Cyclic polypeptide compound and application thereof

Abstract

The invention provides a cyclic polypeptide compound and application thereof. Specifically provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound provided by the invention is good in targeting property and wide in medicinal prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a cyclic polypeptide compound and its application. Background Art

[0002] Integrins belong to the family of cell adhesion receptors and have a transmembrane heterodimer structure composed of an α subunit and a β subunit. Integrin αvβ3 is an important member of the integrin family. It is lowly expressed or not expressed at all in resting endothelial cells and normal tissues, but is highly expressed in some tumor cells and endothelial cells of new blood vessels, thus attracting much attention.

[0003] RGD is a small peptide composed of three amino acids and can specifically bind to a variety of integrin receptors, including integrin αvβ3; by labeling RGD with radionuclides ( 125 I, 99m Tc, 18 F, 68 Ga, 64 Cu, 177 Lu, 225 Ac, etc.), integrin αvβ3-targeted nuclear medicine imaging (including SPECT, PET / CT) or treatment can be achieved. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the defect of few types of RGD polypeptide compounds in the prior art. For this purpose, the present invention provides a cyclic polypeptide compound and its application. The compound of the present invention has a novel structure, is convenient to prepare, and has broad application prospects.

[0005] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof;

[0006]

[0007] Wherein,

[0008] A and B are independently H or a fragment represented by formula I-1:

[0009]

[0010] R 1 is independently C6-C 14 aryl or C6-C 1-1 aryl substituted by one, two or three R 14 ; R 1-1 is C1-C6 alkyl, hydroxyl or halogen;

[0011] R 2 is independently carboxyl (-COOH) or amide (-CONH2);

[0012] R 3 independently is -C1-C6 alkylene-urea (-NH(C=NH)NH2);

[0013] A and B are not both H at the same time;

[0014] -L1- and -L3- are independently a single bond, -C1-C6 alkylene-NHCO-, -C1-C6 alkylene-NHCO-C1-C6 alkylene-, -C1-C6 alkylene-C1-C6 alkylthio-NHCO-, -C1-C6 alkylene-C1-C6 alkoxy-NHCO-, -C1-C6 alkylene-CONHCO-, -C1-C6 alkylene-NHCO-C1-C6 alkylene-SCO-C1-C6 alkylene-NHCO-;

[0015] -L2- is -NHCO-, -NHCO-C1-C6 alkylene-NHCO- or a single bond;

[0016] L is wherein the "*" end is connected to L2;

[0017] T and W are independently C1-C6 alkylene;

[0018] X is

[0019] Y is a single bond, wherein the "*" end is connected to W;

[0020] n1 is an integer from 1 to 20;

[0021] n2 is an integer from 1 to 10;

[0022] G is composed of a chelating group and a diagnostic radionuclide; or, a chelating group and a therapeutic radionuclide.

[0023] In one embodiment, in the compound of formula I and its pharmaceutically acceptable salts, the definitions of certain groups can be as described below, and the definitions of other groups can be as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment"):

[0024] In one embodiment, R 1 wherein the C6-C 14 aryl groups are each independently phenyl or naphthyl, such as phenyl.

[0025] In one embodiment, R 1-1 wherein the halogen is fluorine, chlorine or bromine.

[0026] In one embodiment, R 1-1Among them, each of the C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

[0027] In one embodiment, among -L3-, -L2-, -L1-, R 3 , T and W, each of the C1-C6 alkylene groups is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene or n-pentylene.

[0028] In one embodiment, among -L3- and -L1-, each of the C1-C6 alkylthio groups is independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio.

[0029] In one embodiment, among -L3- and -L1-, each of the C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentyloxy.

[0030] In one embodiment, n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, for example, n1 is an integer from 1 to 10, or n1 is 2.

[0031] In one embodiment, n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, n2 is an integer from 1 to 5, or n2 is 1.

[0032] In one embodiment, in G, the chelating group is a conventional chelating group in the art, such as 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)glutaric acid (DOTA-GA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazanon-1-yl)glutaric acid (NODA-GA), diethylenetriaminepentaacetic acid (DTPA), N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) or a chelating group obtained by removing one hydroxyl group (-OH) from mercaptoacetyltriglycine (MAG3), for example

[0033] In one embodiment, in G, the diagnostic radionuclide is conventional in the art, such as 18 F, 68 Ga, 99m Tc or 64 Cu.

[0034] In one embodiment, in G, the therapeutic radionuclide is conventional in the art, for example 212 Pb, 211 At, 177 Lu, 188 Re, 225 Ac or 67 Cu.

[0035] In one embodiment of the present invention, the valence state of the diagnostic radionuclide is monovalent, divalent, trivalent or tetravalent, for example trivalent.

[0036] In one embodiment of the present invention, the valence state of the therapeutic radionuclide is monovalent, divalent, trivalent or tetravalent, for example trivalent.

[0037] In one embodiment, -L1- and -L3- are independently a single bond, *-C1-C6 alkylene-NHCO-, *-C1-C6 alkylene-NHCO-C1-C6 alkylene-, *-C1-C6 alkylene-C1-C6 alkylthio-NHCO-, *-C1-C6 alkylene-C1-C6 alkoxy-NHCO-, *-C1-C6 alkylene-CONHCO-, *-C1-C6 alkylene-NHCO-C1-C6 alkylene-SCO-C1-C6 alkylene-NHCO-, wherein the "*" end is connected to A or B.

[0038] In one embodiment, -L2- is -NHCO-*, -NHCO-C1-C6 alkyl-NHCO-* or a single bond, wherein the "*" end is connected to L.

[0039] In one embodiment, R 1 is independently C6-C 14 aryl.

[0040] In one embodiment, -L1-, -L3- and -L2- are not simultaneously single bonds.

[0041] In one embodiment, -L1- and -L3- are independently -C1-C6 alkylene-NHCO-C1-C6 alkylene-.

[0042] In one embodiment, -L2- is -NHCO-C1-C6 alkylene-NHCO-;

[0043] In one embodiment, Y is In one embodiment, n1 is 2.

[0044] In one embodiment, G is composed of and 177 chelated with Lu, for example In one embodiment, is

[0045] In one embodiment, -L- is X, n1, and n2 are independently as described in any one of the present invention, wherein the "*" end is connected to L2. Preferably, -L- is wherein the "*" end is connected to L2.

[0046] In one embodiment, -L- is

[0047] wherein the "*" end is connected to L2.

[0048] In one embodiment, the compound represented by Formula I is

[0049]

[0050]

[0051] The present invention provides a compound represented by Formula II or a pharmaceutically acceptable salt thereof;

[0052]

[0053] wherein, G1 is composed of a chelating group and a non-radioactive nuclide;

[0054] The chelating group, A, B, -L1-, -L3-, -L2-, and -L- are independently as described in any one of the present invention. The present invention provides a compound represented by Formula I-2 or a pharmaceutically acceptable salt thereof;

[0055]

[0056] wherein, g is a chelating group;

[0057] The chelating group, A, -L1-, -L2-, -L3-, -L-, and B are independently as described in any one of the present invention.

[0058] In one embodiment, the compound represented by Formula I-2 is

[0059]

[0060] The present invention provides a compound represented by Formula I-3;

[0061]

[0062] wherein, E is an alkynyl group or an azide group (-N3);

[0063] T, A, -L1-, -L2-, -L3- and B are independently as described in any aspect of the present invention.

[0064] In one aspect, the compound represented by Formula I-3 is

[0065]

[0066] The present invention provides a pharmaceutical composition comprising a compound represented by Formula I, a compound represented by Formula II, a compound represented by Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound represented by Formula I, the compound represented by Formula II, or the compound represented by Formula I-2) and a pharmaceutical excipient.

[0067] The present invention also provides a kit comprising a compound represented by Formula I, a compound represented by Formula II, a compound represented by Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound represented by Formula I, the compound represented by Formula II, or the compound represented by Formula I-2) and an instruction manual.

[0068] The present invention also provides an application of a compound represented by Formula I, a compound represented by Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound represented by Formula I or the compound represented by Formula I-2) as described above in the preparation of a contrast agent for diagnosing tumors.

[0069] The present invention also provides an application of a compound represented by Formula I, a compound represented by Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound represented by Formula I or the compound represented by Formula I-2) as described above in the preparation of a drug for treating and / or preventing tumors.

[0070] In certain preferred embodiments of the present invention, the tumor is a solid tumor, such as lung cancer, rectal cancer or pancreatic cancer.

[0071] Term Explanation:

[0072] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe and suitable for use by patients) acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0073] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0074] The term "alkyl" refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0075] In the present invention, the term "alkylene" refers to a saturated straight-chain or branched-chain divalent hydrocarbon group. C 1-6 The alkylene group refers to an alkylene group having 1-6 carbon atoms, specifically, for example, methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-), n-pentylene or n-hexylene.

[0076] In the present invention, the term "alkoxy" refers to -O-alkylene-, where the alkylene group is defined as above.

[0077] In the present invention, the term "alkylthio" refers to -S-alkylene-, where the alkylene group is defined as above.

[0078] The term "aryl" refers to a cyclic group composed only of carbon atoms having a specified number of carbon atoms (e.g., C6-C 10 ) and is a monocyclic or fused ring. Aryl groups include, but are not limited to, phenyl or naphthyl, and the like.

[0079] The terms "pharmaceutically acceptable excipients" and "pharmaceutical excipients" refer to excipients and additives used in the production of drugs and the formulation of prescriptions, and are all substances included in pharmaceutical preparations except for the active ingredients. For specific details, refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0080] The term "treatment" refers to any of the following situations: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; (3) slowing down the development of one or more biological manifestations of the disease.

[0081] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0082] The reagents and raw materials used in the present invention are all commercially available.

[0083] The positive and progressive effects of the present invention are as follows: The compound of the present invention has a novel structure and a high level of specific tumor uptake. Description of the Drawings

[0084] Figure 1 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 0.5 h in vivo;

[0085] Figure 2 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 1 h in vivo;

[0086] Figure 3 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 4 h in vivo;

[0087] Figure 4 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 10 h in vivo;

[0088] Figure 5 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 24 h in vivo;

[0089] Figure 6 is 177 SPECT / CT imaging map of Lu-DOTA-Tri-RGD in mice at 48 h in vivo;

[0090] Figure 7 is 177 SPECT / CT imaging map of Lu-DOTA-RGD in mice at 0.5 h in vivo;

[0091] Figure 8 is 177 SPECT / CT imaging map of Lu-DOTA-RGD in mice at 1 h in vivo;

[0092] Figure 9 is 177 SPECT / CT imaging map of Lu-DOTA-RGD in mice at 4 h in vivo;

[0093] Figure 10 is 177 SPECT / CT imaging map of Lu-DOTA-RGD in mice at 10 h in vivo;

[0094] Figure 11 is 177 SPECT / CT imaging map of Lu-DOTA-RGD in mice at 24 h in vivo;

[0095] Figure 12 is177 SPECT / CT imaging of Lu-DOTA-RGD in mice within 48 hours Detailed implementation mode

[0096] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product instructions.

[0097] Example 1 177 Preparation of Lu-DOTA-Tri-RGD

[0098]

[0099] 1. Radionuclide 177 Labeling of DOTA-N3 with Lu

[0100] 177 The hydrochloric acid solution of Lu is 177 A mixed solution of LuCl3 and 0.04 mol / L hydrochloric acid, where 177 The radioactivity of Lu is 11.4 mCi. The acetic acid / sodium acetate solution of DOTA-N3 (Formula 12) is a mixed solution prepared by dissolving DOTA-N3 (Formula 12) in a 0.5 M acetic acid-sodium acetate solution with a pH of 5.2 ± 0.1, where the concentration of DOTA-N3 is 0.30 mg / mL.

[0101] Mix 12 μL of 177 The hydrochloric acid solution of Lu (11.4 mCi) and 90 μL of the acetic acid / sodium acetate solution of DOTA-N3 (Formula 12) (0.30 mg / mL), heat at 95 °C for 15 min to obtain 177 Lu-DOTA-N3. The labeling rate detected by Radio-HPLC is 86.02%, as shown in Table 1. The labeled product is purified by a C18 column to obtain a product with a radiochemical purity of 94.18%, as shown in Table 2.

[0102]

[0103] Table 1

[0104]

[0105]

[0106] Table 2

[0107]

[0108] Radio-HPLC detection conditions:

[0109] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0110] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0111] Gradient: 0 - 5 - 10 - 14 - 15 - 17 min, 1 - 1 - 10 - 10 - 1 - 1% B

[0112] Flow rate: 1 mL / min

[0113] Wavelength: 220 nm

[0114] Column temperature: 30 °C

[0115] Purification conditions of C18 column:

[0116] Activation of C18 column (Waters, Sep-Pak Light-C18 solid phase extraction column): First, rinse with 5 mL of ethanol

[0117] Then, rinse with 5 mL of deionized water.

[0118] Purification of product by C18 column: Dilute the reaction solution with 1 mL of sterile water for injection, and pass it through the C18 column; rinse the C18 column with 0.5 mL of sterile water for injection to remove radioactive impurities; rinse the C18 column with anhydrous ethanol to obtain the target product 177 Lu-DOTA-N3.

[0119] 2. Preparation of Formula 13 (RGD-alkynyl)

[0120]

[0121] N-(tert-Butoxycarbonyl)-L-glutamic acid (Boc-Glu-OH, 1 eq) is dissolved in DMF, 1,3-dicyclohexylcarbodiimide (DCC, 1 eq) and N-hydroxysuccinimide (HOSu, 3 eq) are added, and the reaction is carried out for 5 min. Then, Compd 1 (1 eq) is added, and the reaction is carried out at room temperature for 2 h. The reaction is monitored by LC-MS. After the raw materials react completely, TFA is added, and the mixture is concentrated under vacuum and washed twice with ether to prepare the crude product Compd 2.

[0122] Boc-β-Ala-OH (1 eq) is dissolved in DMF, 2-succinimidyloxy-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU, 1 eq) is added and the reaction is carried out for 5 min. Then, Compd 2 (1 eq) is added, and the reaction is carried out at room temperature for 2 h. The reaction is monitored by LC-MS. After the raw materials react completely, TFA is added, and the mixture is concentrated under vacuum and washed twice with ether to prepare the crude product Compd 3.

[0123]

[0124] Compound 3 (1 eq) was dissolved in DMF, and then N,N-diisopropylethylamine (DIPEA, 5 eq) and Compound 4 (2 eq) were added successively. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by LC-MS. After the raw materials were completely reacted, the mixture was concentrated under vacuum, dried, and purified by reverse phase to obtain the target product Formula 13 (RGD-alkyne) (25 mg, 35%).

[0125]

[0126] 3. 77 Preparation of Lu-DOTA-Tri-RGD

[0127] Preparation of RGD-alkyne solution: The obtained RGD-alkyne (Formula 13) was dissolved in DMF to prepare a solution with a concentration of 0.7 mg / mL for RGD-alkyne.

[0128] Preparation of copper sulfate solution: Copper sulfate was dissolved in an acetic acid-sodium acetate buffer solution with a concentration of 0.5 M and a pH of 5.2 ± 0.1 to prepare a solution with a concentration of 3.2 mg / mL for copper sulfate.

[0129] Preparation of sodium ascorbate solution: Sodium ascorbate was dissolved in an acetic acid-sodium acetate buffer solution with a concentration of 0.5 M and a pH of 5.2 ± 0.1 to prepare a solution with a concentration of 16 mg / mL for sodium ascorbate.

[0130] 45 μL of RGD-alkyne (0.7 mg / mL) (Formula 13) solution was mixed with the purified Lu-DOTA-N3 reaction solution (30 μL) prepared above, 20 μL of 0.5 M acetic acid-sodium acetate buffer solution with pH = 5.2 ± 0.1, 15 μL of copper sulfate solution (3.2 mg / mL), and 17 μL of sodium ascorbate solution (16 mg / mL). The mixture was heated at 40 °C for 60 min to obtain 177 127 μL of the reaction solution of Lu-DOTA-Tri-RGD. The radiochemical purity was detected by Radio-HPLC to be 95.57%, as shown in Table 3. 177 Table 3

[0131] Table 3

[0132]

[0133] Radio-HPLC detection conditions:

[0134] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0135] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0136] Gradient: 0 - 10 - 20 - 30 - 35 - 38 - 40 - 45 min, 1 - 10 - 20 - 40 - 40 - 100 - 1 - 1% B

[0137] Flow rate: 1 mL / min

[0138] Wavelength: 220 nm

[0139] Column temperature: 30 °C

[0140] Effect test example 1

[0141] 1. In vitro stability

[0142] The reaction solution after the reaction in Example 1 ( 177 Lu-DOTA-Tri-RGD, 20 μL) was diluted with 1 mL of 0.5 M acetic acid - sodium acetate buffer at pH = 5.2 and placed in a stability test chamber at 25 °C. After 24 h, the radiochemical purity of the product remained basically unchanged, being 95.38%.

[0143] 2. Biodistribution

[0144] Control compound: 177 Lu-DOTA-RGD, the structure is shown as follows,

[0145]

[0146] The preparation method refers to the existing literature Shi, J., Liu, Z., Jia, B., Yu, Z., Zhao, H., & Wang, F. Potential therapeutic radiotracers: preparation, biodistribution and metabolic characteristics of 177 Lu-labeled cyclic RGDfK dimer. Amino Acids, 2009, 39(1), 111–120 (i.e., compound 177 Lu-DOTA-RGD2) in this literature).

[0147] U87MG male tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., NO. 202347670) were used, and the radioactively labeled compound 177Lu-DOTA-Tri-RGD (1 mCi / mL, obtained by diluting the reaction solution obtained in Example 1 with an acetic acid-sodium acetate buffer solvent (0.5 mol / L, pH 5.2 ± 0.1)) was injected into mice via the tail vein (about 100 μCi / mouse). The animals were sacrificed at 0.5 h, 1 h, 4 h, and 24 h after injection, and the tissues and organs of interest were dissected and weighed. The radioactivity count was measured using a gamma counter, and the ID% / g of the tissues and organs was calculated. ID% / g = tissue count / total count injected into the mouse / tissue weight * 100%.

[0148] In this example, 177 the organ distribution of Lu is shown (see Tables 4 and 5), and compared with 177 Lu-DOTA-RGD, 177 Lu-DOTA-Tri-RGD shows a higher specific tumor uptake; after 24 h, the kidney uptake is close to complete metabolism (1.09 ± 0.11 ID% / g), and the tumor uptake remains at a comparable level to that reported in the literature; after 24 h, there is still a high tumor-to-background ratio (tumor / blood: 100; tumor / muscle: 11.11).

[0149] Table 4 177 Comparison of tissue uptake of Lu-DOTA-Tri-RGD and 177 Lu-DOTA-RGD in U87MG tumor-bearing mice at 24 h after administration (unit: ID% / g)

[0150] <![CDATA 177 Lu-DOTA-Tri-RGD]]> <![CDATA 177 Lu-DOTA-RGD]]> Blood 0.01 0.01 Heart 0.09 0.10 Liver 0.47 0.80 Spleen 0.63 1.20 Kidney 1.09 1.80 Muscle 0.09 0.10 Bone 0.31 0.50 Tumor 1.00 0.80 Tumor / Blood 100 13.00 Tumor / Muscle 11.11 7.00 Tumor / Kidney 0.92 0.80

[0151] Table 5 177 Comparison of tissue uptake of Lu-DOTA-Tri-RGD in U87MG tumor-bearing mice at different time points after administration (unit: ID% / g)

[0152] 0.5h 1h 4h 24h Blood 1.17±0.71 0.40±0.05 0.05±0.01 0.01±0.00 Heart 0.62±0.28 0.36±0.03 0.17±0.01 0.09±0.01 Liver 1.62±0.55 1.61±0.07 0.99±0.15 0.47±0.01 Spleen 1.09±0.30 1.15±0.17 0.80±0.19 0.63±0.09 Lung 1.81±0.64 1.33±0.18 0.48±0.04 0.29±0.01 Kidney 3.88±131 3.20±0.42 2.19±0.33 1.09±0.11 Muscle 0.46±0.15 0.26±0.07 0.10±0.05 0.09±0.01 Bone 0.50±0.15 0.47±0.08 0.31±0.06 0.31±0.03 Tumor 1.81±0.61 1.91±0.29 1.33±0.41 1.00±0.18 Tumor / Blood 1.55 4.78 26.60 100.00 Tumor / Muscle 3.93 7.35 13.30 11.11 Tumor / Kidney 0.47 0.60 0.61 0.92 .

[0153] Effect Test Example 2 Small Animal SPECT / CT Imaging

[0154] Using U87MG glioblastoma model mice, an injection solution containing the radiolabeled compound 177 Lu-DOTA-Tri-RGD (1 mCi / mL, obtained by diluting the reaction solution obtained in Example 1 with an acetic acid-sodium acetate buffer solvent (0.5 mol / L, pH 5.2 ± 0.1)) and containing 177The injection solution of Lu-DOTA-RGD was respectively injected into mice via the tail vein (about 600 μCi / mouse, 5 mice in each group). The small animals were subjected to in vivo scanning at 0.5 h, 1 h, 4 h, 10 h, 24 h, and 48 h after injection. The results are shown in Figure 1 - Figure 12 .

[0155] For both compounds, the model mice still had good tumor uptake at 24 h. However, the uptake of 177 Lu-DOTA-Tri-RGD in normal tissues was significantly lower than that of 177 Lu-DOTA-RGD, and the clearance rate in normal tissues was higher than that of 177 Lu-DOTA-RGD.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof; Wherein, A and B are independently H or a fragment of formula I-1: R 1 Independently C6-C 14 aryl or C6-C 1-1 aryl substituted with one, two or three R 14 R 1-1 is C1-C6 alkyl, hydroxy or halogen; R 2 independently -COOH or -CONH2; R 3 independently -C1-C6 alkylene -NH(C=NH)NH2; A and B are not both H at the same time; -L1- and -L3- are independently a single bond, -C1-C6 alkylene-NHCO-, -C1-C6 alkylene-NHCO-C1-C6 alkylene -, -C1-C6 alkylene-C1-C6 alkylthio-NHCO-, -C1-C6 alkylene-C1-C6 alkoxy-NHCO-, -C1-C6 alkylene-CONHCO-, -C1-C6 alkylene-NHCO-C1-C6 alkylene-SCO-C1-C6 alkylene-NHCO-; -L2- is -NHCO-, -NHCO-C1-C6 alkylene-NHCO- or a single bond; L is where the "*" end is connected to L2; T and W are independently C1-C6 alkylene; X is Y is a single bond, wherein the "*" end is connected to W; n1 is an integer from 1 to 20; n2 is an integer from 1 to 10; G consists of a chelating group and a diagnostic radionuclide; or, a chelating group and a therapeutic radionuclide.

2. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, The compound of formula I satisfies one or more of the following conditions: (1)R 1 Among them, the C6-C 14 aryl groups are each independently phenyl or naphthyl, such as phenyl; (2)R 1-1 wherein the halogen is fluorine, chlorine or bromine; (3)R 1-1 wherein each of the C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl; (4)-L3-, -L2-, R 3 , -L1-, T and W, each of said C1-C6 alkylene groups is independently methylene, ethylene, n-propylene, isopropylidene, n-butylene, isobutylene, tert-butylene or n-pentylene; (5) In -L3- and -L1-, the C1-C6 alkylthio is independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio; (6) In -L3- and -L1-, the C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentyloxy; (7) n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, for example, n1 is an integer from 1 to 10, or n1 is 2; (8) n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, n2 is an integer from 1 to 5, or n2 is 1; In (9)G, the chelating group is a chelating group obtained by removing one hydroxyl group from 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)glutaric acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazanon-1-yl)glutaric acid, diethylenetriaminepentaacetic acid, N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid, or mercaptoacetyltriglycine, for example In (10)G, the diagnostic radionuclide is 18 F, 68 Ga, 99m Tc or 64 Cu; (11) The valence state of the diagnostic radionuclide is monovalent, divalent, trivalent or tetravalent, for example, trivalent; In (12)G, the therapeutic radionuclide is 212 Pb, 211 At, 177 Lu, 188 Re, 225 Ac or 67 Cu; (13) The valence state of the therapeutic radionuclide is monovalent, divalent, trivalent or tetravalent, for example, trivalent.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula I satisfies one or more of the following conditions: (1) -L1- and -L3- are independently a single bond, *-C1-C6 alkylene-NHCO-, *-C1-C6 alkylene-NHCO-C1-C6 alkylene-, *-C1-C6 alkylene-C1-C6 alkylthio-NHCO-, *-C1-C6 alkylene-C1-C6 alkoxy-NHCO-, *-C1-C6 alkylene-CONHCO-, *-C1-C6 alkylene-NHCO-C1-C6 alkylene-SCO-C1-C6 alkylene- NHCO-, where the "*" end is connected to A or B; (2) -L2- is -NHCO-*, -NHCO-C1-C6 alkyl-NHCO-* or a single bond, where the "*" end is connected to L.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula I satisfies one or more of the following conditions: (1)R 1 independently C6-C 14 aryl; (2) -L1-, -L3- and -L2- are not all single bonds at the same time; (3) -L1- and -L3- are independently C1-C6 alkylene-NHCO-C1-C6 alkylene-; (4) -L2- is -NHCO-C1-C6 alkylene-NHCO-; (5)Y is (6) n1 is 2; Preferably, -L- is wherein the "*" end is connected to L2, and X, n1, and n2 are independently as described in claim 1; Further preferably, -L- is n1 and n2 are independently as described in claim 1; wherein the "*" end is connected to L2; For example, -L- is where the "*" end is connected to L2; (7)G consists of chelated with 177 Lu, for example 5. The compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound of formula I is 7. A compound of formula II or a pharmaceutically acceptable salt thereof; Among them, G1 consists of a chelating group and a non-radioactive nuclide; the chelating group, A, B, -L1-, -L3-, -L2- and -L- are independently as described in any one of claims 1-6.

8. A compound of formula I-2 or a pharmaceutically acceptable salt thereof; Among them, g is a chelating group; the chelating group, A, -L1-, -L2-, -L3-, -L- and B are independently as described in any one of claims 1-6; preferably, the compound of formula I-2 is 9. A compound of formula I-3; Among them, E is an alkynyl or azido group; the T, A, -L1-, -L2-, -L3- and B are independently as described in any one of claims 1-6; preferably, the compound of formula I-3 is 10. A pharmaceutical composition comprising the compound of formula I as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, the compound of formula II as described in claim 7 or a pharmaceutically acceptable salt thereof, the compound of formula I-2 as described in claim 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

11. A kit comprising the compound of formula I as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, the compound of formula II as described in claim 7 or a pharmaceutically acceptable salt thereof, the compound of formula I-2 as described in claim 8 or a pharmaceutically acceptable salt thereof, and an instruction manual.

12. Use of the compound of formula I as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and the compound of formula I-2 as described in claim 8 or a pharmaceutically acceptable salt thereof in the preparation of a contrast agent for tumor diagnosis; For example, the tumor is a solid tumor, preferably lung cancer, rectal cancer or pancreatic cancer.

13. Use of the compound of formula I as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and the compound of formula I-2 as described in claim 8 or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment and / or prevention of tumors; For example, the tumor is a solid tumor, such as lung cancer, rectal cancer or pancreatic cancer.

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