A cyclic polypeptide compound and use thereof

Abstract

The application provides a cyclic polypeptide compound and application thereof. Specifically provided is a compound shown in formula I or a pharmaceutically acceptable salt thereof. The compound provided by the application has good targeting property and wide pharmaceutical prospect.

Description

Technical Field

[0001] This invention relates to a cyclic polypeptide compound and its applications. Background Technology

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

[0003] RGD is a small peptide composed of 3 amino acids that can specifically bind to various integrin receptors, including integrin αvβ3; it utilizes radionuclides ( 125 I, 99m Tc, 18 F, 68 Ga、 64 Cu、 177 Lu、 225 Ac and other markers for RGD can enable nuclear medicine imaging (including SPECT, PET / CT) or therapy targeting integrin αvβ3. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the limitation of the limited variety of RGD polypeptide compounds in existing technologies. To this end, this invention provides a cyclic polypeptide compound and its applications. The compound of this invention has a novel structure, is easy to prepare, and has broad application prospects.

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

[0006]

[0007] in,

[0008] A and B are independently H or the segment shown in Equation I-1:

[0009]

[0010] R 1 Independently for C6-C 14 The aryl group may be surrounded by one, two, or three R groups. 1-1 Replacement C6-C 14 Aryl; R 1-1 It is a C1-C6 alkyl, hydroxyl, or halogen;

[0011] R 2 It can be a carboxyl group (-COOH) or an amide group (-CONH2) independently;

[0012] R 3 Independently, it is a -C1-C6 alkylene-urea (-NH(C=NH)NH2);

[0013] A and B are not both H;

[0014] -L1- and -L3- are independently single bonds, -C1-C6 alkylene-NHCO-, -C1-C6 alkylene-NHCO-C1-C6 alkylene-, -C1-C6 alkylene-C1-C6 alkylthion-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- can be -NHCO-, -NHCO-C1-C6 alkylene-NHCO-, or a single bond;

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

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

[0018] X is

[0019] Y represents a single bond. The "*" end is connected to W;

[0020] n1 is an integer between 1 and 20;

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

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

[0023] In one embodiment, certain groups in the compound represented by Formula I and its pharmaceutically acceptable salt may be defined as follows, and other groups may be defined as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment"):

[0024] In one of the schemes, R 1 In the context, the C6-C 14 Each aryl group can be either phenyl or naphthyl, for example, phenyl.

[0025] In one of the schemes, R 1-1 In this context, the halogen is fluorine, chlorine, or bromine.

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

[0027] In a certain scheme, -L3-, -L2-, -L1-, R 3 In T and W, the C1-C6 alkylene groups are each independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, or n-pentylene.

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

[0029] In one embodiment, in -L3- and -L1-, the C1-C6 alkoxides are each independently methyleneoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, or n-pentoxy.

[0030] In a certain scheme, 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 a certain scheme, 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-tetraazacyclododecane-1-yl)glutaric acid (DOTA-GA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-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 a hydroxyl group (-OH) from mercaptoacetyltriglycine (MAG3), for example...

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

[0034] In one embodiment, 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 aspect of the present invention, the diagnostic radionuclide is in a monovalent, divalent, trivalent, or tetravalent state, for example, trivalent.

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

[0037] In one scheme, -L1- and -L3- are independently single bonds, *-C1-C6 alkylene-NHCO-, *-C1-C6 alkylene-NHCO-C1-C6 alkylene-, *-C1-C6 alkylene-C1-C6 alkylthion-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 scheme, -L2- is -NHCO-*, -NHCO-C1-C6 alkyl-NHCO-*, or a single bond, wherein the "*" end is connected to the L phase.

[0039] In one of the schemes, R 1 Independently for C6-C 14 Aryl.

[0040] In one scheme, -L1-, -L3-, and -L2- are not all single bonds at the same time.

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

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

[0043] In one particular scheme, Y is In one possible solution, n1 is 2.

[0044] In one scheme, G is determined by... and 177 Lu chelate composition, for example In one of the schemes, for

[0045] In one scheme, -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 The "*" end is connected to L2.

[0046] In one scheme, -L- is

[0047] The "*" end is connected to L2.

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

[0049]

[0050]

[0051] This invention provides a compound of formula II or a pharmaceutically acceptable salt thereof;

[0052]

[0053] G1 is composed of chelating groups and non-radioactive nuclides;

[0054] The chelating groups, A, B, -L1-, -L3-, -L2-, and -L-, are independently as described in any embodiment of the invention. The invention provides a compound of formula I-2 or a pharmaceutically acceptable salt thereof;

[0055]

[0056] Wherein, g is a chelating group;

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

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

[0059]

[0060] This invention provides a compound represented by formula I-3;

[0061]

[0062] Where E is an alkynyl group. Or azide group (-N3);

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

[0064] In one embodiment, the compound represented by formula I-3 is...

[0065]

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

[0067] The present invention also provides a kit comprising a compound of Formula I, a compound of Formula II, a compound of Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound of Formula I, the compound of Formula II, or the compound of Formula I-2) and instructions for use.

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

[0069] The present invention also provides the use of the compound of Formula I, the compound of Formula I-2, or a pharmaceutically acceptable salt thereof (referring to the compound of Formula I or the compound of Formula I-2) in the preparation of a medicament for treating and / or preventing tumors.

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

[0071] Terminology 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 patient use) acid or base. When a compound contains a relatively acidic functional group, a 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, an 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 alkyl group having a specified number of carbon atoms (e.g., C1 to 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, etc.

[0075] In this invention, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. 1-6 Alkylene refers to an alkylene having 1 to 6 carbon atoms, such as 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 this invention, the term "alkeneoxy" refers to -O-alkylene-, wherein the definition of alkylene is as described above.

[0077] In this invention, the term "alkylenethionyl" refers to -S-alkylene-, wherein the definition of alkylene is as described above.

[0078] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 Aryl groups are cyclic groups consisting only of carbon atoms, and can be monocyclic or fused-ring. Aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0079] The terms "pharmaceuticalally acceptable excipients" and "pharmaceutical excipients" refer to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. They are all substances included in pharmaceutical preparations, excluding the active ingredient. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009).

[0080] The term “treatment” refers to any of the following: (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; or (3) slowing the development of one or more biological manifestations of a disease.

[0081] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

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

[0083] The positive and progressive effects of this invention are: the compound structure of this invention is novel and has a high level of specific tumor uptake. Attached Figure Description

[0084] Figure 1 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 0.5 h;

[0085] Figure 2 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 1 hour;

[0086] Figure 3 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 4 hours;

[0087] Figure 4 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 10 hours;

[0088] Figure 5 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 24 hours;

[0089] Figure 6 for 177 SPECT / CT images of Lu-DOTA-Tri-RGD in mice after 48 hours;

[0090] Figure 7 for 177 SPECT / CT images of Lu-DOTA-RGD in mice after 0.5 hours;

[0091] Figure 8 for 177 SPECT / CT images of Lu-DOTA-RGD in mice after 1 hour;

[0092] Figure 9 for 177 SPECT / CT images of Lu-DOTA-RGD in mice after 4 hours;

[0093] Figure 10 for 177 SPECT / CT images of Lu-DOTA-RGD in mice after 10 hours;

[0094] Figure 11 for 177 SPECT / CT images of Lu-DOTA-RGD in mice after 24 hours;

[0095] Figure 12 for177 SPECT / CT images of Lu-DOTA-RGD in mice after 48 hours. Detailed Implementation

[0096] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

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

[0098]

[0099] 1. Radionuclides 177 Lu marks DOTA-N3

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

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

[0102]

[0103] Table 1

[0104]

[0105]

[0106] Table 2

[0107]

[0108] Radio-HPLC detection conditions:

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

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

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

[0112] Flow rate: 1 mL / min

[0113] Wavelength: 220nm

[0114] Column temperature: 30℃

[0115] C18 column purification conditions:

[0116] C18 column activation (Waters, Sep-Pak Light-C18 solid phase extraction column): Wash with 5 mL of ethanol first.

[0117] C18 column, followed by 5 mL deionized water rinse.

[0118] C18 column purification: Dilute the reaction solution with 1 mL of sterile water for injection and pass it through a 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-Alynyl)

[0120]

[0121] N-(tert-Butoxycarbonyl)-L-glutamic acid (Boc-Glu-OH, 1 eq) was dissolved in DMF, and 1,3-dicyclohexylcarbodiimide (DCC, 1 eq) and N-hydroxysuccinimide (HOSu, 3 eq) were added. The reaction was carried out for 5 min, and then Compd 1 (1 eq) was added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS. After the starting material was completely reacted, TFA was added, and the mixture was concentrated under vacuum and washed twice with diethyl ether to obtain Compd 2 from the crude product.

[0122] Boc-β-Ala-OH (1 eq) was dissolved in DMF, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU, 1 eq) was added and reacted for 5 min. Then Compd 2 (1 eq) was added and reacted at room temperature for 2 h. The reaction was monitored by LC-MS. After the starting material was completely reacted, TFA was added, and the mixture was concentrated under vacuum and washed twice with diethyl ether to obtain Compd 3 from the crude product.

[0123]

[0124] Compd3 (1 eq) was dissolved in DMF, and then N,N-diisopropylethylamine (DIPEA, 5 eq) and Compd4 (2 eq) were added sequentially. The mixture was reacted at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reaction of the starting material was complete, the mixture was concentrated under vacuum, dried, and purified by reverse phase to obtain the target product, formula 13 (RGD-alkynyl) (25 mg, 35%).

[0125]

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

[0127] Preparation of RGD-alkynyl solution: The obtained RGD-alkynyl (Formula 13) was dissolved in DMF to prepare the solution, wherein the concentration of RGD-alkynyl was 0.7 mg / mL.

[0128] Preparation of copper sulfate solution: Copper sulfate was prepared by dissolving it in a 0.5M acetate-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of copper sulfate was 3.2 mg / mL.

[0129] Preparation of sodium ascorbate solution: Sodium ascorbate was prepared by dissolving sodium ascorbate in 0.5M acetate-sodium acetate buffer solution with pH 5.2±0.1, wherein the concentration of sodium ascorbate was 16 mg / mL.

[0130] 45 μL of RGD-alkynyl (0.7 mg / mL) (Formula 13) solution was mixed with the aforementioned purified solution containing... 177 The following solutions were mixed: 30 μL of Lu-DOTA-N3 reaction solution, 20 μL of 0.5 M acetate-sodium acetate buffer (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 the desired product. 177 The reaction solution of Lu-DOTA-Tri-RGD was 127 μL, and the radiochemical purity was 95.57% as determined by Radio-HPLC (see Table 3).

[0131] Table 3

[0132]

[0133] Radio-HPLC detection conditions:

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

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

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

[0137] Flow rate: 1 mL / min

[0138] Wavelength: 220nm

[0139] Column temperature: 30℃

[0140] Example 1 of the effect test

[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 acetate-sodium acetate buffer (pH 5.2) and placed in a stability test chamber at 25 °C. After 24 h, the radiochemical purity of the product remained essentially unchanged at 95.38%.

[0143] 2. Biological distribution

[0144] Reference compound: 177 The structure of Lu-DOTA-RGD is shown below.

[0145]

[0146] The preparation method refers to 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., the compound in this literature) 177 Lu-DOTA-RGD2).

[0147] Using U87MG male tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., NO.202347670), radiolabeled compounds were applied... 177Lu-DOTA-Tri-RGD (1 mCi / mL, obtained by diluting the reaction solution obtained in Example 1 with an acetate-sodium acetate buffer (0.5 mol / L, pH 5.2 ± 0.1)) was injected into mice via the tail vein (approximately 100 μCi / mouse). The animals were sacrificed at 0.5 h, 1 h, 4 h, and 24 h after injection. 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 in the injected mouse / tissue weight * 100%.

[0148] In this embodiment, 177 The organ distribution of Lu is shown (see Tables 4 and 5), compared with 177 Compared to Lu-DOTA-RGD, 177 Lu-DOTA-Tri-RGD showed high specific tumor uptake; after 24 hours, renal absorption was nearly completely metabolized (1.09±0.11 ID% / g), and tumor uptake remained at a level comparable to that reported in the literature; after 24 hours, it still had a high tumor to background ratio (tumor / blood: 100; tumor / muscle: 11.11).

[0149] Table 4 177 Lu-DOTA-Tri-RGD and 177 Comparison of Lu-DOTA-RGD uptake in various tissues of U87MG tumor-bearing mice 24 hours 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 Lu-DOTA-Tri-RGD uptake in various tissues of 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] Example 2: SPECT / CT Imaging of Small Animals

[0154] Using U87MG glioblastoma model mice, radiolabeled compounds were introduced. 177 Lu-DOTA-Tri-RGD injection (1 mCi / mL, obtained by diluting the reaction solution obtained in Example 1 with an acetate-sodium acetate buffer (0.5 mol / L, pH 5.2 ± 0.1)) and containing 177Lu-DOTA-RGD injection solution was injected into mice via the tail vein (approximately 600 μCi / mouse, 5 mice per dose). In vivo scans were performed on the mice at 0.5h, 1h, 4h, 10h, 24h, and 48h post-injection. Results are shown below. Figures 1-12 .

[0155] For both compounds, the model mice still showed good tumor uptake at 24 hours, but our designed... 177 The uptake of Lu-DOTA-Tri-RGD in normal tissues was significantly lower than that in normal tissues. 177 Lu-DOTA-RGD, and its clearance rate in normal tissues is higher than 177 Lu-DOTA-RGD.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof; ； in, A and B are independently the segments shown in Equation I-1: ； R 1 Independently for C6-C 14 The aryl group may be surrounded by one, two, or three R groups. 1-1 Replacement C6-C 14 Aryl; R 1-1 It is a C1-C6 alkyl, hydroxyl, or halogen; R 2 Independently -COOH or -CONH2; R 3 Independently -C1-C6 alkylene-NH(C=NH)NH2; -L1- and -L3- are independently -C1-C6 alkylene-NHCO- or -C1-C6 alkylene-NHCO-C1-C6 alkylene; -L2- is NHCO-C1-C6 alkylene-NHCO-; L is ,in" "The terminal is connected to L2; T and W are independently C1-C6 alkylene groups; X is ; Y is ,in" "The end is connected to W; n1 is 1, 2, or 3; G consists of a chelating group and a diagnostic radionuclide; or, a chelating group and a therapeutic radionuclide. In 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-tetraazacyclododecane-1-yl)glutaric acid, or 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid. In G, the diagnostic radionuclide is 18 F, 68 Ga、 99m Tc or 64 Cu; In G, the therapeutic radionuclide is 212 Pb, 211 At、 177 Lu、 188 Re、 225 Ac or 67 Cu.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) R 1 In the context, the C6-C 14 Each aryl group can be either phenyl or naphthyl; (2) R 1-1 In this context, the halogen is fluorine, chlorine, or bromine; (3) R 1-1 In this context, 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 In -L1-, T and W, the C1-C6 alkylene groups are each independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene or n-pentylene.

3. The compound of formula I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or two of the following conditions: (1) R 1 In the context, the C6-C 14 The aryl group is phenyl; (2) In G, the chelating group is .

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) -L1- and -L3- are independent of each other. -C1-C6 alkylene-NHCO- or -C1-C6 alkylene-NHCO-C1-C6 alkylene-, where " "The end is connected to A or B;" (2) -L2- is --NHCO-C1-C6 alkyl-NHCO- ,in" The terminal is connected to L.

5. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) R 1 Independently for C6-C 14 Aryl; (2) -L1- and -L3- are independently -C1-C6 alkylene-NHCO-C1-C6 alkylene-; (3) -L2- is -NHCO-C1-C6 alkylene-NHCO-; (4) n1 is 2; (5) G is from and 177 Lu chelate composition.

6. The compound of formula I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, -L- is ;in" The terminal is connected to L2, and X, n1, and n2 are independently as described in claim 1.

7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, -L- is or ; n1 and n2 are independently as described in claim 1; wherein " The terminal is connected to L2.

8. The compound of formula I as claimed in claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, -L- is ,in" The terminal is connected to L2.

9. The compound of formula I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, G is .

10. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, for .

11. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is: or .

12. A compound of formula II or a pharmaceutically acceptable salt thereof; ； in, G1 is composed of chelating groups and non-radioactive nuclides; 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-tetraazacyclododecane-1-yl)glutaric acid, or 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid. The non-radioactive nuclides are F, Ga, Tc, Cu, Pb, At, Lu, Re, Ac, or Cu; A, B, -L1-, -L3-, -L2-, and -L- are independently described in any one of claims 1-11.

13. A compound of formula I-2 or a pharmaceutically acceptable salt thereof; ； in, g is a chelating group; 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-tetraazacyclododecane-1-yl)glutaric acid, or 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid. A, -L1-, -L2-, -L3-, -L- and B are independently described in any one of claims 1-11.

14. The compound of formula I-2 as claimed in claim 13, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula I-2 is: 。 15. A compound represented by Formula I-3; ； in, E is an alkynyl group or an azide group; The T, A, -L1-, -L2-, -L3- and B are independently as described in any one of claims 1-11.

16. The compound of formula I-3 as described in claim 15, characterized in that, The compound represented by formula I-3 is: 。 17. A pharmaceutical composition comprising a compound of Formula I as claimed in any one of claims 1-11 or a pharmaceutically acceptable salt thereof, a compound of Formula II as claimed in claim 12 or a pharmaceutically acceptable salt thereof, a compound of Formulas I-2 as claimed in claim 13 or 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

18. A kit comprising a compound of formula I as claimed in any one of claims 1-11 or a pharmaceutically acceptable salt thereof, a compound of formula II as claimed in claim 12 or a pharmaceutically acceptable salt thereof, a compound of formulas I-2 as claimed in claim 13 or 14 or a pharmaceutically acceptable salt thereof, and instructions for use.

19. The use of a compound of Formula I as claimed in any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a compound of Formula I-2 as claimed in claims 13 or 14, or a pharmaceutically acceptable salt thereof, in the preparation of a contrast agent for diagnosing tumors; The tumor is a solid tumor; The solid tumor is lung cancer, rectal cancer, pancreatic cancer, or glioblastoma.

20. The use of a compound of Formula I as claimed in any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a compound of Formula I-2 as claimed in claims 13 or 14, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing tumors; The tumor is a solid tumor; The solid tumor is lung cancer, rectal cancer, pancreatic cancer, or glioblastoma.

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