 95 / 0.1 (10 minutes) ~ 35 / 65 / 0.1 (40 minutes)], Flow rate: 4mL / min. Yield: 5.0 mg (12%). MS(ESI)m / z925.3[M+H] + .

[0187] (2) 111 In label (Comparative Example 2-1) Except for using PSMA-DB instead of PSMA-DA1, the target radiolabeled compound ([ 111 In[In-PSMA-DB) was obtained. As a result, the radiochemical yield was 61-90%, and the radiochemical purity was over 95%.

[0188] Furthermore, a compound in which PSMA-DB is coordinated to non-radioactive In can be produced, for example, by the following method. To a solution of PSMA-DB (1 equivalent) in H2O / MeCN / TFA (49.95 / 49.95 / 0.1,300 μL), anhydrous indium(III) chloride (10 equivalents) was added. After stirring at room temperature for 18 hours, the solution was purified by reverse-phase HPLC. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6 x 150mm), Mobile phase: MeCN / H2O / TFA [5 / 95 / 0.1 (0~10 minutes), 5 / 95 / 0.1 (10 minutes) ~ 35 / 65 / 0.1 (40 minutes)], Flow rate: 1mL / min.

[0189] (3) 90 Y label (comparative example 2-2) Except for using PSMA-DB instead of PSMA-DA1, the target radiolabeled compound ([ 90 Y[Y-PSMA-DB) was obtained. As a result, the radiochemical yield was 49-79%, and the radiochemical purity was over 95%.

[0190] (4) 225 Ac label (Comparative Example 2-3) Except for using PSMA-DB instead of PSMA-DA1, the target radiolabeled compound ([ 225 Ac[Ac-PSMA-DB) was obtained. As a result, the radiochemical yield was 48-49%, and the radiochemical purity was 83-87%.

[0191] <Plasma stability evaluation> Mouse plasma (200 μL) [ 111 In]In-PSMA-DA1 (370kBq) or [ 90 A solution of Y]Y-PSMA-DA1 (3.7 MBq) in physiological 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 10000 × 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 (4.6×250mm), Mobile phase: MeCN / H2O / TFA [20 / 80 / 0.1 (0 minutes) ~ 50 / 50 / 0.1 (30 minutes)], Flow rate: 1mL / min.) As a result, more than 95% of all labeled compounds remained stable in mouse plasma even after standing at 37°C for 24 hours.

[0192] <Coupling 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 at 37°C under 5% CO2 conditions in Nacalai Tesque RPMI1640 containing antibiotics (penicillin and streptomycin) and 10% inactivated fetal bovine serum.

[0193] LNCaP cells and PC-3 cells were each divided into 4.0 × 10⁶ cells. 5 Cells were seeded in a 12-well plate at a rate of cells / well and left to stand for 48 hours at 37°C under 5% CO2. Remove the culture medium, [ 111 In]In-PSMA-DA1 or [ 111 A solution of assay medium (RPMI1640 medium containing 0.5% FBS) containing In]In-PSMA-DB (37 kBq) (1 mL) was added. The plate was then left to stand at 37°C under 5% CO2 for 1 hour. In the inhibition experiment, after removing the culture medium, [ 111 In]In-PSMA-DA1 or [ 111Assay medium (1 mL) containing In]In-PSMA-DB (37 kBq) and 2-(phosphonomethyl)pentanedioic acid (2-PMPA) (final concentration 100 μM) was added. The plate was then left to stand at 37°C under 5% CO2 for 1 hour. After removing the assay medium, each well was washed with assay medium (1 mL) that did not contain the radiolabeled compound or 2-PMPA, and the cells were lysed with 1 N sodium hydroxide aqueous 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 the Thermo Fisher Scientific BCA Protein Assay Kit. The percentage of sample radioactivity relative to the added radioactivity (%ID) divided by the total protein amount (%ID / mg protein) was calculated for each sample. Data are expressed as mean ± standard deviation. Significant difference testing was performed using Student's t-test, with p<0.05 considered statistically significant.

[0194] Figure 4 shows the results of the binding evaluation to cultured cells. A higher value indicates a greater abundance of the radiolabeled compound and a higher accumulation of the compound. [ 111 In]In-PSMA-DA1 and [ 111 In]In-PSMA-DB 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 PSMA inhibitor (2-PMPA). From these results, [ 111 In]In-PSMA-DA1 and [ 111 In]In-PSMA-DB has been shown to specifically bind to PSMA-highly expressing cells.

[0195] <Evaluation of binding to albumin> [ 111 In]In-PSMA-DA1 or [ 111The PBS solution (37 kBq, 50 μL) of In-PSMA-DB was added to 200 μL of PBS, mouse plasma, human plasma, or the PBS solution (45 mg / mL) of human serum albumin (HSA) respectively, and left to stand at 37 °C for 10 minutes. Then, the reaction solution was added to a spin column (Sephadex G-100 manufactured by Cytiva), and centrifuged at 1500×g and 4 °C for 2 minutes. After separation, the radioactivity of the column and the eluate was measured with a gamma counter respectively. The data were expressed as mean ± standard deviation. The significance test was performed using Student's t-test, and p < 0.05 was considered to be significant.

[0196] The results of the binding evaluation to albumin are shown in Fig. 5. The higher the value, the higher 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 by the gel in the column. 111 In-PSMA-DA1 and 111 After In-PSMA-DB was left to stand in PBS and then applied to the column, no significant radioactivity was observed in the eluate. On the other hand, when left to stand in mouse plasma, human plasma, and HSA solution, 111 compared with In-PSMA-DB 111 the radioactivity in the eluate of In-PSMA-DA1 was significantly higher, 111 indicating that In-PSMA-DA1 binds to plasma albumin.

[0197] <In Vivo Radioactivity Distribution Evaluation Using LNCaP or PC-3 Tumor-Bearing Mice> The animal experiment was carried out in accordance with the guidelines of the Animal Experiment Committee of Kyoto University. Male CB17 / IcrJcl-Prkdc scid ​Mice were purchased from CREA Japan Co., Ltd. The animals were housed under a 12-hour / 12-hour day-night cycle and were given free access to food and water. LNCaP cells (1.0 × 10⁶) were added to a mixture of PBS and Corning Life Sciences' Matrigel (1:1,150 μL). 7 cells / mouse) or PC-3 cells (1.0 × 10⁻⁶) 7 The cells (or mouse cells) were suspended and subcutaneously transplanted into the right shoulder of mice under isoflurane anesthesia. The mice were then kept in captivity for 40-60 days. In LNCaP or PC-3 tumor-grafted mice, [ 111 In]In-PSMA-DA1, or [ 111 A saline solution of In]In-PSMA-DB (185 kBq, 100 μL) was administered via 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 the mass and radioactivity of the organs were measured. This value is expressed as the percentage of radioactivity relative to the injected dose (%ID) divided by the blood mass or organ mass (g) (%ID / g). A higher %ID / g value indicates a greater abundance of the radiolabeled compound and higher accumulation of the compound in the target organ.

[0198] LNCaP tumor transplanted mice and [ 111 The results for In]In-PSMA-DA1 (mean ± standard deviation, n=3 for each) are shown in Table 4 and Figure 6 below. LNCaP tumor transplanted mice and [ 111 The results (mean ± standard deviation, n=3 each) for the In-PSMA-DB are shown in Table 5 and Figure 6 below. [ 111 In]In-PSMA-DA1 showed high uptake 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 after 48 hours after administration. On the other hand,[ 111 In-PSMA-DB is used at any time point, 111Lower tumor accumulation than In-PSMA-DA1 was observed, and a low tumor / kidney ratio was shown. From these results, 111 In-PSMA-DA1 has high accumulation in PSMA highly expressed tumors and 111 was found to have an excellent in vivo distribution compared to In-PSMA-DB.

[0199]

Table 4

[0200]

Table 5

[0201] PC-3 tumor transplanted mice and 111 The results in In-PSMA-DA1 (mean ± standard deviation, n = 3 each) are shown in Table 6 below. PC-3 tumor transplanted mice and 111 The results in In-PSMA-DB (mean ± standard deviation, n = 3 each) are shown in Table 7 below. 111 Both In-PSMA-DA1 and 111 In-PSMA-DB showed lower accumulation in PC-3 tumors than the results of accumulation in LNCaP tumors at the same time point, indicating that both radiolabeled compounds selectively accumulate in PSMA-positive tumors.

[0202]

Table 6

[0203]

Table 7

[0204] <SPECT / CT using LNCaP tumor transplanted mice> ​In the LNCaP tumor-transplanted mice created using the method described above, 111 In]In-PSMA-DA1 or [ 111 In]In-PSMA-DB in a saline solution (1.9-3.0 MBq, 150 μL) was administered via tail vein. SPECT / CT was performed 24 and 48 hours after administration using a Gamma Medica-Ideas FX3300 pre-clinical imaging system. Under isoflurane anesthesia, imaging was performed using a 1.0 mm diameter pinhole collimator with a rotation radius of 35 mm, 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 3D ordered subset expectation maximization method (8 subsets, 5 iterations).

[0205] The SPECT / CT results are shown in Figure 7. In the figure, the areas indicated by arrows are the locations of the tumors, and the areas indicated by circles are the locations of the kidneys. A higher SUV indicates a higher concentration of radioactivity. [ 111 SPECT / CT imaging using In]In-PSMA-DA1 showed significant radioactivity accumulation in LNCaP tumors (arrows in the figure) at 24 and 48 hours after administration. High radioactivity accumulation was also observed in the kidneys (circles in the figure), but the radioactivity signal was similar to that of the tumors at 48 hours after administration. On the other hand,[ 111 In SPECT / CT imaging using In]In-PSMA-DB, radioactivity accumulation was observed in LNCaP tumors (arrows in the figure), but the accumulation was lower compared to the kidney (circles in the figure). From these results, [ 111 In]In-PSMA-DA1 makes it possible to clearly visualize PSMA-high-expression tumors by SPECT, and [ 111 It was shown to be superior to In[In-PSMA-DB].

[0206] < 90 Evaluation of tumor growth suppression by Y-labeled compounds> [ obtained by the method described above 90Y]Y-PSMA-DA1(3.7MBq) or [ 90 A 100 μL solution of Y]Y-PSMA-DB (3.7 MBq) in physiological saline was administered via tail vein to LNCaP tumor-grafted mice (n=7). As a control group, 100 μL of physiological saline was administered via tail vein to LNCaP tumor-grafted 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 It was calculated based on the formula "[ / 2]". 90 The tumor volume on the day of initiation of Y-labeled compound administration was [ 90 Y]Y-PSMA-DA1,[ 90 In the groups administered Y]Y-PSMA-DB and physiological saline, the values ​​were 63.1±8.7, 66.1±30.7, and 66.7±25.7 mm, respectively. 3 That was the case.

[0207] The results of this evaluation are shown in Figure 8. In LNCaP tumor-transplanted mice, [ 90 Y]Y-PSMA-DA1 and [ 90 When [Y]Y-PSMA-DB was administered, significant differences in tumor volume were observed compared to the saline administration group at 9 days and 33 days after administration, respectively. 90 Compared to Y]Y-PSMA-DB, [ 90 Y]Y-PSMA-DA1 showed a tendency to suppress tumor growth. 90 Administration of Y]Y-PSMA-DA1 caused a slight decrease in the body weight of mice, but it subsequently recovered to levels comparable to those of the group administered with physiological saline.

[0208] < 225 Evaluation of tumor growth suppression by Ac-labeled compounds> [ obtained by the method described above 225 Ac]Ac-PSMA-DA1 (20kBq) or [ 225Ac]Ac-PSMA-DB (20 kBq) was dissolved in 5% ethanol-containing acetate buffer (158 mM, pH 6.5, 100 μL) and administered via tail vein to LNCaP tumor-grafted mice (n=6 or 5). As a control group, 100 μL of 5% ethanol-containing acetate buffer (158 mM, pH 6.5) was administered via tail vein to LNCaP tumor-grafted mice (n=4). 225 After administration of the Ac-labeled compound, tumor volume and body weight were measured three times per week. 225 The tumor volume on the day of starting administration of Ac-labeled compound was [ 225 Ac]Ac-PSMA-DA1,[ 225 In the groups administered Ac]Ac-PSMA-DB and 5% ethanol-containing acetate buffer, the values ​​were 75.3±26.0, 80.6±20.8, and 91.1±15.9 mm, respectively. 3 That was the case.

[0209] The results of this evaluation are shown in Figure 9. In LNCaP tumor-transplanted mice, [ 225 Ac]Ac-PSMA-DA1 and [ 225 When Ac]Ac-PSMA-DB was administered, tumor growth was significantly suppressed compared to the group administered with physiological saline. In particular, [ 225 In the Ac]Ac-PSMA-DA1 treatment group, tumor growth was minimal, and sustained growth inhibition was observed up to 6 weeks after administration. [ 225 The weight loss, which was thought to be due to the administration of Ac]Ac-PSMA-DA1, was transient. 225 Weight loss, which was thought to be due to the administration of Ac]Ac-PSMA-DB, temporarily accelerated, but no signs of recovery were observed thereafter.

[0210] [Example 6 and Comparative Example 3] In this example, two compounds (E4DA1 and E4D) targeting the GLP-1 receptor were synthesized. Subsequently, these compounds were treated with a radioactive metal as 111 A radiolabeled compound with an In ion coordinated to it was obtained. The schematic of the reaction pathway is shown below as reaction pathways (VII-1) and (VII-2). The E4DA1 used in Example 6 contains a chelate, a target molecule binding, and an albumin binding site in its structure. The E4D used in Comparative Example 3 contains a chelate and a target molecule binding site in its structure, but does not contain an albumin binding site.

[0211] [ka]

[0212] [ka]

[0213] <Synthesis of Compound 61> Fmoc-Lys(Mtt)-OH (200 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL), and tert-butyl trichloroacetimidate (140 mg, 0.64 mmol) was slowly added. BF3·OEt2 (10 μL) was then added, and the mixture was stirred at room temperature for 24 hours. The solvent was then removed by vacuum distillation. Hexane was added to the residue, and after filtration, H2O was added to the filtrate for liquid-liquid separation. The organic layer was removed by vacuum distillation. The residue was then purified by medium-pressure column chromatography (hexane / ethyl acetate). The yield, NMR spectrum, and MS results are as follows.

[0214] Yield: 47.3 mg (22%). 1 H-NMR:(400MHz,CDCl3)δ7.90(d,2H),7.55(d,2H),7.30(t,17H),7.09(s,2H),4.70(d,2H),4.46( t,2H),4.16(s,1H),2.53(t,2H),2.19(s,3H),1.88(t,2H),1.42(s,9H),1.39(t,2H),1.25(t,2H). 13C-NMR:(100MHz,CDCl3)δ171.5,155.9,145.0(2C),143.6(2C),142.6(2C),142.0,135.9,129.2(6C),127.0(4C),1 26.7(2C),126.2(2C),125.2(2C),120.5(2C),82.1,78.3,67.3,58.6,47.0,44.3,30.8(2C),28.7(3C),25.0,21.3. MS(ESI):m / z681.4[M+H] + .

[0215] <Synthesis of Compound 62> Compound 61 (100 mg, 0.147 mmol) was added to a trifluoroacetic acid (TFA) / triisopropylsilane / dichloromethane mixed solution (1 / 5 / 94, 5 mL) and stirred at room temperature. After 48 hours, the solvent was removed by distillation under reduced pressure. The residue was then purified by medium-pressure column chromatography (chloroform / methanol). The yield, NMR spectrum, and MS were as follows.

[0216] Yield: 50.3 mg (81%). 1 H-NMR:(400MHz,CDCl3)δ7.90(d,2H),7.55(d,2H),7.38(t,3H),4.51(t,1H),4.46(t ,2H),2.69(t,2H),1.88(t,2H),1.53(t,2H),1.50(d,2H),1.42(s,9H),1.25(t,2H). 13 C-NMR:(100MHz,CDCl3)δ171.5,155.9,143.6(2C),142.6(2C),126.7(2C),126 .2(2C),125.2(2C),120.5(2C),82.1,67.3,42.0,30.8,29.0,28.7(3C),22.7. MS(ESI):m / z425.3[M+H] + .

[0217] <Synthesis of Compound 63> 4-(4-iodophenyl)butyryl acid (42.5 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (DMF), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (38.3 mg, 0.2 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (27.2 mg, 0.2 mmol) were added and the mixture was stirred at 0°C. After 15 minutes, compound 62 (29.0 mg, 0.1 mmol) dissolved in DMF (5 mL) was added and the mixture was stirred at 0°C. After 10 hours, the DMF was removed by distillation under reduced pressure. The residue was then purified by medium-pressure column chromatography (chloroform / methanol). The yield, NMR spectrum, and MS were as follows.

[0218] Yield: 41.7 mg (60%). 1 H-NMR:(400MHz,CDCl3)δ7.90(d,2H),7.70(s,1H),7.57(d,2H),7.55(d,2H),7.38(t,3H),7.28(t,2H),6.97(d,2H),4.70(d,2H), 4.51(t,1H),4.46(t,2H),3.00(t,2H),2.63(t,2H),2.34(t,2H),1.88(t,2H),1.70(t,2H),1.53(t,2H),1.42(s,9H),1.25(t,2H). 13 C-NMR:(100MHz,CDCl3)δ172.6,171.5,155.9,143.6(2C),142.6(2C),140.9,137.7(2C),129.7(2C),126.7(2C),126. 2(2C),125.2(2C),120.5(2C),91.6,82.1,67.3,58.6,47.0,42.0,39.2,36.1,34.7,30.8,29.7,28.7(3C),27.4,22.7. MS(ESI):m / z697.3[M+H] + .

[0219] <Synthesis of Compound 64> Compound 63 (34.8 mg, 0.050 mmol) was dissolved in DMF (5 mL), 20% piperidine (500 μL) was added, and the mixture was stirred at room temperature. After 2 hours, the mixture was separated with ethyl acetate / hexane = 1:5 (50 mL) and H2O (50 mL), and the organic layer was removed by vacuum distillation. The residue was then purified by medium-pressure column chromatography (chloroform / methanol). The yield, NMR spectrum, and MS results are as follows.

[0220] Yield: 17.6 mg (74%). 1 H-NMR:(400MHz,CDCl3)δ8,76(s,2H),7.70(s,1H),7.57(d,2H),6.97(d,2H),3.36(t,1H),3.00(t ,2H),2.63(t,2H),2.34(t,2H),1.88(t,2H),1.70(t,2H),1.53(t,2H),1.42(s,9H),1.25(t,2H). 13 C-NMR:(100MHz,CDCl3)δ174.0,172.6,140.9,137.7(2C),129.7(2C),91.6,82.1,52.9,39.2,36.1,34.7,31.3,29.7,28.7(3C),27.4,22.7. MS(ESI):m / z475.2[M+H] + .

[0221] <Synthesis of Compound 65> Similar to Example 5, it was synthesized in three steps from 1,4,7,10-tetraazacyclododecane (Chem Commun. 2008, 28, 3248-3250).

[0222] <Synthesis of Compound 66> Compound 65 (50 mg, 0.065 mmol) and N-(2-aminoethyl)maleimide hydrochloride (11.4 mg, 0.065 mmol) were added to DMF (10 mL) and stirred at room temperature. After 10 minutes, N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU) (137.0 mg, 0.32 mmol) and N,N-diisopropylethylamine (DIPEA) (4.80 μL, 0.32 mmol) were added and stirred at room temperature. After 36 hours, purification was performed by reverse-phase HPLC under the following conditions. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 20.8 mg (36%). MS(ESI):m / z895.4[M+H] + .

[0223] <Synthesis of Compound 67> Compound 66 (20.0 mg, 0.022 mmol) and compound 68 (10.6 mg, 0.022 mmol), described later, were added to DMF (5 mL) and stirred at room temperature for 10 minutes. Then COMU (47.1 mg, 0.11 mmol) and DIPEA (1.65 μL, 0.11 mmol) were added. After stirring at room temperature for 4 hours, purification was performed by reverse-phase HPLC under the following conditions. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 5.8 mg (20%). MS(ESI):m / z1351.4[M+H] + .

[0224] <Synthesis of Compound 68> Compound 67 (5.75 mg, 4.2 μmol) was mixed with TFA (2 mL), stirred at room temperature for 1 hour, and then purified by reverse-phase HPLC under the following conditions. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 4.3 mg (95%). MS(ESI):m / z1071.1[M+H] + .

[0225] <Synthesis of Compound 69 (E4DA1)> Compound 68 (4.27 mg, 3.99 μmol) and Exendin-4-Cys (17.1 mg, 3.99 μmol) were dissolved in phosphate-buffered saline (PBS) (pH 7.5, 2 mL) and stirred at 3°C. After 24 hours, purification was performed by reverse-phase HPLC under the following conditions: [H2O (0.1% TFA) / MeCN (0.1% TFA) = 90 / 10 to 40 / 60 gradient, 30 minutes]. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 3.8 mg (18%). MS(ESI):m / z1787.5[M+3H] 3+ ,1072.8[M+5H] 5+ .

[0226] <Synthesis of Compound 6A> Compound 66 (20 mg, 0.022 mmol) was mixed with TFA (2 mL) and stirred at room temperature for 2 hours. The mixture was then purified by reverse-phase HPLC under the following conditions. The yield and MS results are as follows. Purification conditions: Cosmosil 5C 18-AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 13.2mg(90%).MS(ESI)m / z671.2[M+H] + .

[0227] <Synthesis of compound 6B(E4D)> Compound 6A (2.4 mg, 3.58 μmol) and Exendin-4-Cys (15.3 mg, 3.58 μmol) were dissolved in PBS (pH 7.5, 2 mL) and stirred at 3°C. After 24 hours, purification was performed by reverse-phase HPLC under the following conditions. The yield and MS results are as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 60 / 40 / 0.1 (30 min)], Flow rate: 5 mL / min. Yield: 1.8 mg (10%). MS(ESI):m / z827.4[M+6H] 6+ .

[0228] < 111 In labeling (Example 6 and Comparative Example 3) [ 111 Mix in an In[InCl3] solution (74 kBq, 20 μL) and let stand at room temperature for 10 minutes. Add a dimethyl sulfoxide (DMSO) solution (10 μM, 30 μL) of the precursor compound (compound 69 or compound 6B) to the reaction solution and let stand at 90°C for 30 minutes. Then, purify the reaction mixture by reverse-phase HPLC under the following conditions to obtain the desired radiolabeled compound ([ 111 In]In-E4DA1, or [ 111 In]In-E4D) was obtained. Purification conditions: Cosmosil 5C 18-AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 60 / 40 / 0.1 (40 minutes)], Flow rate: 1mL / min. the result,[ 111 The radiochemical yield of In]In-E4DA1 was 11.6%, and the radiochemical purity was 95% or higher. 111 The radiochemical yield of In]In-E4D was 4.6%, and the radiochemical purity was over 95%.

[0229] <Coupling evaluation using cultured cell lines> INS-1 cells (rat insulinoma) were used. INS-1 cells were cultured at 37°C under 5% CO2 conditions in RPMI1640 from Nacalai Tesque, Inc., containing sodium pyruvate (1 mM), β-mercaptoethanol (50 μM), HEPES, sodium bicarbonate (1.5 g / L), antibiotics (penicillin and streptomycin), and 10% inactivated fetal bovine serum.

[0230] INS-1 cells (4.0×10 5 Cells ( / well) were seeded into a 12-well plate and left to stand at 37°C under 5% CO2 for 48 hours. The culture medium was removed, and then, as the assay medium, [ 111 RPMI1640 solution (1 mL) containing In]In-E4DA1 (9.8 kBq), or [ 111 RPMI1640 solution (1 mL) containing In]In-E4D (9.8 kBq) was added. In the inhibition experiment, after removing the culture medium, the assay medium was used as [ 111 RPMI1640 solution (1 mL) containing In]In-E4DA1 (9.8 kBq) and Exendin-4-Cys (final concentration 10 μM), or [ 111 RPMI1640 solution (1 mL) containing In]In-E4D (9.8 kBq) and Exendin-4-Cys (final concentration 10 μM) was added. The plate was then left to stand at 37°C under 5% CO2 for 2 hours. After removing the assay medium, each well was washed with PBS (1 mL), and the cells were lysed with 1 N sodium hydroxide solution (200 μL x 2). The radioactivity of each component in the cell lysate was measured using a gamma counter. Separately, the total protein concentration in the cell lysate was calculated using the BCA method, similar to the method described above. For each sample, the percentage of the sample's radioactivity relative to the added radioactivity (%ID) was divided by the total protein content (%ID / mg protein) to calculate the value. Data are expressed as mean ± standard deviation. Significant difference testing was performed using Student's t-test, with p<0.05 considered statistically significant.

[0231] Figure 10 shows the results of the binding evaluation to cultured cells. A higher value indicates a greater abundance of the radiolabeled compound and higher accumulation of the compound. [ 111 In]In-E4DA1 showed binding affinity to INS-1 cells (16% dose / mg protein), and this binding was significantly reduced by the addition of an excess amount of Exendin-4-Cys (1.0% dose / mg protein). Similarly, [ 111 The binding affinity of In]In-E4D to INS-1 cells (5.4% dose / mg protein) and the amount of binding decreased upon addition of Exendin-4-Cys (1.2% dose / mg protein) were observed. From these results, [ 111 In]In-E4DA1 was shown to specifically bind to GLP-1 receptor-highly expressing cells, and the introduction of an albumin-binding site improved its binding affinity to GLP-1 receptor-highly expressing cells.

[0232] <Evaluation of binding to albumin> [ 111 In]In-E4DA1 in PBS solution (37kBq, 50μL), or [ 111 A PBS solution of In]In-E4D (37 kBq, 50 μL) was added to a PBS and human albumin (HSA) solution (45 mg / mL) and allowed to stand at 37°C for 10 minutes. Subsequently, the reaction solution was added to a spin column (Sephadex G-100 manufactured by Cytiva), and centrifuged at 1500 g for 2 minutes at 4°C. After centrifugation, the radioactivity of the column and the eluate was measured with a gamma counter respectively. The data were expressed as mean ± standard deviation. The significance test was performed using Student's t-test, and p < 0.05 was considered to indicate a significant difference.

[0233] The results of the evaluation of binding to albumin are shown in Table 8. 111 When [In]In-E4DA1 was allowed to stand in PBS or HSA solution and then applied to the column, the radioactivity ratio of the eluate in the HSA solution (65.6%) was significantly higher than that in the PBS solution (5.9%). Also, 111 the radioactivity ratio of the eluate of [In]In-E4DA1 in the HSA solution was 111 significantly higher than that of [In]In-E4D (20.2%). From these results, 111 it was shown that [In]In-E4DA1 has binding affinity for albumin, and the binding affinity for albumin is retained even when an albumin-binding moiety is introduced together with a structure containing a peptide with a large molecular weight such as Exendin-4.

[0234]

Table 8

[0235] <Evaluation of in vivo radioactivity distribution using INS-1 tumor-bearing mice> Animal experiments were conducted in accordance with the guidelines of the Animal Experiment Committee of Kyoto University. Male BALB / c-nu / nu nude mice were purchased from Japan SLC, Inc. The animals were housed under a 12-hour / 12-hour light / dark cycle condition, and food and water were provided ad libitum. INS-1 cells (5.0×10 6 ​The cells / mouse were suspended and subcutaneously transplanted into the right shoulder of BALB / c-nu / nu nude mice under isoflurane anesthesia. Tumor-transplanted mice were used when the tumor diameter reached 10 mm. In INS-1 tumor-grafted mice, [ 111 In]In-E4DA1 in a saline solution (37kBq, 100μL), or [ 111 A saline solution of In]In-E4D (30 kBq, 100 μL) was administered via the tail vein (n=4). Mice were euthanized 1, 4, 24, 48, and 96 hours after administration. Blood and organs were then collected, and the mass and radioactivity of the organs were measured. This value is expressed as the percentage of radioactivity relative to the injected dose (%ID) divided by the blood mass or organ mass (g) (%ID / g). A higher %ID / g value indicates a greater abundance of the radiolabeled compound and higher accumulation of the compound in the target organ.

[0236] INS-1 tumor-transplanted mice and [ 111 The results for In]In-E4DA1 (mean ± standard deviation, n=4 for each) are shown in Table 9 and Figure 11 below. INS-1 tumor-transplanted mice and [ 111 The results for In]In-E4D (mean ± standard deviation, n=4 for each) are shown in Table 10 and Figure 11 below. [ 111 In]In-E4DA1 showed high accumulation in INS-1 tumors (66.1-132% ID / g 1-24 hours after administration). It also showed retention in the blood (6.01% ID / g 24 hours after administration), and the tumor / kidney ratio was high (1.96-2.80 1-96 hours after administration). 111 Similar experiments were conducted with In]In-E4D, comparing radioactivity accumulation in tumors, blood, and kidneys, as well as tumor / blood accumulation ratios and tumor / kidney accumulation ratios. At all time points, [ 111 In comparison with In-E4D, 111 Low renal uptake of In]In-E4DA1 was observed, along with high tumor uptake. From these results, [ 111In]In-E4DA1 has a high accumulation property for tumors with high GLP-1 receptor expression and, 111 was found to have a better in-vivo distribution than In]In-E4D.

[0237]

Table 9

[0238]

Table 10

[0239] <SPECT / CT of INS-1 tumor-bearing mice> To the INS-1 tumor-bearing mice prepared by the above method, 111 an aqueous physiological saline solution of In]In-E4DA1 (0.30 MBq, 100 μL) or 111 an aqueous physiological saline solution of In]In-E4D (1.2 MBq, 100 μL) was administered via the tail vein. Six hours after administration, SPECT / CT was performed using a FX3300 pre-clinical imaging system manufactured by Gamma Medica-Ideas. Under isoflurane anesthesia, imaging was performed using a pinhole collimator with a diameter of 1.0 mm at a rotation radius of 35 mm, a projection time of 70 seconds, and 32 projection times. After SPECT, CT (tube voltage: 60 kV, tube current: 350 μA) was performed. Image reconstruction of the SPECT projection data was performed by the three-dimensional ordered subset expectation maximization method (8 subsets, 5 iterations).

[0240] The results of SPECT / CT are shown in Fig. 12. In the figure, the part indicated by the arrow is the location of the tumor, and the part indicated by the circle is the location of the kidney. The higher the SUV, the higher the radioactivity accumulation. 111 In SPECT / CT imaging using In]In-E4DA1, high radioactivity accumulation was observed in the tumor, but almost no radioactivity signal was observed in the kidney. On the other hand, 111 ​In In]In-E4D, higher radioactivity accumulation was observed in the kidneys compared to tumors. These results suggest that the presence of an albumin-binding site improves the distribution within the body, [ 111 In]In-E4DA1 has been shown to enable clear visualization of tumors with high GLP-1 receptor expression.

[0241] [Example 7] In this example, a compound (PtDA) was synthesized using a click reaction between an azide group and dibenzylcyclooctin (DBCO) to bond the chelate moiety and the target molecule, with (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid (structure in formula (C3) above, where a is 2 and b is 4) as the target molecule binding site, with PSMA as the target molecule. Subsequently, these compounds were treated with radioactive metals. 111 Radiolabeled compounds with coordinated In ions were obtained. The general outline of the reaction pathways is shown below as reaction pathways (VIII-1) to (VIII-4). The compound used in Example 7 contains a chelate, a target molecule binding, and an albumin binding site in its structure. Also, 111 There are two reaction pathways for coordinating with the In ion (see reaction pathway (VIII-4)), but the resulting radiolabeled compound is the same regardless of which pathway is used.

[0242] [ka]

[0243] [ka]

[0244] [ka]

[0245] [ka]

[0246] <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 tert-butyl trichloroacetimidate (699.5 mg, 3.2 mmol) and BF3·OEt2 (25 μL) were added. The reaction solution was stirred at room temperature for 42 hours. After removing the solvent, the residue was washed with H2O (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL × 2). The organic layer was dried over sodium sulfide and filtered. After removing the filtrate under reduced pressure, the residue was purified by medium-pressure column chromatography (ethyl acetate / hexane). The yield, NMR spectrum, and MS were as follows.

[0247] Yield: 569 mg (52%). 1 H-NMR(400MHz,CDCl3)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). 13C-NMR(100MHz,CDCl3)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] + .

[0248] <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 the mixture was 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.

[0249] Yield: 355 mg (100%). 1 H-NMR(400MHz,CDCl3)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,1H),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,CDCl3)δ171.5,156.2,143.6(2C),141.1(2C),127.6(2C),127.0(2C),1 25.0(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] + .

[0250] <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, and the mixture was stirred at 0°C for 15 minutes. Then, compound 72 (355 mg, 0.84 mmol) and triethylamine (169 mg, 1.7 mmol) were added, and the mixture was stirred at 0°C. After 15 hours, the reaction solution was washed with H2O (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. After removing the filtrate under reduced pressure, the residue was purified by medium-pressure column chromatography (ethyl acetate / hexane). The yield, NMR spectrum, and MS were as follows.

[0251] Yield: 226 mg (39%). 1 H-NMR(400MHz,CDCl3)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,CDCl3)δ172.8,171.5,156.0,143.5(2C),141.0-140.9(3C),137.1(2C),130.3(2C),127.5(2C),12 6.9(2C),124.9(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] + .

[0252] <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 washed with H2O (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. After removing the filtrate under reduced pressure, the residue was purified by medium-pressure column chromatography (methanol / chloroform). The yield, NMR spectrum, and MS were as follows.

[0253] Yield: 133 mg (87%). 1 H-NMR(400MHz,CDCl3)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,CDCl3)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] + .

[0254] <Synthesis of Compound 75> Similar to the examples described above, it was synthesized in three steps from 1,4,7,10-tetraazacyclododecane (Chem Commun. 2008, 28, 3248-3250).

[0255] <Synthesis of Compound 76> To a solution of compound 75 (317 mg, 0.41 mmol) in DMF (2 mL), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU) (176 mg, 0.41 mmol) was added 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 mixture and the mixture was stirred for another 15 minutes at 0°C, 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 results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (20×250mm), Mobile phase: MeCN / H2O / TFA [30 / 70 / 0.1 (0 min) to 90 / 10 / 0.1 (40 min)], Flow rate: 5 mL / min. Yield: 229 mg (55%). HRMS(ESI)m / z1229.6182[M+H] + .

[0256] <Synthesis of Compound 77> To a solution of compound 76 (106 mg, 0.086 mmol) in DMF (0.6 mL), COMU (147 mg, 0.34 mmol) was added 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 for another 15 minutes at 0°C, after which dibenzocyclooctinamine (ADIBO-NH2) (36 mg, 0.22 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 results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (20×250mm), Mobile phase: MeCN / H2O / TFA [20 / 80 / 0.1 (0 min) to 90 / 10 / 0.1 (35 min)], Flow rate: 5 mL / min. Yield: 51 mg (40%). HRMS(ESI):m / z1487.7351[M+H] + .

[0257] <Synthesis of Compound 78 (ADA)> To a solution of compound 76 (50 mg, 0.041 mmol) in MeCN (0.4 mL), COMU (70 mg, 0.16 mmol) was added and the mixture was stirred at 0°C for 15 minutes. DIPEA (89 mg, 0.69 mmol) was added to the reaction mixture and stirred for another 15 minutes at 0°C, after which N-hydroxysuccinimide (19 mg, 0.16 mmol) was added. After stirring at room temperature for 24 hours, the solution was washed with H2O (100 mL) and extracted with ethyl acetate / hexane (1 / 5, 100 mL x 2). The organic layer was dried over sodium sulfide and filtered. After removing the filtrate under reduced pressure, 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), and ADIBO-NH2 (6.2 mg, 0.023 mmol) was added. After stirring the reaction mixture at room temperature for 24 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 (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. Yield: 6.7 mg (27%). HRMS(ESI):m / z1207.4213[M+H] + .

[0258] <Synthesis of Compound 7A> (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (31 mg, 0.064 mmol) was dissolved in DMF (0.5 mL), and 2,5-dioxopyrrolidin-1-yl 1-azido-3,6,9,12-tetraoxapentadecan-15-oate1 (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.

[0259] Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [30 / 70 / 0.1 (0 minutes) ~ 90 / 10 / 0.1 (30 minutes)], Flow rate: 4mL / min. Yield: 35 mg (72%). 1 H-NMR(400MHz,CDCl3)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,CDCl3)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] + .

[0260] <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 reverse-phase HPLC under the following conditions. The yield, NMR spectrum, and MS were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (10×250mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) to 40 / 60 / 0.1 (30 min)], Flow rate: 4 mL / min. Yield: 11 mg (63%). 1 H-NMR (400MHz, CDCl3) 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] + .

[0261] <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. TFA (1.9 mL), thioanisole (60 μL), triisopropylsilane (20 μL), and H2O (20 μL) were added to the residue, and the mixture was stirred at room temperature for 10 hours. After removing the solvent, the residue was purified by reverse-phase HPLC under the following conditions. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. Yield: 1.0 mg (4.2%). HRMS(ESI):m / z900.3488[M+2H] 2+ .

[0262] <By Route A[ 111Synthesis of In-ADA Add to 2-(N-morpholino)ethanesulfonic acid (MES) buffer (0.1M, pH 5.7, 100 μL) [ 111 In]InCl3 solution (9.2 MBq, 100 μL) and dimethyl sulfoxide (DMSO) solution of compound 78 (0.60 mM, 7 μL) were added, and the mixture was allowed to stand at 90°C for 5 minutes. The reaction solution was then purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], Flow rate: 1mL / min. Radiochemical conversion rate ([ 111 [In]InCl3's radioactivity 111 The percentage of radioactivity (of In)In-ADA and the radiochemical yield are shown in Table 11 below.

[0263] <By Route A[ 111 Synthesis of In-PtDA Add phosphate-buffered saline (PBS) / DMSO mixture (9 / 1,200 μL) or DMSO (200 μL) to [ 111 In]In-ADA (0.80 MBq) was added, followed by compound 7B (0.2 mg). After standing at 37°C for 10 or 30 minutes, the reaction solution was purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], Flow rate: 1mL / min. Radiochemical conversion rate ([ 111 In-ADA's response to radioactivity 111 The radioactivity ratio (of In]In-PtDA) and radiochemical yield are shown in Table 11 below.

[0264] <By Route B[ 111 Synthesis of In-PtDA In MES buffer (0.1M, pH 5.7, 150μL) [ 111 In]InCl3 solution (2.1 MBq, 100 μL) and compound 7C in DMSO solution (0.56 mM, 2 μL) were added, and the mixture was allowed to stand at 90°C for 5 minutes. The reaction solution was then purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], Flow rate: 1mL / min. Radiochemical conversion rate ([ 111 [In]InCl3's radioactivity 111 The radioactivity ratio (of In]In-PtDA) and radiochemical yield are shown in Table 11 below.

[0265] [Table 11]

[0266] Furthermore, In-ADA and In-PtDA, which are coordinated with non-radioactive In, can be manufactured by the following method. <Synthesis of non-radioactive In-ADA> Compound 78 (1 equivalent) was dissolved in acetate buffer (1.0 M, pH 5.0, 100 μL), and anhydrous indium(III) chloride (10 equivalents) was added. The reaction mixture was stirred at 90°C for 5 minutes, and the solution was purified by reverse-phase HPLC. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 30.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. MS(ESI):m / z1319.3[M+H] + .

[0267] <Synthesis of non-radioactive In-PtDA> To a solution of compound 7C (0.5 mg, 1.25 mmol) in H2O / MeCN / TFA (49.95 / 49.95 / 0.1, 300 μL), anhydrous indium(III) chloride (0.62 mg, 2.8 μmol) was added. After stirring at room temperature for 18 hours, the solution was purified by reverse-phase HPLC. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. Yield: 0.05 mg (9.4%). HRMS(ESI):m / z956.2893[M+2H] 2+ .

[0268] <Evaluation of distribution coefficient> In a mixture of PBS (pH 7.4, 3 mL) and 1-octanol (3 mL), [ 111 In]In-PtDA (111 kBq) was added, and the mixture was vortexed for 2 minutes to disperse it, then centrifuged at 4000 × g for 5 minutes. 1 mL each 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 formula is: (Distribution coefficient) = Log 10 The formula used was: [(1-octanol layer radioactivity [kBq]) / (PBS layer radioactivity [kBq])]. the result,[ 111 The LogP of In[In-PtDA] was "-3.08±0.02".

[0269] <Evaluation of plasma stability> Mouse plasma (200 μL) [ 111 In]In-PtDA (259 kBq) was added to physiological saline (20 μL) and allowed to stand at 37°C for 24 hours (n=3). MeCN (400 μL) was added and the mixture was centrifuged at 10000 × 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 (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], Flow rate: 1mL / min. As a result, as shown in Figure 13, [ 111 In]In-PtDA remained stable in mouse plasma at a concentration of over 95% even after standing at 37°C for 24 hours.

[0270] <Coupling evaluation using cultured cell lines> Similar to Example 5-1 described above, LNCaP cells and PC-3 cells were cultured and cell binding experiments were performed. As the assay medium, [ 111 The evaluation was performed using the same experimental procedure and statistical methods as in Example 5-1, except that RPMI1640 medium (1 mL) containing 0.5% FBS with In]In-PtDA (37 kBq) was used.

[0271] The results are shown in Figure 14. [ 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 this binding was significantly reduced by the addition of an excess amount of PSMA inhibitor (2-PMPA) (0.36% ID / mg protein). From these results, [ 111 In]In-PtDA has been shown to specifically bind to PSMA-positive cells.

[0272] <Evaluation of binding to albumin> Similar to Example 5-1 described above, binding to albumin was evaluated using PBS, mouse plasma, human plasma, and human albumin. 111 The evaluation was performed using the same experimental procedure and statistical methods as in Example 5-1, except that a PBS solution of In]In-PtDA (37 kBq, 50 μL) was used.

[0273] The results are shown in Figure 15. [ 111After standing In-PtDA in PBS and then subjecting it to a column, little radioactivity was detected in the eluate (6.9%). On the other hand, when it was left standing in mouse plasma, human plasma, and human albumin solution, high radioactivity was observed in the eluate (67.2, 79.0, and 92.4% respectively), 111 It was shown that In-PtDA binds to plasma albumin.

[0274] <Evaluation of In Vivo Radioactivity Distribution Using LNCaP Tumor-Bearing Mice> To LNCaP tumor-bearing mice prepared in the same manner as in Example 5-1, 111 an aqueous physiological saline solution of 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. Thereafter, blood and each organ were collected, and the mass and radioactivity of the organ were measured. The value obtained by dividing the percentage of radioactivity (%ID) with respect to the injected dose by the blood mass or organ mass (g) is shown as %ID / g. The higher the value of %ID / g, the greater the abundance of the radiolabeled compound and the higher the accumulation of the compound in the target organ.

[0275] LNCaP tumor-bearing mice and 111 The results of In-PtDA (mean ± standard deviation, n = 3 for each) are shown in Table 12 below. 111 In-PtDA showed high accumulation in LNCaP tumors (16.0 and 18.7%ID / g at 24 and 48 hours after administration respectively), and showed retention in blood (6.33 - 19.8%ID / g from 1 to 48 hours after administration). Also, the kidney accumulation at 1 hour after administration was 37.2%ID / g, which was significantly lower than that of 111 In-PSMA-I&T (kidney: 191%ID / g), which is a known radiolabeled compound targeting PSMA, and 68 Ga-PSMA-11 (kidney: 139%ID / g) (for example, EJNMMI Res, 2012, 2, 23, J Nucl Med, 2017, 58, 235 - 242). ​

[0276] [Table 12]

[0277] <SPECT / CT evaluation using tumor-transplanted mice> Male CB17 / IcrJcl-Prkdc reared in the same manner as in Example 5-1 scid Mice were given a mixture of PBS and Matrigel (1:1,150 μL) containing LNCaP cells (1.0 × 10⁶). 7 The cells (1.0 × 10⁶) were suspended and subcutaneously transplanted into the right shoulder of mice under isoflurane anesthesia. In addition, the same mice were given a mixture of PBS and Matrigel (1:1,150 μL) containing PC-3 cells (1.0 × 10⁶). 7 A suspension of cells (cells / mouse) was subcutaneously transplanted into the left shoulder of mice under isoflurane anesthesia. The mice were then reared for 40-60 days. In this way, tumor-transplanted mice were obtained in which LNCaP cells and PC-3 cells were simultaneously transplanted into a single mouse.

[0278] Next, in this tumor-transplanted mouse, 111 A saline solution of In]In-PtDA (2.7 MBq, 100 μL) was administered via tail vein. SPECT / CT was performed 24 and 48 hours after administration using a Gamma Medica-Ideas FX3300 pre-clinical imaging system. Under isoflurane anesthesia, imaging was performed using a 1.0 mm diameter pinhole collimator with a rotation radius of 35 mm, 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 3D ordered subset expectation maximization method (8 subsets, 5 iterations).

[0279] The SPECT / CT results are shown in Figure 16. [ 111SPECT / CT imaging using In]In-PtDA showed high radioactivity accumulation in LNCaP tumors at 24 and 48 hours after administration, but almost no radioactivity signal was observed in PC-3 tumors. From these results, [ 111 In]In-PtDA has been shown to enable clear visualization of PSMA-positive tumors.

[0280] [Example 8] In this example, a compound (RtDA) was synthesized that contained a cRGD peptide as a target molecule binding site in its structure, and the chelate site and the target molecule binding site were bonded using a click reaction between an azide group and dibenzylcyclooctin (DBCO). Subsequently, these compounds were treated with radioactive metals. 111 Radiolabeled compounds with coordinated In ions were obtained. The general outline of the reaction pathways is shown below as reaction pathways (IX-1) to (IX-2). The compound used in Example 8 contains a chelate, a target molecule binding, and an albumin binding site in its structure. Also, 111 There are two reaction pathways for coordinating to the In ion (see reaction pathway (IX-2)), but the resulting radiolabeled compound is the same regardless of the pathway used. The synthesis methods for compound 77 and compound 78 (ADA) are the same as in Example 7.

[0281] [ka]

[0282] [ka]

[0283] <Synthesis of compound 7D(RtDA)> Compound 77 (3.9 mg, 2.6 μmol) was dissolved in DMF (0.4 mL), and cyclo[Arg-Gly-Asp-D-Phe-Lys(azide)] (1.7 mg, 2.6 μmol) was added. After stirring at room temperature for 12 hours, the solvent was removed. TFA (1.9 mL), thioanisole (60 μL), triisopropylsilane (20 μL), and H2O (20 μL) were added to the residue, and the mixture was stirred at room temperature for 10 hours. After removing the solvent, the residue was purified by reverse-phase HPLC under the following conditions. The yield and MS results were as follows. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. Yield: 2.8 mg (58%). HRMS(ESI)m / z918.8662[M+2H] 2+ .

[0284] <By Route A[ 111 In] Synthesis of In-RtDA > Add [ PBS / DMSO mixture (9 / 1,200 μL) 111 In]In-ADA (1.5 MBq) was added, followed by cyclo[Arg-Gly-Asp-D-Phe-Lys(azide)] (0.2 mg). After standing at 37°C for 10 minutes, the reaction solution was purified by reverse-phase HPLC under the following conditions. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], Flow rate: 1mL / min. Radiochemical conversion rate ([ 111 In-ADA's response to radioactivity 111 The percentage of radioactivity (In) in-RtDA and the radiochemical yield are shown in Table 13 below.

[0285] <By Route B[ 111In] Synthesis of In-RtDA > Add to MES buffer (0.1M, pH 5.7, 150μL) 111 In]InCl3 solution (2.1 MBq, 80 μL) and compound 7D in DMSO solution (0.27 mM, 2 μL) were added, and the mixture was allowed to stand at 90°C for 5 minutes. The reaction solution was then purified by reverse-phase HPLC. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6 x 150 mm), mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 minutes) to 70 / 30 / 0.1 (30 minutes)], flow rate: 1 mL / min. Radiochemical conversion rate ([ 111 [In]InCl3's radioactivity 111 The percentage of radioactivity (In) in-RtDA and the radiochemical yield are shown in Table 13 below.

[0286] [Table 13]

[0287] Furthermore, In-RtDA with non-radioactive In coordinated can be manufactured by the following method.

[0288] <Synthesis of non-radioactive In-RtDA> To a solution of compound 7D (0.8 mg, 0.40 μmol) in H2O / MeCN / TFA (49.95 / 49.95 / 0.1, 300 μL), anhydrous indium(III) chloride (1.0 mg, 4.0 μmol) was added. After stirring at room temperature for 18 hours, the solution was purified by reverse-phase HPLC. Purification conditions: Cosmosil 5C 18 -AR-II column (4.6×150mm), Mobile phase: MeCN / H2O / TFA [10 / 90 / 0.1 (0 min) ~ 90 / 10 / 0.1 (40 min)], Flow rate: 1 mL / min. Yield: 0.06 mg (7.7%). HRMS(ESI):m / z974.7980[M+2H] 2+ . [Industrial applicability]

[0289] According to the present invention, it is possible to achieve both improved accumulation in target tissues and reduced accumulation in non-target tissues, particularly the kidneys.

Claims

1. A compound represented by the following general formula (1). 【Chemistry 1】 (In formula (1), A is a chelate portion capable of coordinating with a radioactive metal ion, B is an atomic group containing an albumin binding portion, and C is an atomic group containing a target molecule binding portion.) B is attached to any part of A, C is bound to A at a site different from the site where B is bound to A.

2. In formula (1) above, A has a cyclic structure, and the cyclic structure has two or more nitrogen atoms, and each nitrogen atom is connected with two or more adjacent carbon atoms separated by them, or A has a chain-like structure, and the chain-like structure has two or more nitrogen atoms, and each nitrogen atom is connected with two or more adjacent carbon atoms separated by them. A has a group of nitrogen-bonded atoms that are directly bonded to the nitrogen atoms constituting the cyclic structure or the chain structure, The nitrogen-bonded atomic group comprises one or more of the following: a carboxyl group, a phosphate group, an amide group, a benzene ring, and a pyridine ring. The compound according to claim 1, wherein if B is bonded to the nitrogen-bonding atomic group, C is bonded to a nitrogen-bonding atomic group other than the atomic group to which B is bonded.

3. The compound according to claim 1 or 2, wherein A in formula (1) has a structure derived from a compound represented by the following formula (A1). 【Chemistry 2】 (In formula (A1), R 11 , R 12 , R 13 and R 14 are each independently a group selected from - (CH ２ ) ｐ COOH, - (CH ２ ) ｐ C ５ H ５ N, - (CH ２ ) ｐ PO ３ H ２ , - (CH ２ ) ｐ CONH ２ , - (CHCOOH)(CH ２ ) ｐ COOH, and p is an integer of 0 or more and 3 or less.)

4. The compound according to any one of claims 1 to 3, wherein the albumin-binding portion in formula (1) is a structure derived from one or more of the following: γ-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 hydrocarbons having 13 to 20 carbon atoms and being saturated or unsaturated, cyanine dyes, dyes having sulfonic acid groups, diazo dyes, pentamethine cyanine dyes, blue dextran, bromocresol green, and Evans blue, and derivatives thereof, or an antibody or peptide capable of binding to albumin.

5. The compound according to any one of claims 1 to 4, wherein the albumin binding portion of formula (1) has a structure represented by the following formula (B1) or (B2). 【Transformation 3】 (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 dashed line is a bond with another structure.) In formula (B2), R b1 R b11 Each of these is 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. The parts indicated by the dashed lines are bonding parts with other structures.

6. The compound according to any one of claims 1 to 5, wherein the target molecule binding portion of formula (1) has a structure that binds to a target molecule expressed in cancer tissue.

7. A compound according to any one of claims 1 to 6, represented by the following general formula (2). 【Chemistry 4】 (In formula (2), R B1 R is an atomic group containing an albumin binding site, C1 R is an atomic group containing the target molecule binding site, B2 and R C2 Both are hydroxyl groups, or R B2 R is an atomic group containing an albumin binding site, C2 R is an atomic group containing the target molecule binding site, B1 and R C1 (Both are hydrogen atoms, or each is independently a carboxyalkyl group having 1 to 5 carbon atoms.)

8. A compound according to any one of claims 1 to 7, used as a labeling precursor.

9. A radiolabeled compound comprising a compound according to any one of claims 1 to 8, coordinated to an ion of a radioactive metal.

10. The aforementioned radioactive metal is 44 Sc, 51 Cr, 57 Co, 58 Co, 60 Co, 59 Fe, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 89 Sr, 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 Bi, 213 Bi, 212 Pb, 227 The or 225 The radiolabeled compound according to claim 9, wherein Ac.

11. The radiolabeled compound according to claim 9 or 10, wherein the radioactive metal is an alpha-emitting nuclide.

12. The radiolabeled compound according to claim 9 or 10, wherein the radioactive metal is a beta-emitting nuclide.

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