Linker, targeting ligand, radiopharmaceutical and preparation method and application thereof

Abstract

The embodiment of the invention relates to the technical field of targeted imaging molecules, and discloses a linker, a targeted ligand, a radiopharmaceutical and a preparation method and application thereof. Wherein the linker is composed of 2-3 amino acids, the amino acids at least comprise acidic amino acids, the acidic amino acids are selected from one or more of aspartic acid, glutamic acid and 3-sulfoalanine, and the linker is used for coupling a targeted pharmacophore and a radionuclide binding group to prepare a targeted ligand and a targeted radiopharmaceutical. The connexon has the characteristics of high hydrophilicity and high binding force with plasma protein by limiting the number of amino acids and selecting acidic amino acids, so that the tumor uptake and residence time are prolonged, and the imaging contrast ratio is further improved.

Description

Technical Field

[0001] The embodiments of the present application relate to the technical field of targeted imaging molecules, and in particular to a linker, a targeting ligand, a radiopharmaceutical, and a preparation method and application thereof. Background Art

[0002] Serious diseases such as cancer and cardiovascular and cerebrovascular diseases are increasingly endangering human health and are the leading cause of death. The situation is particularly dire in my country, where the incidence of cancer continues to rise. Malignant tumors are characterized by heterogeneity, and the heterogeneity of the tumor microenvironment is particularly prominent. This poses significant challenges to cancer diagnosis, the development of treatment strategies, the assessment of efficacy, and patient prognosis, making the tumor microenvironment a focus of disease treatment and new drug development.

[0003] The integration of nuclear medicine diagnosis and treatment is becoming increasingly important in the treatment of major diseases, but its development is inseparable from the innovation and advancement of targeted radiopharmaceuticals. These drugs typically consist of a pharmacophore that targets a specific target in the lesion tissue, a linker, and a labeled radionuclide. The effectiveness of nuclear medicine diagnosis and treatment depends largely on the pharmacokinetic properties of the radiopharmaceutical in the body, its uptake and retention in the lesion, and the contrast between the lesion and the background. Once the pharmacophore and radionuclide are determined, these properties are primarily determined by the physicochemical properties of the linker. Therefore, the construction of a suitable radiopharmaceutical linker is crucial.

[0004] Both cleavable and non-cleavable linkers play a key role in the construction of targeted radiopharmaceuticals. They have, to a certain extent, optimized the pharmacokinetic properties, lesion uptake and retention, and lesion-background contrast of some radiopharmaceuticals. However, most current targeted radiopharmaceuticals still have unfavorable pharmacokinetic properties, such as high uptake in organs such as the liver, gallbladder, pancreas, intestine, and kidney. To date, no ideal linker has been found to address these issues, which may be related to factors such as the drug's affinity, total charge, charge distribution, structural size, and lipid-water distribution coefficient. Although studies have shown that the combination of glutamate and histidine can reduce the uptake of targeted radiopharmaceuticals in normal tissues, significant challenges remain in improving lesion uptake and retention, as well as enhancing lesion-background contrast.

[0005] Therefore, how to provide a new targeted radioactive drug to improve the contrast between lesions and background is an urgent problem that needs to be solved. Summary of the Invention

[0006] To address the above-mentioned issues, the first aspect of the present application aims to provide a linker. By limiting the number and types of amino acids, the linker possesses high hydrophilicity and a certain binding affinity with plasma proteins, thereby enhancing tumor uptake and retention time, and further improving imaging contrast. Furthermore, the present invention provides a targeted radiopharmaceutical comprising the linker, a method for preparing the targeted radiopharmaceutical, and its use.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] In the first aspect, the present invention provides a linker, which is composed of 2 to 3 amino acids, wherein the amino acids include at least acidic amino acids, and the acidic amino acids are selected from one or more of aspartic acid (Asp), glutamic acid (Glu) and 3-cysteic acid (SP). The linker is used to couple a targeting pharmacophore and a radionuclide binding group to prepare a targeting ligand and a targeted radiopharmaceutical.

[0009] Preferably, the amino acid combination further includes basic amino acids, and the basic amino acids are selected from one or more of arginine (Arg), lysine (Lys) and histidine (His).

[0010] In some embodiments, the linker is a composition formed by linking one arginine and one aspartic acid, the linker is a composition formed by linking two 3-cysteic acid residues and one aspartic acid, or the linker is a composition formed by linking one 3-cysteic acid residue and one aspartic acid.

[0011] In some embodiments, the linker is a composition formed by connecting two 3-cysteic acid residues.

[0012] In a second aspect, the present invention further provides a targeting ligand, comprising the above-mentioned linker and a targeting pharmacophore and a chelating group coupled to the linker, wherein the chelating group, the linker and the targeting pharmacophore are connected in sequence.

[0013] In a third aspect, the present invention further provides a targeted radiopharmaceutical comprising the aforementioned targeting ligand and having the following general structural formula:

[0014]

[0015] Wherein, *R is a radionuclide ion, M is a chelating group for binding to the radionuclide, C is a binding group containing *R, L is the linker, P is the targeting pharmacophore, MLP is the targeting ligand, and R*-MLP, i.e., CLP, is the targeted radiopharmaceutical.

[0016] The lipid-water distribution coefficient logD of the targeted radioactive drug is less than -2.5.

[0017] In some embodiments, the targeting pharmacophore P is one of a pharmacophore targeting fibroblast activation protein (FAP) (FAPI), a pharmacophore targeting glypican (GPC3) (GPC3P), a pharmacophore targeting somatostatin receptor (SSTR) (JR11), a pharmacophore targeting prostate-specific membrane antigen (PSMA) (PSMAL), and a pharmacophore targeting mesenchymal-epithelial transition factor (C-Met) (MetP);

[0018] The chelate group M is at least one of 1,4,7-triazacyclononacanyl-N',N""-diacetyl-N-acetyl (-NOTA) or its analogs, or 1,4,7,10-tetraazacyclododecane-N',N"N""-triacetyl-N-acetyl (DOTA).

[0019] Preferably, the radionuclide ion (*R) is selected from positron-emitting radionuclides 18 F. 68 Ga, 64 Cu, 89 Zr, therapeutic radionuclides 177 Lu, 90 Y. 188 Re or single-photon emitting radionuclides 99m Tc, 111 One of the ions formed by In.

[0020] In a fourth aspect, the present invention further provides a method for preparing a targeted radiopharmaceutical, comprising the following steps:

[0021] (1) Modifying the amino acid linker L with the targeted pharmacophore P to obtain the LP combination ligand;

[0022] (2) LP combined ligands are connected to chelating groups M (such as NOTA or DOTA) to obtain a targeting ligand, wherein the general structural formula of the targeting ligand is MLP; wherein the chelating group M is NOTA or DOTA;

[0023] (3) Using NOTA-LP as the precursor, the radioactive metal nuclide ions [Al 18 F] 2+ 、 68 Ga 3+ and 177 Lu 3+ Chelating reaction occurs respectively, and after separation and purification by small column, the products are made of 18 F. 68 Ga and 177Lu-labeled targeted radiopharmaceutical (*R-NOTA-LP); or

[0024] Using DOTA-LP as precursor material, and radioactive nuclide ions 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Chelating reaction occurs respectively, and after separation and purification by small column, the product is made of 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Labeled targeted radiopharmaceutical (*R-DOTA-LP).

[0025] In some embodiments, the radionuclide ions further include positron-emitting radionuclides 89 Zr, single-photon emitting radionuclides 99m Tc and 111 In, and therapeutic radionuclides 90 Y or 188 Any one of Re.

[0026] In a fifth aspect, the present invention further provides an application of a targeted radiopharmaceutical, using the above-mentioned targeted radiopharmaceutical, or a targeted radiopharmaceutical containing a linker obtained by the above-mentioned method for preparing the targeted radiopharmaceutical, wherein the targeted radiopharmaceutical includes the following applications:

[0027] The application of targeted radiopharmaceuticals in the diagnosis and treatment of tumors and cardiovascular and cerebrovascular diseases;

[0028] Application of positron-emitting radionuclide-LP in PET imaging of lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as in PET imaging of other tumors and diseases.

[0029] Applications of single-photon emitting radionuclides (LPs) in SPECT imaging, including: lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as applications in SPECT imaging of other tumors and diseases;

[0030] The application of diagnostic radionuclide-LP in nuclear medicine diagnosis and treatment includes: diagnosis and treatment of lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as its application in the diagnosis and treatment of other tumors and diseases.

[0031] Based on the above technical solutions, the present invention has the following technical effects:

[0032] 1. The linker provided by the present invention is composed of 2-3 amino acids, including at least acidic amino acids selected from one or more of aspartic acid, glutamic acid, and 3-cysteic acid. The linker is used to couple a targeting pharmacophore with a radionuclide binding group to prepare a targeting ligand and a targeted radiopharmaceutical. This linker has a certain binding affinity with plasma proteins, thereby enhancing tumor uptake and retention time, improving the in vivo pharmacokinetic properties of the radiopharmaceutical, and increasing the ratio of radiopharmaceutical uptake in tumor lesions to background, thereby enhancing imaging contrast.

[0033] 2. The targeted radiopharmaceutical provided by the present invention comprises the aforementioned linker, a targeting pharmacophore, and a radionuclide group. This targeted radiopharmaceutical constructed with the linker exhibits excellent in vivo pharmacokinetic properties, high lesion uptake values and lesion / background radioactivity uptake ratios, and a prolonged radioactivity retention time in the lesion. It can also significantly reduce renal radioactivity uptake, accelerate renal radioactivity clearance, significantly increase the lesion / kidney ratio, and reduce renal toxicity, significantly facilitating nuclear medicine diagnosis and treatment of tumors and other diseases, enhancing disease diagnosis and treatment outcomes.

[0034] 3. The preparation method of the targeted radioactive drug provided by the present invention has the characteristics of high yield and high purity automated synthesis, which can meet the needs of scientific research and clinical nuclear medicine diagnosis and treatment.

[0035] 4. The application of the targeted radioactive drug provided by the present invention is extensive and can be further applied to the nuclear medicine imaging evaluation of the efficacy of the above-mentioned multiple solid tumors, and can also be applied to the nuclear medicine diagnosis and treatment of tumors and other diseases with high expression of its target, which is of great significance in influencing diagnosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 For NOTA-SP2A-FAPT( Figure 1 A), NOTA-FAPT2( Figure 1 B) and NOTA-AA-FAPT( Figure 1 C) Schematic diagram of molecular docking with FAP protein.

[0037] Figure 2 For NOTA-SP2A-PSMAL( Figure 2 A) and NOTA-SPA-PSMATL( Figure 2 B) Schematic diagram of molecular docking with PSMA protein.

[0038] Figure 3 Schematic diagram of molecular docking of NOTA-SP2A-MetP and cMET protein.

[0039] Figure 4 Schematic diagram of molecular docking between NOTA-SP2-GPC3P and GPC3 protein ( Figure 4 A); Schematic diagram of molecular docking between NOTA-SP2-JR11 and SSTR2 protein ( Figure 4 B).

[0040] Figure 5 The representative UV HPLC analysis spectrum of NOTA-SP2A-FAPT precursor ( Figure 5 A);[ 18 Representative radioactive HPLC analysis of F-SP2A-FAPT products ( Figure 5 B) and in vitro PBS buffer ( Figure 5 C), serum ( Figure 5 D) Radioactive HPLC analysis spectrum at 2h; [ 18 Representative radioactive HPLC analysis of F-SP2A-FAPT injection ( Figure 5 E) and urine in Kunming mice ( Figure 5 F), serum ( Figure 5 G) Radioactive HPLC analysis spectrum at 1h; [ 18 F]F-SP2A-FAPT, [ 18 F]F-FAPT, [ 18 Comparison of ester-water distribution coefficients of three drugs (F]F-FAPI-42 Figure 5 H);[ 18 F]F-SP2A-FAPT, [ 18 F]F-FAPI-42 binding rate in mouse serum albumin ( Figure 5 I).

[0041] Figure 6 for[ 18 F]F-SP2A-FAPT, [ 18 Results of cell experiments on the uptake and inhibition of F]F-FAPI-42 on A549-FAP cells at different time points ( Figure 6 A);[ 18 Figure 2. Cell efflux experiment results of F-SP2A-FAPT on A549-FAP cells at different time points ( Figure 6 B);[ 18 F]F-SP2A-FAPT, [ 18 Competitive inhibition experiment results of F]F-FAPI-42 on A549-FAP cells ( Figure 6 C);[ 18 Results of the 1-hour cell internalization experiment of F]F-SP2A-FAPT on A549-FAP cells ( Figure 6 D).

[0042] Figure 7 for 18 The binding rate of F-SP2A-MetP in mouse serum albumin ( Figure 7 A);[ 177 Cellular experimental results of uptake and inhibition of Lu]Lu-FAPT2 on A549-FAP cells at different time points ( Figure 7 B).

[0043] Figure 8 for[ 18 F] Small animal PET / CT images of F-SP2A-FAPT at different times in the A549-FAP lung adenocarcinoma model with high FAP expression ( Figure 8 A);[ 18 F] Small animal PET / CT images of F-SP2A-FAPT at different times in the U87MG glioma model with high FAP expression ( Figure 8 B);[ 18 F] Changes of %ID values of F-SP2A-FAPT uptake in tumor and normal tissues over time in A549-FAP model ( Figure 8 C);[ 18 Figure 2 Changes of %ID value of F-SP2A-FAPT uptake in A549-FAP tumor and kidney over time ( Figure 8 D);[ 18 F] Changes of %ID values of F-SP2A-FAPT uptake in tumor and normal tissues over time in U87MG model ( Figure 8 E);[ 18 Figure 2 Changes of %ID values of F-SP2A-FAPT uptake in U87MG tumor and kidney over time ( Figure 8 F).

[0044] Figure 9 for[ 18 F]F-FAPT2 in the A549-FAP lung adenocarcinoma model with high FAP expression at different times ( Figure 9 A);[ 18 F]F-FAPT2 uptake %ID value changes over time in tumor and normal tissues in A549-FAP model ( Figure 9 B);[ 18 F]F-FAPT2 tumor-to-muscle ratio changes over time in A549-FAP tumor-bearing mice ( Figure 9 C).

[0045] Figure 10 for[ 18Small animal PET / CT images of F-AA-FAPT at different times in the A549-FAP lung adenocarcinoma model with high FAP expression ( Figure 10 A);[ 18 The changes of %ID values of F-AA-FAPT uptake in tumor and normal tissues over time in A549-FAP model ( Figure 10 B).

[0046] Figure 11 for 18 Small animal PET / CT images of F-SP2A-PSMAL at different time points in 22Rv1 tumor-bearing mice ( Figure 11 A); Changes of tumor uptake %ID values of two drugs over time ( Figure 11 B); 18 Small animal PET / CT images of F-PSMA-BCH at different time points in 22Rv1 tumor-bearing mice ( Figure 11 C); Changes of tumor-muscle ratio of two drugs over time ( Figure 11 D). 18 Small animal PET / CT images of F-SPA-PSMATL at different time points in 22Rv1 tumor-bearing mice ( Figure 11 E); Changes of tumor uptake %ID values of the two drugs over time ( Figure 11 F); 18 Small animal PET / CT images of F-PSMA-BCH at different time points in 22Rv1 tumor-bearing mice ( Figure 11 G); Changes of tumor-muscle ratio of two drugs over time ( Figure 11 H). Figure 12 for 18 Small animal PET / CT images of F-SP2A-MetP at different time points in Capan2 tumor-bearing mice ( Figure 12 A); 18 The changes of %ID values of F-SP2A-MetP uptake in tumor and normal tissues in Capan2 model over time ( Figure 12 B); 18 The change of tumor-to-muscle ratio of F-SP2A-MetP in Capan2 model over time ( Figure 12 C).

[0047] Figure 13 for 18 Uptake and inhibition biodistribution of F-SP2A-FAPT at 60 min in A549-FAP lung adenocarcinoma model with high FAP expression ( Figure 13 A); 18 F-FAPT and 18Comparison of the biodistribution of F-FAPT2 uptake at 60 min in the A549-FAP lung adenocarcinoma model with high FAP expression ( Figure 13 B).

[0048] Figure 14 For injection 18 F-FAPI-42( Figure 14 A) 18 F-FAPT( Figure 14 B) 18 F-SP2A-FAPT( Figure 14 C) 18 F-FAPT2( Figure 14 D) and 18 F-FAPT2( Figure 14 E) PET / CT whole-body scan 60 minutes later. DETAILED DESCRIPTION

[0049] To facilitate understanding of the present invention, the present invention will be described more fully below with reference to specific embodiments. The present invention provides preferred embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, the purpose of providing these embodiments is to provide a more thorough and comprehensive understanding of the disclosure of the present invention.

[0050] Before further describing the various embodiments of the compounds / compositions and methods of the present disclosure in more detail through exemplary descriptions, examples and results, it should be understood that the embodiments of the present disclosure are not limited in application to the details of the methods and compositions described in the following description. The description provided herein is for illustrative purposes only and is not to be interpreted in a limiting sense. The inventive concepts of the present disclosure are capable of other embodiments or can be practiced or implemented in various ways. Therefore, the language used herein is intended to give the broadest scope and meaning; and the embodiments are intended to be exemplary, not exhaustive, and are not intended to limit the present disclosure to these specific embodiments. Moreover, it should be understood that the wording and terminology used herein are for descriptive purposes and should not be considered restrictive unless otherwise stated. In addition, in the following detailed description, many specific details are listed in order to provide a more thorough understanding of the present disclosure.

[0051] However, it is obvious to one skilled in the art that the embodiments of the present disclosure can be practiced without these specific details. In other cases, features well known to one skilled in the art have not been described in detail to avoid unnecessary complexity of the description. It is intended that all alternatives, replacements, modifications and equivalents obvious to one skilled in the art are included within the scope of the present disclosure. Based on the present disclosure, all compounds / compositions disclosed herein and their preparation methods, applications and uses can be prepared and implemented without undue experimentation.

[0052] Thus, while the compounds / compositions and methods of the present disclosure have been described with respect to specific embodiments, it will be apparent to those skilled in the art that variations may be made in the formulations, compounds or compositions and / or methods, as well as in the steps or order of steps of the methods described herein, without departing from the spirit and scope of the inventive concepts of the present disclosure.

[0053] As used herein, any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase "in one embodiment" in multiple places in the specification are not necessarily all referring to the same embodiment.

[0054] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present disclosure shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0055] The present invention provides a linker, which is composed of a combination of 2 to 3 amino acids, wherein the amino acid combination includes at least acidic amino acids, and the acidic amino acids are selected from one or more of aspartic acid (Asp), glutamic acid (Glu) and 3-cysteic acid (SP). The linker is used to couple a targeting pharmacophore and a radionuclide binding group to prepare a targeting ligand and a targeting radiopharmaceutical.

[0056] Preferably, the amino acid combination further includes basic amino acids, and the basic amino acids are selected from one or more of arginine (Arg), lysine (Lys) and histidine (His).

[0057] In some embodiments, the linker is a composition formed by linking one arginine and one aspartic acid, the linker is a composition formed by linking two 3-cysteic acid groups and one aspartic acid, or the linker is a composition formed by linking one 3-cysteic acid and one aspartic acid.

[0058] In some embodiments, the linker is a composition formed by two 3-cysteic acid linkages.

[0059] It should be noted that the hydrophilic linker provided by the present invention has a certain binding affinity with plasma proteins. In particular, the acidic amino acid 3-cysteic acid (SP) binds to plasma proteins better than aspartic acid (Asp) or glutamic acid (Glu), and the basic amino acid arginine (Arg) binds to plasma proteins better than lysine (Lys) and histidine (His).

[0060] The linker can also be used to prepare a targeting ligand, comprising the linker described above and a targeting pharmacophore and a chelating group coupled to the linker, wherein the chelating group, the linker and the targeting pharmacophore are connected in sequence.

[0061] Furthermore, the targeting ligand is linked to a radionuclide to obtain a targeted radiopharmaceutical. The targeted radiopharmaceutical comprises the above-mentioned linker, and a targeting pharmacophore and a radionuclide group coupled to the linker. The targeting ligand has the following general structural formula:

[0062]

[0063] Wherein, *R is a radionuclide, M is a chelating group used to bind to the radionuclide, C is a binding group containing *R, L is a linker, P is a targeting pharmacophore, MLP is a targeting ligand, R*-MLP, i.e., CLP, is a targeted radiopharmaceutical, and the lipid-water distribution coefficient of the targeting ligand, logD, is <-2.5.

[0064] In some embodiments, the targeting pharmacophore P is one of a pharmacophore targeting fibroblast activation protein (FAP) (FAPI), a pharmacophore targeting glypican (GPC3) (GPC3P), a pharmacophore targeting somatostatin receptor (SSTR) (JR11), a pharmacophore targeting prostate-specific membrane antigen (PSMA) (PSMAL), and a pharmacophore targeting mesenchymal-epithelial transition factor (MetP);

[0065] The bound radionuclide group C includes at least one of 1,4,7-triazacyclononacanyl-N',N"-diacetoxy-N-acetyl (-NOTA) or its analog 1,4,7,10-tetraazacyclododecane-N',N"N"'-triacetoxy-N-acetyl (DOTA).

[0066] Preferably, the radionuclide ion (*R) is selected from the group consisting of positron-emitting radionuclides 18 F. 68 Ga, 64 Cu, 89 Zr, therapeutic radionuclides 177 Lu, 90 Y. 188Re or single-photon emitting radionuclides 99m Tc, 111 One of the ions formed by In, such as 18 F - 、[Al 18 F] 2+ (abbreviation 18 F-AlF), 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ etc.

[0067] In addition, the preparation method of a targeted radiopharmaceutical provided by the present invention can be obtained by the following steps:

[0068] (1) Modifying the amino acid linker L with the targeted pharmacophore P to obtain the LP combination ligand;

[0069] (2) LP combined ligands are linked to chelating groups M (such as NOTA or DOTA) to obtain the targeting ligand MLP;

[0070] (3) Using the targeting ligand NOTA-LP as the precursor, the radioactive metal nuclide ions [Al 18 F] 2+ 、 68 Ga 3+ and 177 Lu 3+ Chelating reaction occurs, and after separation and purification by small column, the products are made of 18 F. 68 Ga and 177 Lu-labeled targeted radiopharmaceutical (*R-NOTA-LP); or

[0071] Using the targeting ligand DOTA-LP as the precursor, the radioactive nuclide ions 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Chelating reaction occurs, and after separation and purification by small column, the product is made of 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Labeled targeted radiopharmaceutical (*R-DOTA-LP).

[0072] Specifically, the targeting ligand may have the following structural formula:

[0073] ① Targeting FAP ligand: ML-FAPI is NOTA-SP2A-FAPT(A),

[0074] NOTA-GAA-FAPT (NOTA-FAPT2, B), NOTA-AA-FAPT (C), such as formula Ⅰ

[0075] As shown; wherein, the target pharmacophores of NOTA-SP2A-FAPT (A) and NOTA-AA-FAPT (C) are quinoline ether-aminoacetyl cyanodifluoropyrrolidine groups, and

[0076] The targeting pharmacophore of NOTA-GAA-FAPT (NOTA-FAPT2, B) is a quinoline ether-aminoacetyl cyanopyrrolidine group, which has two fewer fluorine atoms and has different binding affinity with FAP.

[0077]

[0078] ② PSMA-targeted drugs: NOTA-SP2A-PSMAL (A) and NOTA-SPA-PSMATL (B),

[0079] As shown in formula (II),

[0080]

[0081] ③ Targeting C-Met ligand: NOTA-SP2A-MetP, as shown in formula (III):

[0082]

[0083] ④ Targeting GPC3 ligand: NOTA-SP2-GPC3P, as shown in formula (IV):

[0084]

[0085] ⑤ Targeted SSTR ligand: NOTA-SP2-JR11, as shown in formula (V):

[0086]

[0087] In addition to the structures of the targeting ligands listed above, there are also targeting ligands obtained by replacing NOTA in the above structural formula with DOTA.

[0088] In addition, the above-mentioned linker, or the above-mentioned targeted radiopharmaceutical, or the linker-containing targeted radiopharmaceutical obtained by the above-mentioned method for preparing the targeted radiopharmaceutical can be used in the diagnosis and treatment of tumors, cardiovascular and cerebrovascular diseases.

[0089] Example 1 Molecular docking experiment

[0090] Autocock Vina software was used to perform NOTA-SP2A-FAPT ( Figure 1 A), NOTA-FAPT2( Figure 1 B) and NOTA-AA-FAPT( Figure 1 C) Docking with FAP protein (PDB ID: 1Z68) and visualization using PyMol software. The minimum binding energies of NOTA-SP2A-FAPT, NOTA-FAPT2, and NOTA-AA-FAPT to FAP protein were -9.0 kcal / mol, -8.631 kcal / mol, and -9.662 kcal / mol, respectively. Multiple hydrogen bonds were observed between the ligands and the protein, demonstrating high affinity. The targeting pharmacophores of NOTA-SP2A-FAPT and NOTA-AA-FAPT are quinoline ether-aminoacetylcyanodifluoropyrrolidine groups, while the targeting pharmacophore of NOTA-FAPT2 is quinoline ether-aminoacetylcyanodifluoropyrrolidine groups, which lack two fluorine atoms.

[0091] Molecular docking was performed on NOTA-SP2A-PSMAL and NOTA-SPA-PSMATL to evaluate their binding ability to PSMA protein. Figure 2 A), NOTA-SPA-PSMATL( Figure 2 B) There are multiple hydrogen bond interactions between NOTA-SP2A-PSMAL and NOTA-SPA-PSMATL and PSMA protein, with the lowest binding energies being -10.1 Kcal / mol and -10.7 Kcal / mol, respectively, indicating that NOTA-SP2A-PSMAL and NOTA-SPA-PSMATL have strong binding ability with PSMA protein.

[0092] Molecular docking of NOTA-SP2A-MetP was performed to evaluate the compatibility of the candidate drug with c-Met. Multiple hydrogen bond interactions exist between NOTA-SP2A-MetP and c-Met molecules, with the lowest binding energy being -8.8 kcal / mol ( Figure 3 ), indicating that it has a strong affinity with the ligand.

[0093] Molecular docking of NOTA-SP2-GPC3P was performed to evaluate the compatibility of the drug with GPC3 protein. Multiple hydrogen bond interactions were found between NOTA-SP2-GPC3P and GPC3 protein, with the lowest binding energy being -6.0 kcal / mol ( Figure 4 A), indicating a strong affinity for the ligand.

[0094] Molecular docking of NOTA-SP2-JR11 was performed to evaluate the compatibility of the drug with the SSTR2 protein. Multiple hydrogen bond interactions were found between NOTA-SP2-JR11 and the SSTR2 protein, with the lowest binding energy being -8.3 kcal / mol ( Figure 4 B), indicating a strong affinity for the ligand.

[0095] Example 2 Preparation of NOTA-Hydrophilic Linker-Targeting Pharmacophore Precursor Raw Materials

[0096] Preparation of NOTA-SP2A-FAPT: The pharmacophore of FAPI is modified with -Asp (one aspartic acid group) to form FAPT-Asp, which is then modified with SP2 (two 3-sulfoalanine groups) and finally combined with -NOTA to generate NOTA-SP2A-FAPT. The product peak is separated and purified by preparative HPLC to obtain the purified precursor product NOTA-SP2A-FAPT. NOTA-SP2A-FAPT has a high chemical yield and a purity greater than 95% (see Figure 5 A). The molecular weight (Mr.) of NOTA-SP2A-FAPT was determined by mass spectrometry (MS) (m / z) to be 1301.45.

[0097] Preparation of NOTA-FAPT2: The targeting pharmacophore of NOTA-FAPT2 is a quinoline-ether-aminoacetylcyanopyrrolidine group, which has two fewer fluorine atoms than the quinoline-ether-aminoacetylcyanodifluoropyrrolidine group. The glycopeptide structure (Glc-Asp2) is modified with the chelating group NOTA to form NOTA-Glc-Asp2, which is then modified with PEG2. Finally, the quinoline-ether-aminoacetylcyanopyrrolidine (FAPI) pharmacophore is modified to form the targeting ligand NOTA-GAA-FAPT (NOTA-FAPT2). The product peak is separated and purified by preparative HPLC to obtain the purified precursor product, NOTA-FAPT2. NOTA-FAPT2 has a high chemical yield and a purity greater than 95%. Mass spectrometry (MS) (m / z) determined the molecular weight (Mr) of NOTA-FAPT2 to be 1442.5.

[0098] Preparation of NOTA-AA-FAPT: The pharmacophore of FAPI is modified with -Asp to form FAPT-Asp, which is then modified with -Arg. Finally, the product is conjugated with -NOTA to form NOTA-AA-FAPT. The product peak is separated and purified using preparative HPLC to obtain the purified precursor product, NOTA-AA-FAPT. The chemical yield of NOTA-AA-FAPT is high, with a purity exceeding 95%. Mass spectrometry (MS) (m / z) determines the molecular weight (Mr) of NOTA-AA-FAPT to be 1043.10.

[0099] Preparation of NOTA-SP2A-PSMAL: PSMA pharmacophores are modified with -Asp to form PSMA-Asp, which is then modified with SP2 by PSMA-Asp. Finally, the product is conjugated with -NOTA to form NOTA-SP2A-PSMAL. The product peak is separated and purified using preparative HPLC to obtain the purified precursor product, NOTA-SP2A-PSMAL. NOTA-SP2A-PSMAL has a high chemical yield and a purity greater than 95%. Mass spectrometry (MS) (m / z) determined the molecular weight (Mr) of NOTA-SP2A-PSMAL to be 1358.2.

[0100] Preparation of NOTA-SPA-PSMATL: PSMA pharmacophores are modified with -Asp to form PSMA-Asp, which is then modified with SP. Finally, the product is conjugated with -NOTA to form NOTA-SPA-PSMATL. The product peak is separated and purified using preparative HPLC to obtain the purified precursor NOTA-SPA-PSMATL. NOTA-SPA-PSMATL has a high chemical yield and a purity greater than 95%. Mass spectrometry (MS) (m / z) analysis indicates the molecular weight (Mr) of NOTA-SPA-PSMATL is 1271.36.

[0101] Preparation of NOTA-SP2A-MetP: The MetP pharmacophore is modified with -Asp to form MetP-Asp, which is then modified with SP2 by MetP-Asp. Finally, the product is conjugated with -NOTA to form NOTA-SP2A-MetP. The product peak is separated and purified using preparative HPLC to obtain the purified precursor product, NOTA-SP2A-MetP. NOTA-SP2A-MetP has a high chemical yield and a purity greater than 95%. Mass spectrometry (MS) (m / z) analysis indicates the molecular weight (Mr) of NOTA-SP2A-MetP is 2160.4.

[0102] Preparation of NOTA-SP2-GPC3P: After modifying the GPC3P pharmacophore with SP2, it is conjugated with -NOTA to generate NOTA-SP2-GPC3P. The product peak is separated and purified using preparative HPLC to obtain the purified precursor, NOTA-SP2-GPC3P. NOTA-SP2-GPC3P has a high chemical yield and a purity exceeding 95%. Mass spectrometry (MS) (m / z) determination of the molecular weight (Mr) of NOTA-SP2-GPC3P is 2113.43.

[0103] Preparation of NOTA-SP2-JR11: After modifying SP2 with the JR11 pharmacophore, the JR11 is conjugated with -NOTA to generate NOTA-SP2-JR11. The product peak is then separated and purified using preparative HPLC to obtain the purified precursor, NOTA-SP2-JR11. NOTA-SP2-JR11 has a high chemical yield and a purity exceeding 95%. Mass spectrometry (MS) (m / z) analysis indicates a molecular weight (Mr) of 2033.65 for NOTA-SP2-JR11.

[0104] Example 3 [Al 18 F] 2+ Radiosynthesis of Labeled NOTA-LP Radiopharmaceuticals

[0105] [Al 18 F] 2+ Labeling method. In a reaction bottle containing the precursor material NOTA-LP (50μg / μL, 50μL), add 6μL of 2mmol / L AlCl3 solution, 5μL of glacial acetic acid and 300μL of acetonitrile in sequence and mix well. 18 O(p,n) 18 F produced by nuclear reaction 18 F is captured on a Sep-Pak QMA anion cartridge. Elute the 18F from the QMA anion cartridge with 0.3-0.4 mL of saline or sodium acetate buffer into a vial. Add 50 μL of this solution to the above reaction vial. After stirring, heat the reaction at 100°C for approximately 10-15 minutes. Cool, add 6-8 mL of water to the reaction vial, mix thoroughly, and transfer to a Sep-Pak C18 cartridge. After the entire solution in the reaction vial has been transferred, rinse the cartridge with 3 10 mL of water for injection and air dry. Finally, elute the product with 1.5 mL of ethanol, filter through a sterile membrane, and collect it in a receiving vial. Dilute the product with saline to a 5% ethanol solution to obtain a radiopharmaceutical injection solution that meets the requirements.

[0106] 18 The decay-corrected radiochemical yield of F-SP2A-FAPT was 37.02±10.17%, and the total radiosynthesis time was 30 min. 18 The decay-corrected radiochemical yield of F-FAPT2 was 26.35±5.62%, and the total radiosynthesis time was 30 min. 18 The radiochemical yield of F-AA-FAPT after decay correction was 15.83±8.72%, and the total radiosynthesis time was 30 min. 18 The decay-corrected radiochemical yield of F-SP2A-PSMAL was 33.04±11.04%, and the total radiosynthesis time was 30 min. 18The decay-corrected radiochemical yield of F-SPA-PSMATL was 33.61±21.87%, and the total radiosynthesis time was 30 min. 18 The decay-corrected radiochemical yield of F-SP2A-MetP was 22.37±9.64%, and the total radiosynthesis time was 30 min.

[0107] Other targeting ligands NOTA-LP can be prepared according to the above radiopharmaceutical synthesis method. 18 F marks the drug.

[0108] Example 4 68 Ga 3+ Radiosynthesis of labeled MLP radiopharmaceuticals

[0109] Made of metal 68 Ga 3+ Chelation reaction preparation 68 Ga-NOTA-FAPT2 mainly includes the following steps:

[0110] 68 Washing of Ga generator: Take 4ml of hydrochloric acid (0.05M), push the generator, and 68 The Ga eluent was collected in a vacuum bottle and then 68 The Ga eluent was added to a reaction vial containing NOTA-FAPT2 (50 μg, 50 μl water) and sodium acetate buffer (pH = 4; 0.5 ml; 0.25 M) and mixed thoroughly. The reaction vial was heated at 100°C for 10 minutes. 6 ml of water was added to the reaction mixture, cooled to room temperature, and then transferred to a Sep Pak plus C18 column. The Sep Pak plus C18 column was rinsed once with 10 ml of water, followed by 1.5 ml of 50% ethanol. The product was transferred to a transfer flask. Finally, the product was sterile filtered and collected in a sterile product bottle. 68 The undecay-corrected yield of Ga-NOTA-FAPT2 was 63.66±3.38%, and the radiochemical purity was greater than 95%.

[0111] Other targeting ligands NOTA-LP and DOTA-LP can refer to the above 68 Preparation of Ga-NOTA-FAPT2 by Synthesis Method 68 Ga-labeled drugs.

[0112] Example 5 177 Lu 3+ Radiosynthesis of Labeled NOTA-Hydrophilic Linker-Targeted Pharmacophore Radiopharmaceuticals

[0113] 177Lu labeling. Precursor NOTA-FAPT2 (50 μg), 2 mg gentisic acid, 160 μl sodium acetate and free 177 Lu solution 0.100-1.000mL, heated in a water bath at 106℃ for 15 minutes. The reaction effect was monitored by HPLC. After passing through a C18 column, it was rinsed with 30ml of water and eluted with 1mL of 50% ethanol. The product was collected. Finally, it was diluted with physiological saline and filtered through a sterile filter membrane and collected into a receiving bottle to obtain the product that met the requirements. 177 Lu-labeled NOTA-FAPT2 injection. 177 The undecay-corrected yield of Lu-NOTA-FAPT2 was 96.73±2.16%, and the radiochemical purity was greater than 95%.

[0114] Other targeting ligands NOTA-LP and DOTA-LP can be prepared according to the above-mentioned drug synthesis method. 177 Lu-labeled drugs.

[0115] Determination of radiochemical purity and stability of Example 6 products

[0116] 18 The results of radio-HPLC analysis of F-SP2A-FAPT injection are shown in Figure 5 B (radioactive peak retention time Rt = 11 min), radiochemical purity greater than 95%.

[0117] HPLC method was used to test the stability in vivo and in vitro. 18 In vitro stability of F-SP2A-FAPT in PBS buffer and serum for 2 h. 18 The radiochemical purity of F-SP2A-FAPT in PBS buffer and serum in vitro for 2 h was greater than 90% (see Figure 5 CD), indicating good in vitro stability. 18 When F-SP2A-FAPT was inoculated into Kunming mice for 1 hour, only a single main peak appeared in the urine, and no other secondary peaks were detected, suggesting that 18 F-SP2A-FAPT did not undergo defluorination or decomposition in urine within 1 hour; no obvious defluorination was observed in serum either (see Figure 5 EG).

[0118] The radiochemical purity and stability of other targeted radiopharmaceuticals CLP can be determined according to the above method.

[0119] Example 7 Ester-water partition coefficient determination experiment

[0120] After determination 18 F-SP2A-FAPT, 18 F-FAPT and 18The lipid-water partition coefficients of F-FAPI-42 were logD = -3.52 ± 0.14, -3.14 ± 0.03 and -2.61 ± 0.28 respectively. The results showed that the three drugs had obvious hydrophilicity and 18 F-SP2A-FAPT has the highest hydrophilicity (see Figure 5 H).

[0121] After determination 18 F-SP2A-PSMAL and 18 The lipid-water partition coefficients of F-SPA-PSMATL were logD = -3.50 ± 0.30 and -2.78 ± 0.58, respectively.

[0122] The ester-water partition coefficient of other targeted radioactive drug CLP is determined according to the above method, and the lipid-water distribution coefficient logD is between -2.5 and -3.5.

[0123] Example 8 Albumin binding experiment

[0124] 18 F-FAPI-42 is a commonly used PET drug targeting FAP. 18 F] 2+ The labeling method also prepared 18 F-FAPI-42 was used as a control. 18 F-SP2A-FAPT and 18 The albumin binding rates of F-FAPI-42 were 13.29±2.92% and 2.84±0.09%, respectively. 18 F-SP2A-FAPT has a small amount of binding to mouse plasma albumin (see Figure 5 I).

[0125] According to the above method, 18 The albumin binding experiment of F-SP2A-MetP was determined. 18 The albumin binding rate of F-SP2A-MetP was 42±2%, which was higher than that of Figure 7 (as shown in A).

[0126] Albumin binding experiments were performed for other targeted radiopharmaceuticals CLP according to the above method.

[0127] Example 9 In vitro cell uptake and inhibition experiment

[0128] 18 F-SP2A-FAPT cell uptake and inhibition experimental results: It was rapidly taken up in A549-FAP cells, reaching 167.91±3.86% ID / million cells at 120 minutes, which was relatively 18F-FAPI-42 was slightly higher in the A549-FAP cell inhibition group, and both showed lower uptake values, indicating that 18 F-SP2A-FAPT has high uptake and retention in A549-FAP cells and is specific (see Figure 6 A). In the outflow experiment 18 F-SP2A-FAPT effluxed slowly in A549-FAP cells, with an efflux rate of 29.28±3.43% at 120 min (see Figure 6 Representative competitive binding assay results are shown in Figure 6 As shown in C. The IC50 value of NOTA-SP2A-FAPT is 8.58nM, and the IC50 value of NOTA-FAPI-42 is 8.90nM. The results show that NOTA-SP2A-FAPT has a stronger affinity. 18 F-SP2A-FAPT has a high internalization rate in A549-FAP cells, with an internalization rate of 95.10% at 60 minutes (see Figure 6 D).

[0129] 177 Lu-FAPT2 cell uptake and inhibition experimental results: Lu-FAPT2 was rapidly taken up in A549-FAP cells, reaching 22.70±1.27% ID / million cells at 120 minutes, and it could still maintain nearly half of the uptake value (10.66±1.32% ID / million cells) at 24 hours; in the A549-FAP cell inhibition group, the uptake values were all lower, indicating that 177 Lu-FAPT2 has high uptake and retention in A549-FAP cells and is specific (see Figure 7 shown).

[0130] Other targeted radioactive drugs CLP were subjected to in vitro cellular uptake and inhibition experiments according to the above method.

[0131] Example 10 PET imaging experiment in model animals

[0132] Imaging results in A549-FAP lung adenocarcinoma and U87MG glioma models showed: 18 F-SP2A-FAPT is rapidly excreted through the kidneys, and excretion is basically complete within 15 minutes. 18 F-SP2A-FAPT has high uptake in A549-FAP lung adenocarcinoma and U87MG glioma models. Tumor uptake of the drug remained stable within 4 hours, with no significant decrease. This is beneficial for maintaining high tumor radioactivity accumulation while significantly reducing the nephrotoxicity of the radiopharmaceutical (see Figure 8 shown).

[0133] Imaging results in the A549-FAP lung adenocarcinoma model showed that: 8 F-FAPT2 is rapidly excreted through the kidneys and is essentially eliminated within 60 minutes. 8 F-FAPT2 has a high uptake in the A549-FAP lung adenocarcinoma model. The drug uptake in the tumor remained stable within 2 hours, with no significant decrease. This is beneficial for maintaining a high tumor radioactivity accumulation (see Figure 9 shown).

[0134] Imaging results in the A549-FAP lung adenocarcinoma model showed that: 8 F-AA-FAPT is rapidly excreted through the kidneys, and excretion is basically complete within 60 minutes. 8 F-FAPT2 has a high uptake in the A549-FAP lung adenocarcinoma model. The drug uptake in the tumor remained stable within 1 hour, with no significant decrease. This is beneficial for maintaining a high tumor radioactivity accumulation (see Figure 10 shown).

[0135] The same 22Rv1 tumor-bearing mouse was tested for two consecutive days. 18 F-SP2A-PSMAL, 18 PET / CT imaging of F-PSMA-BCH. 18 F-SP2A-PSMAL, 18 The uptake values of F-PSMA-BCH in 22Rv1 tumors at 1h, 2h, and 6h were 6.6±1.80%ID / g and 5.1±0.97%ID / g, 6.8±1.90%ID / g and 5.0±1.10%ID / g, 7.3±2.00%ID / g, and 4.7±0.78%ID / g, respectively. 18 The tumor uptake value of F-SP2A-PSMAL in 22Rv1 mice was significantly higher than that in 18 F-PSMA-BCH. 18 F-SP2A-PSMAL has high tumor uptake, low background signal and high tumor to muscle ratio in 22Rv1 mice. 18 F-SPA-PSMATL, 18 PET / CT imaging of F-PSMA-BCH. 18 F-SPA-PSMATL, 18 The uptake values of F-PSMA-BCH in 22Rv1 tumors at 1h, 2h, and 6h were (8.3±0.86%ID / g vs 6.6±0.89%ID / g), (9.0±0.83%ID / g vs 6.3±1.40%ID / g), and (8.2±0.96%ID / g vs 5.5±0.53%ID / g), respectively.18 The tumor uptake value of F-SPA-PSMATL in 22Rv1 mice was significantly higher than that in 18 F-PSMA-BCH. 18 F-SPA-PSMATL also has better tumor-to-kidney ratio and tumor-to-muscle ratio ( Figure 11 ).

[0136] Mice carrying Capan2 18 PET / CT scan of F-SP2A-MetP, evaluation 18 The imaging characteristics and detection capabilities of F-SP2A-MetP. In mice bearing Capan2 xenograft tumors, 18 F-SP2A-MetP can show Capan2 tumors. 18 The tumor uptake value after 60 minutes of F-SP2A-MetP was 2.23±0.49%ID / g. 18 The ratio of the uptake value of F-SP2A-MetP in tumors to that in normal tissues (muscle) gradually increases over time. 18 F-SP2A-MetP showed a high contrast image, which is beneficial for the detection of lesions ( Figure 12 ).

[0137] Animal PET imaging experiments were performed with other targeted radioactive drugs CLP according to the above method.

[0138] Example 11 In vivo biodistribution experiment

[0139] 18 The results of the biodistribution experiment of F-SP2A-FAPT in nude mice bearing A549-FAP tumors are as follows: Figure 13 As shown in A. The results show 18 F-SP2A-FAPT had lower radioactive uptake and lower values in the kidney, indicating that the probe had been largely excreted through the kidney at 60 minutes. 18 F-SP2A-FAPT showed a high tumor uptake value and could be specifically inhibited, indicating that the drug had a better uptake effect in the tumor, which was consistent with the previous PET imaging results.

[0140] 18 F-FAPT2 and 18 The control results of the biodistribution experiment of F-FAPT in nude mice bearing A549-FAP tumors are shown in Figure 2. Figure 13 As shown in B. The results show 18 F-FAPT2 had lower radioactive uptake and lower values in the kidney, indicating that the probe had been largely excreted through the kidney at 60 minutes.18 F-FAPT2 compared to 18 F-FAPT showed higher tumor uptake values and lower blood pool uptake values, indicating that the drug was better taken up in the tumor and had a better background value, which was consistent with the previous PET imaging results.

[0141] In vivo biodistribution experiments of other targeted radioactive drugs CLP were performed according to the above method.

[0142] Example 12 Clinical Study of Hydrophilic Targeted Radiopharmaceuticals

[0143] The 5 enrolled patients were injected 18 F-FAPI-42, 18 F-FAPT, 18 F-SP2A-FAPT, 18 F-FAPT2 and 18 PET / CT scan was performed 60 minutes after F-FAPT2.

[0144] The results of the study showed that 18 F-FAPI-42 has a high physiological uptake in organs such as the gallbladder, bile duct, pancreas and intestines (see Figure 14 A); and our previously developed 18 F-FAPT (patent number: CN202110611305.6) comparison, 18 F-FAPT greatly reduces the uptake of the gallbladder, bile duct, and intestine, so the physiological uptake of the gallbladder, bile duct, and intestine is 18 F-FAPT is significantly decreased, however, physiological uptake in the blood pool and pancreas is still significant (see Figure 14 B); This patent describes 18 F-SP2A-FAPT, the lesion uptake was obvious at 60 minutes, and the renal excretion rate was faster than 18 F-FAPT is faster, but 18 F-FAPT still has similar issues with blood pool and high physiological uptake in the pancreas (see Figure 14 C) However, the patent 18 F-FAPT2 is maintaining 18 The advantages of F-FAPT are high tumor uptake and low uptake in the gallbladder, bile duct and intestinal system, and it also solves the problem of 18 F-FAPT and 18 The problem of high blood pool uptake exhibited by F-SP2A-FAPT (see Figure 14 D); In addition, improve 18 The specific activity or radioactivity concentration of F-FAPT2 can significantly reduce pancreatic uptake (see Figure 14E), thus further solving the problem of high pancreatic uptake of FAP-targeted radiopharmaceuticals.

[0145] The above description is merely an example and illustration of the structure of the present invention. Although the description is relatively specific and detailed, it should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art may make various modifications and improvements without departing from the scope of the present invention, and such obvious alternatives are all within the scope of protection of the present invention.

Claims

1. A linker, characterized in that The linker is composed of 2 to 3 amino acids, wherein the amino acids include at least acidic amino acids, and the acidic amino acids are selected from one or more of aspartic acid (Asp), glutamic acid (Glu) and 3-cysteic acid (SP). The linker is used to couple the targeting pharmacophore and the radionuclide binding group to prepare a targeting ligand and a targeting radiopharmaceutical.

2. The linker according to claim 1, characterized in that The amino acid combination further includes basic amino acids, and the basic amino acids are selected from one or more of arginine (Arg), lysine (Lys) and histidine (His).

3. The linker according to claim 1 or 2, characterized in that The linker is a composition formed by linking one arginine and one aspartic acid, the linker is a composition formed by linking two 3-cysteic acid residues and one aspartic acid, or the linker is a composition formed by linking one 3-cysteic acid residue and one aspartic acid.

4. The linker according to claim 1, characterized in that The linker is a composition formed by connecting two 3-cysteic acid groups.

5. A targeting ligand, characterized in that The invention comprises the linker according to any one of claims 1 to 4, and a targeting pharmacophore and a chelating group coupled to the linker, wherein the chelating group, the linker and the targeting pharmacophore are connected in sequence.

6. A targeted radiopharmaceutical, characterized in that: The targeting ligand according to claim 5 has the following general structural formula: Wherein, *R is a radionuclide ion, M is a chelating group for binding to the radionuclide, C is a binding group containing *R, L is the linker, P is the targeting pharmacophore, MLP is the targeting ligand, and R*-MLP, i.e., CLP, is the targeted radiopharmaceutical. The lipid-water distribution coefficient of the targeted radioactive drug is logD<-2..

5.

7. The targeted radiopharmaceutical according to claim 6, characterized in that The targeting pharmacophore P is one of a pharmacophore targeting fibroblast activation protein (FAP) (FAPI), a pharmacophore targeting glypican (GPC3) (GPC3P), a pharmacophore targeting somatostatin receptor (SSTR) (JR11), a pharmacophore targeting prostate-specific membrane antigen (PSMA) (PSMAL), and a pharmacophore targeting mesenchymal-epithelial transition factor (C-Met) (MetP); The chelate group M is at least one of 1,4,7-triazacyclononacanyl-N',N"-diacetyl-N-acetyl (-NOTA) or its analogs, or 1,4,7,10-tetraazacyclododecane-N',N"N"'-triacetyl-N-acetyl (DOTA).

8. The targeted radiopharmaceutical according to claim 6, characterized in that The radionuclide ion (*R) is selected from positron-emitting radionuclides 18 F. 68 Ga, 64 Cu, 89 Zr, therapeutic radionuclides 177 Lu, 90 Y. 188 Re or single-photon emitting radionuclides 99m Tc, 111 One of the ions formed by In.

9. A method for preparing a targeted radiopharmaceutical, characterized in that: The preparation of the targeted radiopharmaceutical according to any one of claims 6 to 8 comprises the following steps: (1) The targeted pharmacophore P is modified with a linker L to obtain a LP combination ligand; (2) LP combined ligands are connected to chelating groups M to obtain a targeting ligand, wherein the general structural formula of the targeting ligand is MLP; wherein the chelating group M is NOTA or DOTA; (3) Using NOTA-LP as the precursor, and radioactive metal nuclide ions [Al 18 F] 2+ 、 68 Ga 3+ and 177 Lu 3+ Chelating reaction occurs respectively, and after separation and purification by small column, the products are made of 18 F. 68 Ga and 177 Lu-labeled targeted radiopharmaceutical (*R-NOTA-LP); or Using DOTA-LP as precursor material, and radioactive nuclide ions 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Chelating reaction occurs respectively, and after separation and purification by small column, the product is made of 68 Ga 3+ 、 64 Cu 2+ and 177 Lu 3+ Labeled targeted radiopharmaceutical (*R-DOTA-LP).

10. Use of targeted radiopharmaceuticals, characterized in that: The targeted radiopharmaceutical according to any one of claims 6 to 8, or the targeted radiopharmaceutical containing a linker obtained by the method for preparing the targeted radiopharmaceutical according to claim 9, wherein the targeted radiopharmaceutical includes the following applications: The application of targeted radiopharmaceuticals in the diagnosis and treatment of tumors and cardiovascular and cerebrovascular diseases; Application of positron-emitting radionuclide-LP in PET imaging of lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as in PET imaging of other tumors and diseases. Applications of single-photon emitting radionuclides (LPs) in SPECT imaging, including: lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as applications in SPECT imaging of other tumors and diseases; The application of diagnostic radionuclide-LP in nuclear medicine diagnosis and treatment includes: diagnosis and treatment of lung cancer, liver cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, prostate cancer, thyroid cancer, as well as its application in the diagnosis and treatment of other tumors and diseases.

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