Radioactive tracer composition and preparation method and application thereof

Abstract

The invention relates to the technical field of nuclear medicine, and discloses a radioactive tracer composition which comprises a component A and a component B, the component A is a targeted fibroblast activating protein (FAP) monomer tracer agent; the component B comprises one of a targeted glucose transporter metabolism monomer tracer agent, a targeted phosphatidylinositol proteoglycan (GP C3) monomer tracer agent, a targeted somatostatin receptor (SSTR) monomer tracer agent or a targeted prostate specific membrane antigen (PSMA) monomer tracer agent; wherein the radioactive concentration ratio of the component A to the component B is (4-6): (6-4). The composition has the following technical effects that the component A and the component B which have certain complementary functions form a single preparation according to the optimal radioactive concentration ratio, so that the imaging quality can be improved, more comprehensive disease diagnosis and treatment information can be provided, and the detection sensitivity and the treatment effect of diseases can be improved. The invention further discloses a preparation method and application of the radioactive tracer composition.

Description

Technical Field

[0001] The invention belongs to the technical field of nuclear medicine, and in particular relates to a radioactive tracer composition and a preparation method and application thereof. Background Art

[0002] Major diseases such as tumors, cardiovascular and cerebrovascular diseases have increasingly threatened human health, especially tumors, the incidence of which has been increasing year by year in my country. Tumor heterogeneity is an important feature of malignant tumors. Tumor heterogeneity is not only manifested in the differences in genotype and phenotype between the same type of malignant tumors in different patients, tumors in different parts of the same patient's body, and cells within the tumor, but also in the diversity of the composition, function and markers of the tumor microenvironment. The heterogeneity of the tumor microenvironment may control the development and progression of tumors and is considered to be a driving factor for tumor aggressiveness, treatment resistance, progression-free survival and poor overall survival. Malignant tumors often show significant tumor microenvironment heterogeneity, which poses a major challenge to the diagnosis and treatment of cancer. The tumor microenvironment has developed into an important target for disease diagnosis and treatment and new drug development.

[0003] Positron emission tomography (PET) and computed tomography (CT) have high sensitivity and specificity. PET / CT can not only provide anatomical information, but also characterize tumor biology and heterogeneity, and guide the selection of the most appropriate treatment method. Among them, the highly specific and sensitive PET imaging technology is an important basis for accurate diagnosis and treatment. In addition, single photon emission computed tomography (SPECT) and radionuclide therapy also play a unique role in tumor diagnosis and treatment, and can accurately solve the problem of integrated visualization diagnosis and treatment of the same radionuclide for tumors. And the precise diagnosis and treatment of nuclear medicine is inseparable from the cooperation of specific targeted tracers.

[0004] At present, there are many monomer tracers that have shown significant diagnostic and therapeutic effects in clinical practice, such as targeted glucose transporter tracers, targeted FAP monomer tracers, and targeted GPC3 monomer tracers. However, due to the heterogeneity of the tumor microenvironment, the diagnostic and therapeutic effects of monomer tracers targeting a single target on tumors are not ideal. Different types of tumors or the same type of tumors have different tumor uptake of monomer tracers, resulting in the inability of monomer tracers to accurately reflect and describe the complex biological characteristics of tumors.

[0005] In the prior art, the deficiency of single tracers is compensated by using dual tracers for PET imaging. Dual tracer PET imaging utilizes the different targeting properties of different single tracers to tumor tissue components, and can provide complementary diagnostic information, thereby more comprehensively reflecting the biological characteristics of the tumor, improving diagnostic accuracy and improving patient management. Dual tracer PET imaging is mainly divided into: (1) dual tracer imaging in two times; (2) dual tracer imaging in two times in a row; (3) dual tracer imaging in a single time. Among them, the dual-tracer imaging with divided administration is the most widely used combined dual-tracer PET imaging in clinical diagnosis. However, since different tracers need to be injected at different times and corresponding PET / CT scans need to be performed, it not only prolongs the examination time, but also increases the time the patient is exposed to radiation, which has a certain impact on the patient. Although the continuous administration of dual tracers for imaging twice can reduce the examination time, the problem of radiation exposure is still not solved. The single administration of dual tracers for simultaneous imaging can image the two monomer tracers at a time, but since the two monomer tracers exist independently and are not combined into a single preparation, the two different monomer tracers will have composition differences, which will affect the quality of imaging to a certain extent, thereby affecting the diagnosis and treatment of the disease. Summary of the invention

[0006] In order to solve the deficiencies of the prior art, the present invention provides a radioactive tracer composition, which combines monomeric tracers with certain complementary functions into an integrated radioactive tracer composition at an optimal radioactive concentration ratio, thereby not only improving the imaging quality, but also providing more comprehensive disease diagnosis and treatment information, and improving the detection sensitivity and treatment effect of the disease. The present invention also provides a preparation method and application of the radioactive tracer composition.

[0007] The technical effects to be achieved by the present invention are achieved through the following technical aspects:

[0008] In a first aspect, the present invention provides a radioactive tracer composition, comprising a component A and a component B respectively labeled with a radioactive metal nuclide;

[0009] The A component is a targeted fibroblast activation protein (FAP) monomer tracer;

[0010] The B component is any one of a monomer tracer targeting glucose transporter metabolism, a monomer tracer targeting phosphatidylinositol protein glycan (GPC3), a monomer tracer targeting somatostatin receptor (SSTR), or a monomer tracer targeting prostate-specific membrane antigen (PSMA);

[0011] Wherein, the radioactivity concentration ratio of the A component to the B component is (4-6):(6-4).

[0012] It should be noted that the A component is a monomer tracer targeting fibroblast activation protein (FAP), but is not limited to the monomer tracer targeting fibroblast activation protein (FAP), and may also be one of the monomer tracers in the B component.

[0013] As a further description of the technical solution of the present invention, the targeted fibroblast activation protein (FAP) monomer tracer is referred to as the targeted FAP monomer tracer, which includes a targeted FAP ligand pharmacophore (FAPI), a linking group, a metal ion chelating group and a radioactive metal nuclide.

[0014] As a further description of the technical solution of the present invention, the targeted glucose transporter metabolic monomer tracer includes a targeted glucose transporter pharmacophore (DG) and a radioactive metal nuclide.

[0015] As a further description of the technical solution of the present invention, the targeted phosphatidylinositol protein glycan (GPC 3) monomer tracer is referred to as the targeted GPC3 monomer tracer, which includes a GPC3 receptor ligand pharmacophore (GPC3P), an albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide.

[0016] As a further description of the technical solution of the present invention, the targeted somatostatin receptor (SSTR) monomer tracer is referred to as the targeted SSTR monomer tracer, which includes a targeted SSTR antagonist pharmacophore (JR11), an aspartic acid (Asp2) linker, a metal ion chelating group and a radioactive metal nuclide.

[0017] As a further description of the technical solution of the present invention, the targeted prostate-specific membrane antigen (PSMA) monomer tracer is referred to as the targeted PSMA monomer tracer, which includes a PSMA receptor ligand pharmacophore (PSMAL), an albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide.

[0018] As a further description of the technical solution of the present invention, the metal ion chelating group is one of 1,4,7-triazacyclononacanyl-N',N"-diacetyl-N-acetyl (NOTA) or 1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetyl-N-acetyl (DOTA).

[0019] As a further description of the technical solution of the present invention, the radioactive metal nuclides include 18 F. 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re,175 Yb, 153 Sm, 166 Ho, 88 Y. 90 Y. 177 Lu, 47 Sc, 212 Bi, 213 Bi, 123 I. 124 I. 131 I. 211 At 153 Eu, 169 Eu, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac or 227 One of Th.

[0020] Preferably, the targeted FAP monomer tracer is 18 F or 68 Ga-labeled glycopeptide FAPI ( 18 F-FAPT / 68 Ga-FAPT);

[0021] The targeted glucose transporter monomer tracer is 18 F-labeled fluorodeoxyglucose ( 18 F-FDG);

[0022] The targeted GPC3 monomer tracer is 18 F-labeled GPC3P containing IPB ( 18 F-IPB-GPC3P);

[0023] The targeted SSTR monomer tracer is 18 F labeled JR11 containing Asp2 ( 18 F-Asp2-JR11);

[0024] The targeted PSMA monomer tracer is 18 F-labeled PSMAL containing IPB ( 18 F-IPB-PSMAL).

[0025] Preferably, the radiotracer composition is 18 F-FAPT and 18 The composition of F-FDG, 68 Ga-FAPT and 18 The composition of F-FDG, 18F-FAPT and 18 Composition of F-IPB-GPC3P, 18 F-FAPT and 18 The composition of F-Asp2-JR11 or 18 F-FAPT and 18 One of the compositions of F-IPB-PSMAL;

[0026] Said 18 F-FAPT+ 18 The chemical structure of F-FDG is:

[0027]

[0028] Said 68 Ga-FAPT+ 18 The chemical structure of F-FDG is:

[0029]

[0030] Said 18 F-FAPT+ 18 The chemical structure of F-IPB-GPC3P is:

[0031]

[0032] Said 18 F-FAPT+ 18 The chemical structure of F-Asp2-JR11 is:

[0033]

[0034] Said 18 F-FAPT+ 18 The chemical structure of F-IPB-PSMAL is:

[0035]

[0036] In a second aspect, the present invention provides a method for preparing the radioactive tracer composition, comprising the following steps:

[0037] Preparation of component A: Using NOTA-FAPT or DOTA-FAPT as a precursor raw material, a chelation reaction occurs with radioactive metal nuclide ions, and after separation and purification, a targeted fibroblast activation protein (FAP) monomer tracer is prepared. When NOTA-FAPT is used as a precursor raw material, radioactive metal nuclide ions [Al 18 F] 2+ , 68 Ga 3+ or 177 Lu3+ When DOTA-FAPT is used as the precursor material, radioactive metal nuclide ions can be selected. 68 Ga 3+ , 64 Cu 2+ or 177 Lu 3+ ;

[0038] Preparation of component B:

[0039] Using trifluoromannose as a precursor, a two-step reaction of nucleophilic fluorination and hydrolysis with radioactive metal nuclide ions is carried out, and a targeted glucose transporter metabolic monomer tracer is prepared after separation and purification. The radioactive metal nuclide ions can be selected 18 F - ;

[0040] Using NOTA-IPB-GPC3P or DOTA-IPB-GPC3P as a precursor raw material, a chelating reaction occurs with radioactive metal nuclide ions, and a targeted phosphatidylinositol protein glycan (GPC 3) monomer tracer is prepared after separation and purification. When NOTA-IPB-GPC3P is used as a precursor raw material, radioactive metal nuclide ions [Al 18 F] 2+ , 68 Ga 3+ or 177 Lu 3+ When DOTA-IPB-GPC3P is used as the precursor material, radioactive metal nuclide ions can be used. 68 Ga 3+ , 64 Cu 2+ or 177 Lu 3 + ;

[0041] Using NOTA-Asp2-JR11 or DOTA-Asp2-JR11 as the precursor material, a chelating reaction is carried out with radioactive metal nuclide ions, and a targeted somatostatin receptor (SSTR) monomer tracer is prepared after separation and purification. The radioactive metal nuclide ions can be [Al 18 F] 2+ , 68 Ga 3+ or 177 Lu 3+ ;

[0042] Using NOTA-IPB-PSMAL or DOTA-IPB-PSMAL as the precursor material, a chelating reaction occurs with radioactive metal nuclide ions, and after separation and purification, a prostate-specific membrane antigen (PSMA) monomer tracer is prepared. The radioactive metal nuclide ions can be [Al 18 F] 2+ , 68 Ga 3+ or 177 Lu 3+ ;

[0043] Preparation of the radioactive tracer composition: preparing component A and any component B at a radioactive concentration ratio of (4-6):(6-4) to obtain a radioactive tracer composition;

[0044] Wherein, the precursor raw material is prepared by a solid phase peptide synthesis method.

[0045] As a further description of the technical solution of the present invention, the radioactive metal nuclide ions include 18 F - 、[Al 18 F] 2+ ( 18 F-AlF), 68 Ga 3+ , 64 Cu 2+ or 177 Lu 3+ One of them.

[0046] The chemical structural formula of the NOTA-FAPT is:

[0047]

[0048] The chemical structural formula of the DOTA-FAPT is:

[0049]

[0050] The chemical structural formula of the NOTA-IPB-GPC3P is:

[0051]

[0052] The chemical structural formula of the DOTA-IPB-GPC3P is:

[0053]

[0054] The chemical structural formula of the NOTA-Asp2-JR11 is:

[0055]

[0056] The chemical structural formula of the NOTA-IPB-PSMAL is:

[0057]

[0058] In a third aspect, the present invention provides the use of the radioactive tracer composition in the preparation of diagnostic and therapeutic agents for tumors and cardiovascular and cerebrovascular diseases.

[0059] As a further description of the technical solution of the present invention, the radioactive tracer composition composed of the targeted FAP monomer tracer and the targeted glucose transporter metabolism monomer tracer is used in the preparation of PET imaging agents for lung cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumors, neuroendocrine tumors, and prostate cancer with high expression of FAP or glucose transporter protein.

[0060] As a further description of the technical solution of the present invention, the radioactive tracer composition composed of the targeted FAP monomer tracer and the targeted GPC3 monomer tracer, or the targeted SSTR monomer tracer, or the targeted PSMA monomer tracer is used in the preparation of PET imaging agents for lung cancer, breast cancer, melanoma, lymphoma, glioma, hepatobiliary tumors, gastrointestinal tumors, neuroendocrine tumors, and prostate cancer with high expression of FAP, or GPC3, or SSTR, or PSMA.

[0061] As a further description of the technical solution of the present invention, the radioactive tracer composition composed of the targeted FAP monomer tracer and the targeted GPC3 monomer tracer, or the targeted SSTR monomer tracer, or the targeted PSMA monomer tracer is used in the preparation of a SPECT imaging agent for tumors or cardiovascular and cerebrovascular diseases.

[0062] In summary, the present invention has at least the following benefits:

[0063] 1. The radioactive tracer composition provided by the present invention is a single preparation, i.e., a radioactive tracer composition, by combining monomeric tracers with certain complementary functions, i.e., component A and component B, at an optimal radioactive concentration ratio. It not only improves the quality and effect of imaging, but more importantly, it can provide more comprehensive information about the tumor microenvironment and malignant cell metabolism. By combining the results of each monomeric tracer in a single scan, it is possible to more comprehensively understand tumor biological information, improve the accuracy of disease diagnosis and treatment effects. In addition, it can also improve the comfort and cooperation of patients during the examination process and reduce radiation damage.

[0064] 2. The preparation method of the radioactive tracer composition provided by the present invention adopts a chemical synthesis method to prepare a monomer tracer, and then two monomer tracers with complementary effects are prepared into a radioactive tracer composition according to an optimal radioactive concentration ratio. By preparing two monomer tracers into a single preparation according to an optimal radioactive concentration ratio, the technical disadvantage of simultaneously imaging two monomer tracers at a single time is improved, and the limitation that each ligand in the multi-target coupled tracer cannot freely bind to its corresponding specific target is overcome, thereby improving the diagnosis level and treatment effect of diseases such as malignant tumors.

[0065] 3. The application of the radiotracer composition provided by the present invention is to apply the radiotracer composition to nuclear medicine imaging agents for tumors and cardiovascular and cerebrovascular diseases, opening up a new direction for molecular imaging. The development and transformation application of the radiotracer composition can be used not only for multi-target multi-modal imaging of radiotracers, but also for integrated diagnosis and treatment of radiotracer compositions, thereby solving the technical bottleneck problem of integrated visualization imaging and diagnosis and treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 For preparation 18 Schematic diagram of the F-FDG synthesizer;

[0067] Figure 2 For preparation 18 Schematic diagram of the F-FAPT synthesizer;

[0068] Figure 3 For radio-HPLC determination 18 F-FAPT+ 18 F-FDG, 18 F-FDG, 18 F-FAPT result diagram;

[0069] Figure 4 For mice bearing U87MG xenografts 18 F-FAPT+ 18 F-FDG, 18 F-FDG, 18 PET / CT image (maximum intensity projection, MIP) of F-FAPT (the arrow points to the tumor);

[0070] Figure 5 For mice bearing HuTu80 and PC3 xenografts 18 F-FAPT+ 18 F-FDG, 18 F-FDG, 18 PET / CT image (maximum intensity projection, MIP) of F-FAPT (the arrow on the left indicates the Hu Tu80 tumor, and the arrow on the right indicates the PC3 tumor);

[0071] Figure 6 Radioactive tracer composition 18 F-FAPT+ 18 F-FDG, monomeric tracer 18 F-FDG and 18 60-minute biodistribution profile of F-FAPT;

[0072] Figure 7 Immunohistochemical staining of U87MG, HuTu80, and PC3 tumors;

[0073] Figure 8 for 18 F-FAPT+ 18 F-FDG abnormal toxicity test results (HE staining);

[0074] Fig. 9 for 18 F-FAPT+ 18 F-FDG and 18 F-FDG in PET / CT of patients with breast tumors;

[0075] Fig.10 For radio-HPLC determination 68 Ga-FAPT+ 18 F-FDG, 18 F-FDG, 18 F-FAPT result diagram;

[0076] Fig.11 Radioactive tracer composition 68 Ga-FAPT+ 18 F-FDG and 18 60-minute biodistribution profile of F-FDG;

[0077] Fig.12 for 68 Ga-FAPT+ 18 F-FDG and 18 F-FDG in PET / CT of patients with rectosigmoid colon cancer;

[0078] Fig.13 for 68 Ga-FAPT+ 18 F-FDG and 18 F-FDG in PET / CT of patients with gastric cancer;

[0079] Fig.14 For radio-HPLC determination 18 F-FAPT+ 18 F-IPB-GPC3P, 18F-IPB-GPC3P, 18 F-FAPT result diagram;

[0080] Fig.15 for 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-FAPT and 18 In vitro uptake experiment of F-IPB-GPC3P in U87MG and Huh7 cells;

[0081] Fig.16 For mice bearing U87MG xenografts 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IPB-GPC3P, 18 PET / CT images (maximum intensity projection, MIP) of F-FAPT (arrows indicate tumors) and immunohistochemical staining of U87MG tumor tissue;

[0082] Fig.17 For mice bearing Huh7 xenografts 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IP B-GPC3P, 18 PET / CT images (maximum intensity projection, MIP) of F-FAPT (arrows indicate tumors) and immunohistochemical staining of Huh7 tumor tissues;

[0083] Fig.18 for 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IPB-GPC3P, 18 F-FAPT biodistribution map;

[0084] Fig.19 for 18 F-FAPT, 18 F-Asp2-JR11, 18 F-FAPT+ 18 Comparison of F-Asp2-JR11 uptake in the bilateral positive model (AR42J on the left, A549-FAP on the right) (A) and quantitative data (B);

[0085] Fig. 20 for 18 F-FAPT, 18 F-Asp2-JR11, 18 F-FAPT+ 18Uptake and inhibition experiments of F-Asp2-JR11 in A549-FAP (A) and AR42J (B) cells. DETAILED DESCRIPTION

[0086] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below in conjunction with specific embodiments and accompanying drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly understood.

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0088] In the first aspect, the present invention provides a radioactive tracer composition, comprising component A and component B respectively labeled with radioactive metal nuclides. Component A is a monomer tracer targeting fibroblast activation protein (FAP). Component B is any one of a monomer tracer targeting glucose transporter metabolism, a monomer tracer targeting phosphatidylinositol proteoglycan (GPC3), a monomer tracer targeting somatostatin receptor (SSTR) or a monomer tracer targeting prostate-specific membrane antigen (PSMA). It should be noted that component A is a monomer tracer targeting FAP, but is not limited to a monomer tracer targeting FAP, and may also be one of component B. The radioactivity concentration ratio of component A to component B is (4-6): (6-4), preferably 5: 5. The targeted FAP monomer tracer has a complementary effect with the targeted glucose transporter metabolism monomer tracer, or with the targeted GPC3 monomer tracer, or with the targeted SSTR monomer tracer, or with the targeted PSMA monomer tracer in disease diagnosis and treatment.

[0089] Among them, the targeted FAP monomer tracer is composed of the targeted FAP ligand pharmacophore (FAPI), a linking group, a metal ion chelating group and a radioactive metal nuclide (*M), referred to as *M-FAPT. The targeted glucose transporter metabolism monomer tracer is composed of the targeted glucose transporter pharmacophore (DG) and a radioactive metal nuclide (*M), referred to as *M-DG. The targeted GPC3 monomer tracer is composed of the GPC3 receptor ligand pharmacophore (GPC3P), the albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide (*M), referred to as *M-IPB-GPC3P. The targeted SSTR monomer tracer is composed of the targeted SSTR antagonist pharmacophore (JR11), an aspartic acid (Asp2) linking group, a metal ion chelating group and a radioactive metal nuclide (*M), referred to as *M-Asp2-JR11. The targeted PSMA monomer tracer is composed of a PSMA receptor ligand pharmacophore (PSMAL), an albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide (*M), referred to as *M-IPB-PSMAL.

[0090] In some embodiments, the metal ion binding chelating group is one of 1,4,7-triazacyclononacanyl-N',N"-diacetoxy-N-acetyl (NOTA) or 1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetoxy-N-acetyl (DOTA).

[0091] In some embodiments, the radiometal nuclide (*M) is selected from 18 F. 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 175 Yb, 153 Sm, 166 Ho, 88 Y. 90 Y. 177 Lu, 47 Sc, 212 Bi, 213 Bi, 123 I. 124 I. 131 I. 211 At 153 Eu, 169 Eu, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re,198 Au, 225 Ac or 227 Preferably, a radioactive metal nuclide (*M) ion is used, for example, 18 F - 、[Al 18 F] 2+ ( 18 F-AlF), 68 Ga 3+ , 64 Cu 2+ or 177 Lu 3+ .

[0092] In some embodiments, the targeted FAP monomer tracer is preferably 18 F or 68 Ga-labeled glycopeptide FAPI, referred to as 18 F-FAPT or 68 Ga-FAPT; targeted glucose transporter monomer tracer is preferably 18 F-labeled fluorodeoxyglucose 18 F-FDG; the targeted GPC3 monomer tracer is preferably 18 F-labeled GPC3P containing IPB, referred to as 18 F-IPB-GPC3P; the targeted SSTR monomer tracer is preferably 18 F marks JR11 containing Asp2, referred to as 18 F-Asp2-JR11; the targeted PSMA monomer tracer is preferably 18 F marks PSMAL containing IPB, referred to as 18 F-IPB-PSMAL.

[0093] The general formula of the radioactive tracer composition is: component A + component B, for example, it can be expressed as 18 F-FAPT+ 18 F-FDG, 18 F-FAPT+ 18 F-IPB-GPC3P, etc. In some embodiments, the preferred radiotracer composition is 18 F-FAPT+ 18 F-FDG, 68 Ga-FAPT+ 18 F-FDG, 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-FAPT+ 18 F-Asp2-JR11 or 18 F-FAPT+18 One of the F-IPB-PSMALs.

[0094] 18 F-FAPT+ 18 The chemical structure of F-FDG is:

[0095]

[0096] 68 Ga-FAPT+ 18 The chemical structure of F-FDG is:

[0097]

[0098] 18 F-FAPT+ 18 The chemical structure of F-IPB-GPC3P is:

[0099]

[0100] 18 F-FAPT+ 18 The chemical structure of F-Asp2-JR11 is:

[0101]

[0102] 18 F-FAPT+ 18 The chemical structure of F-IPB-PSMAL is:

[0103]

[0104] In a second aspect, the present invention provides a method for preparing the above-mentioned radioactive tracer composition, comprising the following steps:

[0105] (I) Preparation of component A

[0106] Monomer tracer 18 Preparation of F-FAPT: Using NOTA-FAPT as a precursor, 18 F-AlF and NOTA-FAPT undergo chelation reaction and are automatically synthesized in the AllInOne module 18 F-FAPT. The amount of the precursor NOTA-FAPT was 200 μg, the pH value of the buffer solution containing sodium acetate (NaOAc) was about 4.0, the reaction temperature was 100°C, the total radiochemical synthesis time was about 40 minutes, and the product was separated and purified using a plus C18 column. 18 The synthetic route of F-FAPT is as follows:

[0107]

[0108] Monomer tracer 68 Preparation of Ga-FAPT: Using DOTA-FAPT as a precursor, 68 Ga 3+ Metal chelation reaction with -DOTA, radiosynthesis 68 Ga-FAPT. DOTA-FAPT is 200 μg, the pH value of the buffer solution containing sodium acetate (NaOAc) is about 4.0, the reaction temperature is 100°C, the total radioactive synthesis time is about 20 minutes, and the product is separated and purified using a plus C18 column. 68 The synthetic route of Ga-FAPT is as follows:

[0109]

[0110] (II) Preparation of component B

[0111] Monomer tracer 18 Preparation of F-FDG: Using trifluoromannose as a precursor, a two-step method of fluorination and on-column hydrolysis was used to prepare 18 F-FDG Tracerlab FXFDG module (Beijing PET Biotechnology Co., Ltd.) automatic synthesis 18 F-FDG. The optimal dosage of the precursor trifluoromannose is 20 mg, the reaction temperature is 80-90°C, the total time of radioactive synthesis is about 40 minutes, and Sep-Pakplus C18 column and composite column (Beijing Pat Company) are used to neutralize the pH of the solution and separate and purify. 18 The synthetic route of F-FDG is as follows:

[0112]

[0113] Monomer tracer 18 Preparation of F-IPB-GPC3P: Using NOTA-IPB-GPC3P as the precursor, 18 F-AlF and -NOTA undergo metal chelation reaction and radiosynthesis 18 F-IPB-GPC3P. The amount of the precursor NOTA-IPB-GPC3P was 50 μg, the pH value of the acetic acid (AcOH) buffer was about 4.0, the reaction temperature was 100°C, the total radioactive synthesis time was about 20 minutes, and the product was separated and purified using a plus C18 column. 18 The synthetic route of F-IP B-GPC3P is as follows:

[0114]

[0115] Monomer tracer 18 Preparation of F-Asp2-JR11: Using NOTA-Asp2-JR11 as the precursor, 18F-AlF and -NOTA undergo metal chelation reaction and radiosynthesis 18 F-Asp2-JR11. Precursor NOTA-Asp2

[0116] -JR11 dosage was 50 μg, pH value of acetic acid (AcOH) buffer was about 4.0, reaction temperature was 100°C, total radioactive synthesis time was about 20 minutes, and the product was separated and purified using plus C18 column. 18 The synthetic route of F-Asp2-JR11 is as follows:

[0117]

[0118] Monomer tracer 18 Preparation of F-IPB-PSMAL: Using NOTA-IPB-PSMAL as the precursor, 18 F-AlF and -NOTA undergo metal chelation reaction and radiosynthesis 18 F-IPB-PSMAL. The amount of the precursor NOTA-IPB-PSMAL was 50 μg, the pH value of the acetic acid (AcOH) buffer was about 4.0, the reaction temperature was 100°C, the total radioactive synthesis time was about 20 minutes, and the product was separated and purified using a plus C18 column. 18 The synthetic route of F-IPB-PSMAL is as follows:

[0119]

[0120] (III) Preparation of Radiotracer Composition

[0121] Radiotracer compositions 18 F-FAPT+ 18 F-FDG and 68 Ga-FAPT+ 18 Preparation of F-FDG: Determination by activity meter 18 F-FAPT or 68 Ga-FAPT and 18 The radioactivity concentration of F-FDG was then 18 F / 68 Ga-FAPT and 18 F-FDG was prepared into three different radioactive concentration ratios (4 / 6, 5 / 5 and 6 / 4). 18 F / 68 Ga-FAPT+ 18 F-FDG was determined by high performance liquid chromatography (Shimadzu 40AD) and a ZORBAX Eclipse XDB-C18 analytical column (4.6 × 150 mm, 1.8 μm). 18 F-FAPT+ 18F-FDG and 68 Ga-FAPT+ 18 The radioactivity concentration ratio of each monomer tracer of F-FDG.

[0122] Radiotracer compositions 18 F-FAPT+ 18 Preparation of F-IPB-GPC3P: Determination by activity meter 18 F-FAPT and 18 The radioactivity concentration of F-IPB-GPC3P was then 18 F-FAPT and 18 F-IPB-GPC3P was prepared with a radioactivity concentration ratio of 5:5 18 F-FAPT+ 18 F-IPB-GPC3P, measured by HPLC (Shimadzu 40AD) and ZORBAX Eclipse XDB-C18 analytical column (4.6×150 mm, 1.8 μm) 18 F-FAPT+ 18 The radioactivity concentration ratio of each monomer tracer of F-IPB-GPC3P. 18 F-FAPT+ 18 F-Asp2-JR11 and 18 F-FAPT+ 18 The preparation method of F-IPB-PSMAL can be found in 18 F-FAPT+ 18 F-IPB-GP C3P, again no further description is given.

[0123] Preclinical and clinical studies have shown that [ 18 F-FAPT+ 18 F-FDG](5 / 5) 18 F-FDG and 18 F-FA PT has more imaging advantages, showing good cancer detection and clear ability to distinguish lesions, and the radiotracer composition [ 18 F-FAPT+ 18 F-FDG] single PET / CT scan protocol is an alternative 18 F-FDG PET / CT provides this possibility. 68 Ga-FAPT+ 18 F-FDG](5 / 5) showed 18 F-FDG has comparable or even better detection capabilities. 68 Ga-FAPT+ 18F-FDG](5 / 5) shows high tumor uptake and low background signal, which is conducive to producing high-contrast images and has an advantage in imaging small lesions. Studies have shown that radiotracer compositions [ 68 Ga-FAPT+ 18 F-FDG](5 / 5) has feasibility and application potential in PET imaging.

[0124] After synthesizing targeted GPC3 monomer tracer 18 F-IPB-GPC3P was evaluated in preclinical biology and demonstrated 18 F-IPB-GPC3P has the potential to diagnose HCC tumors. 18 F-IPB-GPC3P and 18 F-FAP constructs specific radiotracer compositions [ 18 F-FAPT+ 18 F-IPB-GPC3P],[ 18 F-FAPT+ 18 F-IPB-GPC3P] combined with 18 F-IPB-GPC3P and 18 The advantage of F-FAPT is that it overcomes the limitations of a single tracer and exhibits higher tumor uptake and lower background uptake, which is conducive to producing better imaging effects and has great potential in tumor imaging.

[0125] After three consecutive days of continuous testing of the AR42J and A549-FAP dual tumor mouse model, 18 F-FAPT, 18 F-Asp2-JR11 and 18 F-FAPT+ 18 F-Asp2-JR11 small animal PET / CT scans were performed to evaluate the imaging characteristics of the monomeric tracer and the radiotracer combination. The results showed that in three imaging comparisons, the radiotracer combination showed lower background uptake than the monomeric tracer and had good uptake in bilateral tumor tissues. 18 F-FAPT+ 18 F-Asp2-JR11 showed higher expression in AR42J tumors than 18 F-Asp2-JR11 tumor uptake value is half, showing 18 F-FAPT and 18 F-Asp2-JR11 has a complementary effect, resulting in synergistic uptake.

[0126] In some embodiments, the precursor material containing NOTA or DOTA ligand is prepared by solid phase peptide synthesis. Taking the precursor material NOTA-FAPT or DOTA-FAPT, NOTA-IPB-GPC3P or DOTA-IPB-GPC3P as an example, the FAPI pharmacophore is modified with -PEG2 to form FAPI pharmacophore-PEG2, and the FAPI pharmacophore-PEG2 is modified with Asp2 to form FAPI pharmacophore-PEG2-Asp2, and then connected through Glc, and finally modified with chelating group -NOTA or -DOTA, and the product peak is collected by preparative HPLC separation and purification to obtain the purified precursor material NOTA-FAPT or DOTA-FAPT; and the GPC3P pharmacophore is modified with Lys and connected with IPB group, and further connected with chelating group -NOTA or -DOTA, and the product peak is collected by preparative HPLC separation and purification to obtain the purified precursor material NOTA-IPB-GPC3P or DOTA-IPB-GPC3P. The preparation steps of other precursor materials containing NOTA or DOTA ligands can refer to NOTA-FAPT or NOTA-IPB-GPC3P, which will not be described in detail here.

[0127] In a third aspect, the present invention provides the use of the above-mentioned radioactive tracer composition in the preparation of diagnostic and therapeutic agents for tumors and cardiovascular and cerebrovascular diseases.

[0128] Specifically, a radioactive tracer composition consisting of a tracer targeting a FAP monomer and a tracer targeting a glucose transporter metabolism monomer, such as 18 F-FAPT+ 18 F-FDG or 68 Ga-FAPT+ 18 F-FDG is used in the preparation of PET imaging agents for lung cancer, breast cancer, melanoma, lymphoma, brain glioma, digestive system tumors, neuroendocrine tumors, and prostate cancer with high expression of FAP or glucose transfer protein (Glut).

[0129] Specifically, a radioactive tracer composition consisting of a targeted FAP monomer tracer and a targeted GPC3 monomer tracer, or a targeted SSTR monomer tracer, or a targeted PSMA monomer tracer, for example 18 F-FA PT+ 18 F-IPB-GPC3P, 18 F-FAPT+ 18 F-Asp2-JR11 or 18 F-FAPT+ 18F-IPB-PSMAL is used in the preparation of PET imaging agents for lung cancer, breast cancer, melanoma, lymphoma, glioma, hepatobiliary tumors, gastrointestinal tumors, neuroendocrine tumors, and prostate cancer with high expression of FAP, GPC3, SSTR, or PSMA.

[0130] Specifically, the use of a radioactive tracer composition consisting of a targeted FAP monomer tracer and a targeted GPC3 monomer tracer, or a targeted SSTR monomer tracer, or a targeted PSMA monomer tracer in the preparation of a SPECT imaging agent for tumors or cardiovascular and cerebrovascular diseases.

[0131] Radiotracer compositions 64 Cu-FAPT+ 64 Cu-IPB-GPC3P, 177 Lu-FAPT+ 177 Lu-IPB-GPC3P, 177 Lu-FAPT+ 177 Lu-Asp2-JR11, 177 Lu-FAPT+ 177 Lu-IPB-PSMAL is used in the research of integrated diagnosis and treatment of major diseases, and can solve the technical bottleneck problem of integrated visualization nuclear medicine imaging diagnosis and treatment.

[0132] Example 1 18 Automated radiochemical synthesis of F-FDG

[0133] use 18 F-FDG automated synthesizer and two-step on-column hydrolysis method 18 F-FDG, 18 F-FDG automated synthesizer Figure 1 As shown. It mainly includes the following steps:

[0134] (1) 18 FF - Capture: by cyclotron 18 O(p,n) 18 F produced by nuclear reaction 18 FF - , under helium gas carrier, after being placed in a radioactivity meter pre-treated Sep-Pak light QMA anion cartridge, 18 FF - Trapped in the column, 18 O-water was collected in a recovery bottle;

[0135] (2) Solvent evaporation: Under the action of helium, the solution (1.0-1.5 mL) containing K2CO3 and catalyst K222 in bottle No. 1 is eluted by negative pressure on the QMA column.18 F-into the reaction bottle, heat the mixed solution to 95℃, evaporate to dryness under reduced pressure to obtain a dry complex [K / K222] / 18 F - ;

[0136] (3) Fluorination reaction: Under the action of helium, the precursor trifluoromannose in bottle No. 3 is pressed into the reaction bottle and heated at 85°C for 5-15 min. After the fluorination reaction is completed, it is concentrated under reduced pressure and cooled;

[0137] (4) Column capture: Under the action of helium gas flow, H2O (12.0 mL) in bottle 2 was added to the reaction bottle. 18 The F-fluorinated intermediate and H2O mixture was transferred through a Sep-Pak plus C18 cartridge. 18 The F-fluorinated intermediate mixture was trapped by a Sep-Pak plus C18 cartridge, and the cartridge was washed with H2O (15.0 mL) in bottle No. 5 and dried with helium, and the waste liquid containing acetonitrile and water was collected in a waste bottle;

[0138] (5) In-column alkaline hydrolysis: NaOH solution (1.0 mL) in bottle 4 was pressed into the reaction bottle and loaded into the Sep Pakplus C18 column. The hydrolysis reaction time was about 2-5 min.

[0139] (6) Neutralization and separation and purification: The water (15.0 mL) in bottle No. 6 was used to elute the product in the C18 column, and the alkaline solution was neutralized and separated and purified using a composite column (Beijing Paite Company). The eluent was treated with a sterile filter membrane under helium pressure and then collected in a sterile product bottle.

[0140] Example 2 18 F-FAPT and 18 Radiochemical Synthesis of F-IPB-GPC3P

[0141] Preparation using AllInOne module and metal chelation reaction 18 F-FAPT, such as Figure 2 As shown. It mainly includes the following steps:

[0142] (1) 18 FF - Capture: by cyclotron 18 O(p,n) 18 F produced by nuclear reaction 18 FF - , under N2 gas carrier, after being placed in a radioactivity meter, a pre-treated Sep-Pak light QMA anion cartridge was 18 FF - Trapped in the column, 18O-water was collected in a recovery bottle;

[0143] (2) Metal chelation reaction: Sodium acetate buffer (pH 3.9; 0.2 M) containing NOTA-FAPT (200 ug, 50 ul water), AlCl3 (30 ul; 2.0 mM) and dimethyl sulfoxide (DMSO, 300 ul) were added to the reaction bottle and mixed evenly. Fluorine 18 ( 18 F - ) was transferred from the cyclotron to the AllInOne module after production and captured on a QMA column (H position), pretreated with sodium acetate buffer (0.5 M; 450 ul) and water (10 ml), then eluted into the reactor with sodium acetate buffer (300 ul; pH 3.9; QMA) column and heated at 100 °C for 15 min to complete the radiolabeling reaction;

[0144] (3) Capture on column: The mixture was cooled to room temperature, then water (5 mL; position G) was added to the reactor, mixed, and then transferred to a Sep Pak plus C18 column (position I);

[0145] (4) Separation and purification: The Sep Pak plus C18 column was rinsed three times with 10 ml of water (G position), and the product was finally eluted with a 50% ethanol water solution (1.8 ml), and collected in a sterile product bottle after being treated with a sterile filter membrane.

[0146] Prepared by metal chelation reaction 18 F-IPB-GPC3P. Mainly includes the following steps:

[0147] (1) 18 FF - Capture: by PET 800 biomedical cyclotron 18 O(p,n) 18 F produced by nuclear reaction 18 FF - Transfer to a vacuum bottle and extract an appropriate amount 18 FF - Through Sep-Pak light QMA anion cartridge, 18 FF - The Sep-Pak light QMA anion column was pre-treated with sodium bicarbonate solution (0.5 mM; 5 ml) and water (10 ml), and then the Sep-Pak light QMA anion column was eluted with NaCl solution (0.9%, 0.3 ml) and the purified 18 FF - Eluent in EP tube;

[0148] (2) Metal chelation reaction: 80 μL 18 FF - The eluent was added to a reaction bottle containing NOTA-IPB-GPC3P (50 μg, 50 μL water), AlCl3 (6 μL; 2.0 mM), acetate buffer (4 μL, pH 3.9), and acetonitrile (300 μL) and mixed well, and heated at 100 °C for 15 min to complete the metal chelation reaction;

[0149] (3) On-column trapping: After the reaction was completed, the mixture was cooled to room temperature, and then water (6 ml) was added to the reaction bottle, mixed, and then transferred to a Sep-Pak plus C18 column, which was pre-treated with ethanol (5 ml) and water (10 ml);

[0150] (4) Separation and purification: Elute the Sep-Pak plus C18 column 5 times with water (10 ml) to remove excess 18 F - , then eluted with ethanol solution (99%, 1.5 ml) and the product was transferred to a product bottle.

[0151] 18 F-Asp2-JR11 and 18 The preparation methods of F-IPB-PSMAL and others can be found in 18 F-FAPT or 18 F-IPB-GPC3P.

[0152] Example 3 68 Radiochemical Synthesis of Ga-FAPT

[0153] Metal 68 Ga 3+ Chelation reaction preparation 68 Ga-FAPT. Mainly includes the following steps:

[0154] (1) 68 Washing of Ga generator: Draw 4 ml of hydrochloric acid (0.05M) into the syringe, connect it to the inlet tube of the generator through the filter membrane, and slowly push the hydrochloric acid into the generator. 68 The Ga eluent was collected in a vacuum bottle;

[0155] (2) Chelation reaction: 68 The Ga eluent was added to a reaction bottle containing NOTA-FAPT or DOTA-FAPT (50 μg, 50 μl water) and sodium acetate buffer (pH 4; 0.5 ml; 0.25 M), and mixed well. The reaction bottle was heated at 100 °C for 10 min.

[0156] (3) Column trapping: Add 6 ml of water to the reaction mixture, cool to room temperature, and then transfer to a Sep Pak plus C18 column;

[0157] (4) Separation and purification: The Sep Pak plus C18 column was rinsed once with 10 ml of water, and then the Sep Pak plus C18 column was treated with 1.5 ml of 50% ethanol. The product was transferred to a transfer bottle, and finally the product was treated with a sterile filter membrane and collected in a sterile product bottle.

[0158] 68 Ga-IPB-GPC3P, 68 Ga-Asp2-JR11, 68 Ga-IPB-PSMAL and the like can be prepared by referring to the above method.

[0159] Example 4 64 Cu-DOTA-ligand or 64 Cu-NOTA-ligand, 177 Lu-DOTA-ligand or 177 Radiosynthesis of Lu-NOTA-ligands

[0160] 64 Cu-DOTA-ligand or 64 Radiosynthesis of Cu-NOTA-ligand: 100 μL of DOTA-ligand or NOTA-ligand (50 μg / μL) and 64 CuCl2 solution 0.100-1.0mL, adjusted to pH 4.0-5.6 with sodium acetate solution, reacted at room temperature ~ 90℃ for 10-15min, finally diluted with physiological saline and filtered through a sterile filter membrane and collected into a receiving bottle to obtain the required 64 Cu-DOTA-ligand or 64 Cu-NOTA-ligand injection. 64 Cu-DOTA-ligand or 64 The uncorrected radiochemical yields of Cu-NOTA-ligands were 40-70%.

[0161] 177 Lu-DOTA-ligand or 177 Radiosynthesis of Lu-NOTA-ligand: 100 μL of DOTA-ligand or NOTA-ligand (50 μg / μL), 2 mg of gentisic acid, 160 μL of sodium acetate and free 177LuCl3 solution 0.100-1.0mL, heated in a water bath at 106℃ for 15 minutes, monitored the reaction effect by HPLC, and separated by HPLC. The separated product was passed through a C18 column, rinsed with 30ml of water, and passed through the column with 1mL of 50% ethanol. After the product was collected, it was finally diluted with physiological saline and filtered through a sterile filter membrane and collected in a receiving bottle to obtain a product that meets the requirements. 177 Lu-DOTA-ligand or 177 Lu-NOTA-ligand injection. 177 Lu-DOTA-ligand or 177 The uncorrected radiochemical yield of Lu-NOTA-ligand was 50-60%.

[0162] Example 5 Radiotracer composition 18 F-FAPT+ 18 F-FDG and 68 Ga-FAPT+ 18 Preparation of F-FDG and determination of its radiochemical purity

[0163] Radiotracer compositions 18 F-FAPT+ 18 F-FDG and 68 Ga-FAPT+ 18 Preparation of F-FDG: Determination by activity meter 18 F-FAPT or 68 Ga-FAPT and 18 The radioactivity concentration of F-FDG was then 18 F / 68 Ga-FAPT and 18 F-FDG was prepared into three different radioactive concentration ratios (4 / 6, 5 / 5 and 6 / 4). 18 F / 68 Ga-FAPT+ 18 F-FDG was determined by high performance liquid chromatography (Shimadzu 40AD) and a ZORBAX Eclipse XDB-C18 analytical column (4.6 × 150 mm, 1.8 μm). 18 F-FAPT+ 18 F-FDG and 68 Ga-FAPT+ 18 The radioactivity concentration ratio of each monomer tracer of F-FDG.

[0164] Determination of radiochemical purity: Determined by radioactive high performance liquid chromatography (HPLC) 18 F-FAPT+ 18 F-FDG, 68 Ga-FAPT+ 18 F-FDG,18 F-FDG, 18 F-FAPT, 68 Radiochemical purity of Ga-FAPT, determined by retention time. Radioactive HPLC detection of radiotracer composition 18 F-FAPT+ 18 Whether the retention time of each component monomer probe of F-FDG is consistent with that of the single tracer, as well as the percentage of radioactivity of each component monomer probe, confirm the authenticity of the prepared injection solution. After measurement, the radiochemical purity of each assay is greater than 95%. Figure 3 shown.

[0165] HPLC analysis conditions: The analytical column is a ZORBAX Eclipse XDB-C18 analytical column, the mobile phase A is a 0.1% TFA aqueous solution, and the mobile phase B is a 0.1% TFA acetonitrile solution. Gradient elution is performed: in the initial 0-2 minutes, the concentration of mobile phase B increases from 5% to 10%; then, in the time interval of 2-7.5 minutes, the concentration of mobile phase B further increases from 10% to 40%, and the concentration of mobile phase B is maintained at 40% until 9 minutes; finally, the concentration of mobile phase B is gradually reduced until the gradient elution program is completed.

[0166] Example 6 Radioactive Dual Tracer Composition 18 F-FAPT+ 18 Study on small animal PET imaging with F-FDG

[0167] The same mouse carrying U87MG or HuTu80 / PC3 was subjected to different radioactivity concentration ratios for three consecutive days. 18 F-FAPT+ 18 F-FDG, 18 F-FAPT and 18 Small animal PET / CT scans of F-FDG to evaluate the efficacy of different radioactivity concentration ratios (4 / 6, 5 / 5, and 6 / 4) 18 F-FAPT+ 18 Imaging characteristics of F-FDG, screening for the optimal radioactivity concentration ratio.

[0168] In mice bearing U87MG xenografts, the three radioactivity concentration ratios (4 / 6, 5 / 5, and 6 / 4) 18 F-FAPT+ 18 The tumor uptake values ​​of F-FDG were 11.56±0.26%ID / g, 15.6±0.90%ID / g, and 16.2±1.66%ID / g, respectively. Figure 4 The three radioactivity concentration ratios (4 / 6, 5 / 5 and 6 / 4) are shown in 18 F-FAPT+ 18The tumor uptake of F-FDG was significantly higher than 18 F-FDG (4 / 6 ratio: 6.67±0.17%ID / g, p<0.01; 5 / 5 ratio: 6.30±0.22%ID / g, p<0.01; 6 / 4 ratio: 6.30±0.36%ID / g, p<0.01) and 18 F-FAPT (4 / 6 ratio: 7.43±0.49%ID / g, p<0.01; 5 / 5 ratio: 7.53±0.50%ID / g, p<0.01; 6 / 4 ratio: 7.17±0.87%ID / g, p<0.01). 18 F-FAPT+ 18 F-FDG showed high uptake in U87MG tumors because 18 F-FAPT and 18 F-FDG had a complementary effect, resulting in enhanced uptake. 18 F-FAPT+ 18 In F-FDG, the radioactivity concentration ratio is 5 / 5 and 6 / 4 18 F-FAPT+ 18 The uptake value of F-FDG was higher in U87MG tumors.

[0169] In mice bearing HuTu80 / PC3 xenografts, three radioactive concentration ratios (4 / 6, 5 / 5, and 6 / 4) were injected 18 F-FAPT+ 18 After F-FDG, both HuTu80 tumors and PC3 tumors were clearly visible, as shown in Figure 5 In contrast, in HuTu80 tumors, a single 18 The tumor uptake values ​​of F-FDG were relatively low, which were significantly lower than those of the three radioactivity concentration ratios (4 / 6, 5 / 5, and 6 / 4). 18 F-FAPT+ 18 F-FDG (4 / 6 ratio: 5.50±0.57%ID / g vs 3.80±0.22%ID / g, p<0.01; 5 / 5 ratio: 6.60±0.29%ID / g vs 3.63±0.53%ID / g, p<0.01; 6 / 4 ratio: 6.3±0.39%ID / g vs. 3.4±0.16%ID / g, p<0.01).

[0170] In addition, in FAP-negative PC3 tumors, 18 Compared with F-FAPT, the three different radioactivity concentration ratios (4 / 6, 5 / 5 and 6 / 4) 18 F-FAPT+ 18F-FDG showed higher uptake values ​​in PC3 tumors (4 / 6 ratio: 6.63±0.24%ID / g vs 3.67±0.12%ID / g, p<0.01; 5 / 5 ratio: 6.30±0.16%ID / g vs 3.27±0.41%ID / g, p<0.01; 6 / 4 ratio: 5.43±0.83%ID / g vs 3.23±0.25%ID / g, p<0.01).

[0171] These results demonstrate 18 F-FAPT / 18 F-FDG can produce a complementary effect to compensate for the deficiency of each monomer probe and improve tumor detection ability. 18 F-FAPT+ 18 F-FDG showed a higher 18 F-FDG had a higher tumor uptake value (p<0.01), while the radioactivity concentration ratio of 5 / 5 and 4 / 6 18 F-FAPT+ 18 F-FDG showed a higher 18 F-FAPT had a higher tumor uptake value (p<0.01). Based on the above results, it can be concluded that 18 F-FAPT+ 18 The optimal radioactivity concentration ratio for F-FDG is 5 / 5 as it provides the best tumor uptake.

[0172] In terms of normal organ distribution, 18 Compared with F-FDG, the radioactivity concentration ratio of 5 / 5 and 6 / 4 was 18 F-FAPT+ 18 The uptake of F-FDG in the brain and liver is low. Figure 4 and Figure 5 . The 4 / 6 radioactivity concentration ratio 18 F-FAPT+ 18 The uptake of F-FDG in the brain and liver is lower than 18 F-FDG, but it was not statistically significant. 18 F-FAPT+ 18 The differences in F-FDG uptake in the brain and liver are due to 18 The different contents of F-FDG lead to Figure 2-6 The three radioactivity concentration ratios (4 / 6, 5 / 5 and 6 / 4) 18 F-FAPT+ 18 F-FDG uptake in muscle 18There was no significant difference between the two groups (p>0.05). 18 F-FAPT+ 18 The uptake value of F-FDG is high in tumors and low in normal organs, which helps to improve the contrast of images. Figure 4 and Figure 5 In U87MG tumors, 18 Compared with the tumor to brain ratio (T / B), tumor to liver ratio (T / L), and tumor to muscle ratio (T / M) of F-FDG, the three radioactivity concentration ratios (4 / 6, 5 / 5, and 6 / 4) were significantly higher than those of the other two ratios (P < 0.05). 18 F-FAPT+ 18 The T / B, T / L, and T / M of F-FDG showed higher values, as shown in Table 1. In addition, the normal organs of mice bearing HuTu80 / PC3 xenografts 18 F-FAPT+ 18 F-FDG, 18 F-FAPT and 18 F-FDG uptake was similar to that in mice bearing U87MG xenografts. 18 F-FAPT+ 18 The high tumor uptake and low background signal of F-FDG facilitate tumor detection.

[0173] Table 1

[0174]

[0175] Example 7 Radiotracer composition 18 F-FAPT+ 18 Study on the biodistribution of F-FDG

[0176] Mice bearing U87MG and HuTu80 / PC3 xenografts were randomly divided into five groups (three mice in each group) and injected via the tail vein. 18 F-FAPT+ 18 F-FDG, 18 F-FAPT and 18 F-FDG (1.48-2.22 MBq / mouse). Relevant organs and tumors were collected and weighed, and then their radioactivity was measured with a γ counter. After decay correction, the radioactivity of the tissue was calculated as the percentage of injected dose per gram of tissue (% ID / g).

[0177] The biodistribution results showed Figure 6 As shown, 18 F-FAPT,18 Compared with F-FDG, three radioactive concentration ratios were used. 18 F-FAPT+ 18 F-FDG showed higher tumor uptake in mouse U87MG xenografts. Specifically, radioactivity concentration ratios of 5 / 5 and 6 / 4 18 F-FAPT+ 18 The tumor uptake rate of F-FDG is higher, such as Figure 6 As shown in part A. In mice bearing HuTu80 / PC3 xenografts, 18 Compared with F-FDG, the radioactivity concentration ratio was 5 / 5 and 6 / 4. 18 F-FAPT+ 18 The uptake rate of F-FDG was higher in HuTu80 tumors (p<0.001). 18 Compared with F-FAPT, the radioactivity concentration ratio was 5 / 5 and 4 / 6. 18 F-FAPT+ 18 The uptake rate of F-FDG was higher in PC3 tumors (p<0.001). The results of biodistribution studies showed that 18 F-FAPT+ 18 The optimal radioactivity concentration ratio of F-FDG is 5 / 5, which is consistent with the results of corresponding PET imaging studies, such as Figure 6 As shown in part B.

[0178] In normal organ distribution, 18 F-FAPT+ 18 F-FDG uptake is relatively high in the brain, liver, heart, and lungs. 18 F-FDG is low, which is helpful for detecting lesions in these organs. 18 F-FAPT+ 18 Physiological radioactivity level of F-FDG 18 F-FDG is similar (except in blood, pancreas, and spine). However, the physiological uptake in the pancreas, blood, and spine is 18 F-FAPT+ 18 F-FDG uptake is lower than 18 F-FAPT. 18 F-FAP T+ 18 F-FDG has the advantages of high tumor uptake value and low physiological uptake value in normal tissues and organs. 18 F-FAPT+ 18 F-FDG has the ability to better detect cancer and clearly delineate lesions.

[0179] Example 8 Immunohistochemistry of U87MG, HuTu80 and PC3 Tumor Tissues

[0180] Immunohistochemical analysis of tumor tissue samples from U87MG and HuTu80 / PC3 tumor-bearing mice was performed to determine the expression levels of Glut and FAP. The sections were dewaxed using a gradient of xylene and alcohol, and the citric acid antigen retrieval method was used, and then cooled to room temperature after heating. Next, the sections were blocked with immunostaining blocking solution for 15 minutes and then incubated with primary glucose transporter (Glut) antibody (ab115730, Abcam, 1:500) and FAP antibody (AF5344, Affinity Biosciences, 1:50) at 4°C overnight. Subsequently, the sections were incubated with secondary antibodies at 37°C for 1 hour. DAB chromogen was added in sequence, and hematoxylin was used for counterstaining. Finally, the sections were washed, dehydrated, and mounted.

[0181] Immunohistochemical results showed that U87MG and PC3 tumors showed strong positive Glut expression, and HuTu80 tumors showed moderate positive Glut expression, as shown in Figure 7 As shown in parts A, B, and C. Positive FAP expression was observed in both U87MG and HuTu80 tumors, with U87MG showing stronger FAP expression, as shown in Figure 7 In contrast, FAP was weakly expressed in PC3 tumors, as shown in parts D and E. Figure 7 These immunohistochemical results are consistent with the results of the corresponding PET imaging and biodistribution studies.

[0182] Example 9 Radiotracer composition 18 F-FAPT+ 18 Abnormal toxicity experiment of F-FDG

[0183] According to the 2020 edition of the Chinese Pharmacopoeia, 0.5 ml was injected intravenously into 5 Kunming mice (6 weeks old, 20-25 g) within 30 seconds. 18 F-FAPT+ 18 F-FDG. This administration is intended to assess 18 F-FAPT+ 18 Unusual toxicity test of F-FDG regimen.

[0184] Mice were observed for signs of death within 48 hours after administration. After 48 hours, mice were euthanized, and organs of interest (including brain, heart, lung, liver, kidney, and spleen) were collected for further analysis. Figure 8 , in injection 18 F-FAPT+ 18 No death-related signs were observed in the five Kunming mice within 48 hours after F-FDG. After this, the organs of interest (brain, e.g. Figure 8 As shown in part A), heart (as shown in Figure 8 Lungs (as shown in part B) Figure 8 C), liver (as shown in Figure 8 As shown in D), kidney (as shown in Figure 8 E) and spleen (as shown in Figure 8 HE staining was performed as shown in part F of the figure. The staining results showed that there were no abnormal lesions, indicating that 18 F-FAPT+ 18 F-FDG has not been associated with any biological toxicity.

[0185] Example 10 Radiotracer composition 18 F-FAPT+ 18 Clinical Research of F-FDG

[0186] The PET / CT imaging study was performed using a uEXPLORER scanner (China United Imaging Corporation). This clinical trial study was approved by the Ethics Committee of the Chinese Clinical Trial Registration and registered with the Chinese Clinical Trial Registry (ChiCTR2200059004). A 44-year-old female breast cancer patient was included in the pilot study before treatment and signed an informed consent.

[0187] According to the results of preclinical experiments 18 F-FAPT+ 18 The optimal radioactivity concentration ratio of F-FDG is 5 / 5. 18 F-FAPT+ 18 F-FDG( 18 F-FAPT: 1.85MBq / kg, 18 F-FDG: 1.85MBq / kg) was performed PET / CT 60 minutes later, and the next day, the patient underwent paired 18 F-FDG PET / CT scan (3.7MBq / kg) was performed 60 minutes later. The maximum standardized uptake value (SU Vmax) was used to show the radiotracer uptake in normal organs and lesions, which was automatically calculated by the workstation after delineating the region of interest. The patient did not report any drug-related side effects.

[0188] The results of the study show that Fig. 9 , 18 F-FAPT+ 18 F-FDG is mainly excreted through the renal-bladder system. 18 F-FAPT+ 18F-FDG uptake is relatively low in the lungs, breast, liver, gallbladder, bile duct system, spleen, gastrointestinal tract, muscle, and bone, which accounts for the higher tumor-to-background ratio. 18 F-FAPT+ 18 F-FDG uptake was moderate, below 18 F-FDG (6.60vs 12.18). In addition, 18 F-FAPT+ 18 The uptake of F-FDG in the submandibular gland (SUVmax, 7.16), thyroid gland (SUVmax, 5.36), and pancreas (SUVmax, 5.03) was moderate, which was lower than that reported in previous studies. 18 F-FAPT.

[0189] In this breast cancer patient, 18 F-FAPT+ 18 F-FDG PET / CT and 18 F-FDG PET / CT (SU Vmax, 10.70 vs 12.80) can clearly show primary breast tumor lesions and show high tumor uptake. 18 Compared with F-FDG PET / CT, 18 F-FAPT+ 18 F-FDG PET / CT showed additional metastatic lesions with higher uptake (SUVmax of lymph node metastasis 1 was 3.00 vs 1.30; SUVmax of lymph node metastasis 2 was 6.50 vs 4.70).

[0190] Example 11 Radiotracer composition 68 Ga-FAPT+ 18 Clinical Research of F-FDG

[0191] use 68 Ga-FAPT and 18 F-FDG is used to prepare a radioactive tracer composition with an optimal radioactivity concentration ratio of 5 / 5 68 Ga-FAPT+ 18 F-FDG, radio-HPLC detection of radiotracer composition 68 Ga-FAPT+ 18 Whether the retention time of each component monomer probe of F-FDG is consistent with that of the single tracer, as well as the percentage of radioactivity of each component monomer probe, confirm the authenticity of the prepared injection solution. The radiochemical purity is greater than 95%. Fig.10 shown.

[0192] Through 18 A prospective clinical study comparing F-FDG head to head to evaluate68 Ga-FAPT+ 18 F-FDG was used to examine the tumors in patients. Eight patients were recruited and the first day was 68 Ga-FAPT+ 18 F-FDG PET / CT scan, then the next day 18 F-FDG PET / CT scan.

[0193] Image reconstruction: After the PET / CT scan is completed, image reconstruction is performed based on the CT image data according to different nuclides, and reconstructed images of different nuclides are obtained, which are 18 F image and 68 Ga image, then use 18 F image and 68 The Ga image is fused by multi-nuclide image fusion technology. Multi-nuclide image fusion technology: First, the two scanned CT images are registered (python ants registration toolkit), the deformation field between the two CT acquisitions is obtained, and one of the nuclide PET images is fixed (fixed image, 18 F image), applying the CT deformation field to another nuclide PET image (floating image, 68 Ga image) to obtain a registered two-nuclide PET image, and then the two PET images are added to obtain a simulated multi-nuclide fusion image. On the PET image, if the SUVmax of the uptake of the lesion exceeds the SUVmax of the probe uptake of the adjacent background tissue and is accompanied by CT abnormalities, the lesion is positive. Lesions are divided into primary lesions and metastatic lesions. The mean standardized uptake value (SUVmean) is used to display the uptake of normal organs and radioactive tracers, and is automatically calculated by the workstation after delineating the region of interest. If there are more than 50 metastatic lesions in the same organ of the same patient, any 10 lesions are selected under a random field of view (5X) for measurement (a total of 50); if the number of metastatic lesions in the same organ of the same patient does not exceed 50, they are measured one by one.

[0194] Tumor SUVmax / mean measurement: 18 SUVmax / mean measured on the reconstructed PET / CT image, abbreviated as SUVmax / mean- 18 F; in 68 SUVmax / mean measured on the PET / CT image reconstructed by Ga, abbreviated as SUVmax / mean- 68 Ga; according to 68 Ga-FAPT and 18The SUVmax / mean after the F-FDG injection dose ratio is converted is abbreviated as SUVmax / mean-dual. The injection dose ratio conversion formula is: SUVmax / mean-dual = SUVmax / mean- 18 F*A / (A+B)+SUVmax / mean- 68 Ga*B / (A+B), A is 18 The actual injected dose of F-FDG, B is 68 The actual injection dose of Ga-FAPT; 18 The SUVmax / mean measured on the reconstructed image after F-FDG PET / CT scanning is abbreviated as SUVmax / mean-FDG.

[0195] Calculation of tumor to background signal ratio (TBR):

[0196] TBR B -X=SUVmax-X(Tumor) / SUVmean-X(Brian)

[0197] TBR L -X=SUVmax-X(Tumor) / SUVmean-X(Liver)

[0198] TBRc-X=SUVmax-X(Tumor) / SUVmean-X(mediatinal blood pool)

[0199] X= 18 F, 68 Ga, dual or FDG

[0200] As Fig.11 As shown, SUVmean- 18 F. SUVmax- 68 Ga and SUVmean-dual were compared with individual 18 Comparative analysis of SUVmean of F-FDG: 68 Ga-FAPT+ 18 F-FDG is mainly excreted through the renal-bladder system and is found in most tissues and organs. 18 The distribution of F-FDG is consistent with that of PD-1, maintaining a low radioactivity level. 68 Ga-FAPT+ 18 F-FDG(SUVmean- 18 F、SUVmean- 68The uptake values ​​of Ga and SUVmean-dual were lower than 18 F-FDG, but uptake is higher in some glands (parotid, submandibular, thyroid, pancreas) and in the blood pool 18 F-FDG, which is due to 68 The pharmacokinetic characteristics of Ga-FAPT are affected. 68 Ga-FAPT+ 18 F-FDG exhibits low background signal in tumor patients, which is beneficial for producing high-contrast images.

[0201] In terms of the diagnosis of the primary lesions of the tumor, six primary tumors were pathologically diagnosed in seven patients, and all of these tumors could be 68 Ga-FAPT+ 18 F-FDG and 18 F-FDG was detected (6 / 6 vs 6 / 6, as shown in Table 2). B (1.58±1.34vs 2.65±2.42, p>0.05) and TBR L (6.04±5.17vs 7.37±7.17, p>0.05), 68 Ga-FAPT+ 18 F-FDG was higher than 18 F-FDG, which is due to 68 Ga-FAPT+ 18 F-FDG uptake in the brain and liver is low, resulting in a high tumor-to-background signal ratio; C (7.43±6.42vs 6.25±5.80, p>0.05), 68 Ga-FAPT+ 18 F-FDG is slightly lower than 18 F-FDG, as shown in Table 3, due to 68 Ga-FAPT has the property of binding to albumin, which leads to an increase in the background signal of the blood pool.

[0202] Regarding the diagnosis of tumor metastasis, a total of 282 metastatic lesions were identified in 7 tumor patients, and most of the metastatic lesions (lymph nodes, lungs, liver, bones, peritoneum, etc.) could be 68 Ga-FAPT+ 18 F-FDG and 18 F-FDG detected (280 vs 272, p>0.05, as shown in Table 2), reflecting 68 Ga-FA PT+ 18 F-FDG has 18 F-FDG has a comparable diagnostic performance. Fig.12As shown in the figure, in a patient with rectosigmoid colon cancer with lymph node metastasis and extensive metastasis to both lungs, 68 Ga-FAPT+ 18 F-FDG and 18 Like F-FDG, both can clearly show primary tumor lesions and metastatic lesions. B (0.87±0.71vs1.43±0.09, p<0.001) and TBR L (2.29±2.43vs.3.23±2.28, p>0.05), 68 Ga-FAPT+ 18 F-FDG was higher than 18 F-FDG. In TBR C (3.98±3.22vs3.14±2.51, p<0.001), 68 Ga-FAPT+ 18 F-FDG is slightly lower than 18 F-FDG, as shown in Table 3. For metastatic lesions in different tissues and organs, 68 Ga-FAPT+ 18 F-FDG can detect more metastatic lesions in the lungs and lymph nodes, which may indicate 68 Ga-FAPT+ 18 F-FDG ratio 18 F-FDG can detect more small metastatic lesions. 68 Ga-FAPT+ 18 F-FDG has higher tumor uptake and lower background signal, which is beneficial for the detection of small lesions. Fig.13 As shown in the figure, in a patient with gastric cancer and multiple lymph node metastases and multiple peritoneal metastases, 68 Ga-FAPT+ 18 F-FDG can clearly show posterior mediastinal lymph node metastases. 18 F-FDG was negative.

[0203] Table 2

[0204]

[0205] Table 3

[0206]

[0207]

[0208] Example 12 Radiotracer composition 18 F-FAPT+ 18 Preparation of F-IPB-GPC3P and determination of radiochemical purity

[0209] Determined by activity meter 18 F-FAPT and 18 The radioactivity of F-IPB-GPC3P was then 18 F-FAPT and 18 F-IPB-GPC3P was prepared with a radioactivity concentration ratio of 5:5 18 F-FAPT+ 18 F-IPB-GPC3P. Determined by radioactive high performance liquid chromatography (HPLC) 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IPB-GPC3P and 19 The radiochemical purity of F-FAPT was determined 18 F-IPB-GPC3P, 18 F-FAPT retention time. Radioactive HPLC detection 18 F-FAPT+ 18 Whether the retention time of each component monomer probe of F-IPB-GPC3P is consistent with that of the single tracer, as well as the percentage of radioactivity of each component monomer probe, confirms the authenticity of the prepared injection solution. The radiochemical purity is greater than 95%. Fig.14 shown.

[0210] HPLC analysis conditions: The analytical column was a ZORBAX Eclipse XDB-C18 analytical column, the mobile phase A was a 0.1% TFA in water, and the mobile phase B was a 0.1% TFA in acetonitrile. Gradient elution was performed: in the initial 0-2 minute interval, the concentration of mobile phase B was 10%; then, in the 2-14 minute interval, the concentration of mobile phase B was continuously increased from 10% to 80%; finally, the concentration of mobile phase B was maintained at 10% until the end of the gradient elution program.

[0211] 18 F-FAPT+ 18 F-Asp2-JR11 and 18 F-FAPT+ 18 The preparation of F-IPB-PSMAL and the determination of radiochemical purity can be found in 18 F-FAPT+ 18 F-IPB-GPC3P.

[0212] Example 13 Radiotracer composition 18 F-FAPT+ 18 Cell studies of F-IPB-GPC3P

[0213] Cell uptake experiments were performed using U87MG and Huh7 cells to demonstrate 18 F-FAPT+ 18 F-IPB-GP C3P, 18 F-FAPT and 18 The specificity of F-IPB-GPC3P. Fig.15 As shown, 18 F-FAPT+ 18 F-IP B-GPC3P showed high levels of tumor uptake in both U87MG and Huh7 cells. 18 F-FAPT+ 18 The cellular uptake value of F-IPB-GPC3P was higher than 18 The uptake value of F-IPB-GPC3P was (13.51±2.16vs 6.81±0.19), but lower than 18 The cellular uptake value of F-FAPT (21.00±2.06) was higher in Huh7 cells. 18 F-FAPT+ 18 The cellular uptake value of F-IPB-GPC3P (8.62±0.60) was lower than 18 The cell uptake value of F-IPB-GPC3P was (8.62±0.60vs 12.84±1.80), while 18 F-FAPT showed low cellular uptake in Huh7 cells.

[0214] Example 14 Radiotracer composition 18 F-FAPT+ 18 Small Animal PET Imaging Study of F-IPB-GPC3P

[0215] The same mice carrying U87MG or Huh7 were tested on three consecutive days. 18 F-FAPT+ 18 F-IPB-GP C3P, 18 F-FAPT and 18 PET / CT scan of F-IPB-GPC3P, evaluation 18 F-FAPT+ 18 Imaging characteristics and detection capabilities of F-IPB-GP C3P.

[0216] In mice bearing U87MG xenograft tumors, 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IP B-GPC3P and 18 F-FAPT can show U87MG tumors, such as Fig.16 shown.18 F-FAPT+ 18 F-IP B-GPC3P, 18 F-IPB-GPC3P and 18 The uptake values ​​of F-FAPT in tumors were 9.80±0.74%ID / g, 6.67±0.17%ID / g and 13.2±0.92%ID / g, respectively. 18 F-FAPT+ 18 The tumor uptake value of F-IPB-GPC3P was significantly higher than 18 F-IPB-GPC3P (p<0.001), possibly due to 18 F-FAPT targets FAP in tumor tissue. 18 F-IPB-GPC3P produced an enhancement effect, which was consistent with the immunohistochemical results, such as Fig.16 As shown in Parts C and D. In addition, 18 F-FAPT+ 18 The nonspecific uptake of F-IPB-GPC3P in normal tissues (liver and muscle) was significantly lower than 18 F-IPB-GPC3P (liver: 1.53±0.12 vs 3.07±0.12, p<0.001; muscle: 0.73±0.12 vs 0.93±0.09, p>0.05), as Fig.16 As shown in part B. 18 F-FAPT+ 18 F-IPB-GPC3P exhibited high tumor uptake and low background signal, resulting in a higher ratio of tumor to normal tissues and organs (liver and muscle). 18 F-FAPT+ 18 The tumor to liver ratio (Tumor to liver ratio, T / L) and tumor to muscle ratio (Tumor to muscle ratio, T / M) of F-IPB-GPC3P were significantly higher than those of 18 F-IPB-GPC3P's T / L (6.43±0.85 vs 2.18±0.15, p<0.001) and T / M (13.86±3.24 vs 7.22±0.75, p<0.001). 18 F-FAPT+ 18 F-IPB-GPC3P] exhibits high-contrast images, which is beneficial for the detection of lesions.

[0217] In mice bearing Huh7 xenograft tumors, 18 F-FAPT+ 18 F-IPB-GPC3P, 18F-IPB-GPC3P clearly showed Huh7 tumors, such as Fig.17 As shown in Part A. However, 18 F-FAPT showed low uptake in Hu h7 tumors, which was confirmed by immunohistochemical results, as Huh7 tumor tissues were negative for FAP expression. Fig.17 As shown in part C. 18 F-FAPT+ 18 F-IPB-GPC3P, 18 F-IPB-GPC3P and 18 The uptake values ​​of F-FAPT in tumors were 3.80±0.14%ID / g, 4.83±0.78%ID / g, and 2.2±0.14%ID / g, respectively. 18 F-FAPT failed to show tumor lesions. 18 Compared with F-IPB-GPC3P, 18 F-FAPT+ 18 The tumor uptake value of F-IPB-GPC3P was less than 18 F-IPB-GPC3P, but there was no statistical difference (p>0.05), while in terms of nonspecific uptake in normal tissues (liver and muscle), 18 F-FAPT+ 18 F-IPB-GPC3P is significantly lower than 18 F-IPB-GPC3P (liver: 1.26±0.05 vs 2.60±0.29, p<0.001; muscle: 0.57±0.05 vs 0.70±0.08, p>0.05), as Fig.17 As shown in Part B. Therefore, although 18 F-FAPT+ 18 Tumor uptake of F-IPB-GPC3P was higher 18 F-IPB-GPC3P is low, but 18 F-FAPT+ 18 F-IPB-GPC3P has a lower normal organ uptake, which is conducive to a higher ratio of tumor to normal tissues and organs (liver and muscle), resulting in 18 F-FAPT+ 18 F-IPB-GPC3P is more effective in detecting liver tumors 18 F-IPB-GPC3P has more advantages. 18 F-FAPT+ 18 Tumor to liver ratio (T / L) and 18The T / L of F-IPB-GPC3P were 3.00±0.20 and 1.87±0.29, respectively (p<0.001).

[0218] Example 15 Radiotracer composition 18 F-FAPT+ 18 Biodistribution study of F-IPB-GPC3P

[0219] Research 18 F-FAPT+ 18 In vivo biodistribution of F-IPB-GPC3P was investigated in a tumor model. In mice bearing U87MG xenograft tumors, F-IPB-GPC3P showed a significant difference compared to the single-agent combination. 18 Compared with F-IPB-GPC3P, 18 F-FAPT+ 18 The uptake of F-IPB-GPC3P in U87MG tumors was higher due to 18 F-FAPT showed specific uptake in U87MG. 18 F-IPB-GPC3P produces a gain-in-force effect, such as Fig.18 As shown in part A, it reflects the two tracers 18 F-FAPT+ 18 F-IPB-GPC3P complementation. In mice bearing Huh7 xenograft tumors, 18 F-FAPT+ 18 F-IPB-GPC3P and 18 F-IPB-GPC3P showed higher uptake values ​​in Huh7 tumors, but 18 The uptake value of F-IPB-GPC3P was higher (3.45±0.35 vs 5.02±0.63, p<0.01). Fig.18 As shown in part B.

[0220] 18 F-FAPT+ 18 The uptake values ​​of F-IPB-GPC3P in most normal tissues and organs are relatively 18 The uptake value of F-IPB-GPC3P is low, such as heart, lung, liver, kidney, spleen, and blood pool, which is beneficial for detecting lesions in these organs, such as Fig.18 As shown in Part A and Part B. Therefore, 18 F-FAPT+ 18 Although the uptake value of F-IPB-GPC3P in Huh7 tumors was 18 F-IPB-GPC3P is low, but 18 F-FAPT+ 18 The T / L of F-IPB-GPC3P is significantly higher than18 The T / L of F-IPB-GPC3P (7.94±1.29 vs 5.50±0.5, p<0.01) was favorable for the detection of liver tumors. 18 F-FAPT has the lowest absorption rate in most organs. 18 F-FAPT+ 18 F-IPB-GPC3P has the advantages of high tumor uptake value and low physiological uptake value of normal tissues and organs, so it can clearly image tumors and demarcate lesions. The results of biodistribution studies are consistent with the results of small animal PET imaging studies.

[0221] Example 16 Radiotracer composition 18 F-FAPT+ 18 Small Animal PET Imaging Study of F-Asp2-JR11

[0222] The same mice carrying both AR42J (left; SSTR2 positive) and A549-FAP (right; FAP positive) were tested on three consecutive days. 18 F-FAPT, 18 F-Asp2-JR11 and 18 F-FAPT+ 18 Small animal PET / CT scans of F-Asp2-JR11 were performed to evaluate the imaging characteristics of the monomer and compound drugs. Fig.19 As shown, in the three imaging comparisons, 18 F-FAPT+ 18 F-Asp2-JR11 showed lower background uptake than single-agent therapy and had good uptake in bilateral tumors. 18 F-FAPT+ 18 F-Asp2-JR11 showed higher expression in AR42J tumors than 18 F-Asp2-JR11 tumor uptake is half the value, which may be 18 F-FAPT and 18 F-Asp2-JR11 has a complementary effect, resulting in synergistic uptake.

[0223] Example 17 Radiotracer composition 18 F-FAPT+ 18 Cell studies of F-Asp2-JR11

[0224] Cell uptake experiments were performed using AR42J and A549-FAP cells to demonstrate 18 F-FAPT+ 18 F-Asp2-JR11, 18 F-FAPT and 18The specificity of F-Asp2-JR11. Fig. 20 As shown, 18 F-FAPT+ 18 F-Asp2-JR11 showed high levels of tumor uptake in both AR42J and A549-FAP cells. 18 F-FAPT+ 18 The cellular uptake value of F-Asp2-JR11 was higher than 18 F-FAPT uptake value, but lower than 18 Cellular uptake values ​​of F-Asp2-JR11. In A549-FAP cells, 18 F-FAPT+ 18 The cellular uptake value of F-Asp2-JR11 was higher than 18 The uptake value of F-Asp2-JR11 was higher than that of 18 F-FAPT cellular uptake values.

[0225] The above contents are merely examples and illustrations of the structure of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. 64 Cu, 177 Lu, 89 Zr, 99 mTc, 111 In, 90 Y or 188 Re and other specific examples of targeted radiopharmaceuticals labeled, but for ordinary technicians in this field, several modifications and improvements of these radiopharmaceuticals can be made without departing from the concept of the present invention, and these obvious replacement forms all fall within the scope of protection of the present invention.

Claims

1. A radioactive tracer composition, characterized in that It includes component A and component B respectively labeled with radioactive metal nuclides; The A component is a targeted fibroblast activation protein (FAP) monomer tracer; The B component is any one of a monomer tracer targeting glucose transporter metabolism, a monomer tracer targeting phosphatidylinositol protein glycan (GPC3), a monomer tracer targeting somatostatin receptor (SSTR), or a monomer tracer targeting prostate-specific membrane antigen (PSMA); Wherein, the radioactivity concentration ratio of the A component to the B component is (4-6):(6-4).

2. The radioactive tracer composition according to claim 1, characterized in that The targeted fibroblast activation protein (FAP) monomer tracer comprises a targeted FAP ligand pharmacophore (FAPI), a linking group, a metal ion chelating group and a radioactive metal nuclide; The targeted glucose transporter metabolic monomer tracer comprises a targeted glucose transporter pharmacophore (DG) and a radioactive metal nuclide; The targeted GPC3 monomer tracer comprises a GPC3 receptor ligand pharmacophore (GPC3P), an albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide; The targeted somatostatin receptor (SSTR) monomer tracer comprises a targeted SSTR antagonist pharmacophore (JR11), an aspartic acid (Asp2) linker, a metal ion chelating group and a radioactive metal nuclide; The prostate specific membrane antigen (PSMA) targeted monomer tracer comprises a PSMA receptor ligand pharmacophore (PSMAL), an albumin binding group 4-(p-iodophenyl)butyric acid (IPB), a metal ion chelating group and a radioactive metal nuclide.

3. The radioactive tracer composition according to any one of claim 2, characterized in that: The metal ion chelating group is one of 1,4,7-triazacyclononadecyl-N',N"-diacetyl-N-acetyl (NOTA) or 1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetyl-N-acetyl (DOTA).

4. The radioactive tracer composition according to any one of claim 2, characterized in that: The radioactive metal nuclides include 18 F. 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 175 Yb, 153 Sm, 166 Ho, 88 Y. 90 Y. 177 Lu, 47 Sc, 212 Bi, 213 Bi, 123 I. 124 I. 131 I. 211 At 153 Eu, 169 Eu, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac or 227 One of Th.

5. The radioactive tracer composition according to claim 4, characterized in that The targeted fibroblast activation protein (FAP) monomer tracer is 18 F or 68 Ga-labeled glycopeptide FAPI ( 18 F-FA PT / 68 Ga-FAPT); The targeted glucose transporter monomer tracer is 18 F-labeled fluorodeoxyglucose ( 18 F-FDG); The targeted GPC3 monomer tracer is 18 F-labeled GPC3P containing IPB ( 18 F-IPB-GPC3P); The targeted somatostatin receptor (SSTR) monomer tracer is 18 F labeled JR11 containing Asp2 ( 18 F-Asp2-JR11); The targeted prostate specific membrane antigen (PSMA) monomer tracer is 18 F-labeled PSMAL containing IPB ( 18 F-IPB-PSMAL).

6. The radioactive tracer composition according to claim 5, characterized in that The radioactive tracer composition is 18 F-FAPT and 18 The composition of F-FDG, 68 Ga-FAPT and 18 The composition of F-FDG, 18 F-FAPT and 18 The composition of F-IPB-GPC3P, 18 F-FAPT and 18 The composition of F-Asp2-JR11 or 18 F-FAPT and 18 One of the compositions of F-IPB-PSMAL.

7. The method for preparing the radioactive tracer composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: Preparation of component A: Using NOTA-FAPT or DOTA-FAPT as a precursor raw material, a chelating reaction occurs with radioactive metal nuclide ions, and a targeted fibroblast activation protein (FAP) monomer tracer is prepared after separation and purification; Preparation of component B: Using trifluoromannose as a precursor, a two-step reaction of nucleophilic fluorination and hydrolysis with radioactive metal nuclide ions was carried out, and a targeted glucose transporter metabolic monomer tracer was prepared after separation and purification. Using NOTA-IPB-GPC3P or DOTA-IPB-GPC3P as a precursor material, a chelating reaction occurs with radioactive metal nuclide ions, and a targeted phosphatidylinositol protein glycan (GPC 3) monomer tracer is prepared after separation and purification; Using NOTA-Asp2-JR11 or DOTA-Asp2-JR11 as a precursor material, a chelating reaction occurs with radioactive metal nuclide ions, and a somatostatin receptor (SSTR) targeted monomer tracer is prepared after separation and purification; Using NOTA-IPB-PSMAL or DOTA-IPB-PSMAL as precursor material, a chelating reaction occurs with radioactive metal nuclide ions, and a prostate-specific membrane antigen (PSMA)-targeted monomer tracer is prepared after separation and purification. Preparation of the radioactive tracer composition: preparing component A and any component B at a radioactive concentration ratio of (4-6):(6-4) to obtain a radioactive tracer composition; Wherein, the precursor raw material is prepared by a solid phase peptide synthesis method.

8. The preparation method according to claim 7, characterized in that: The radioactive metal nuclide ions include 18 F - 、[Al 18 F] 2+ ( 18 F-AlF), 68 Ga 3+ , 64 Cu 2+ or 177 Lu 3+ One of them.

9. The use of the radioactive tracer composition according to any one of claims 1 to 6, characterized in that: The radioactive tracer composition is used in preparing diagnostic and therapeutic agents for tumors and cardiovascular and cerebrovascular diseases.

10. The use according to claim 9, characterized in that: The invention discloses an application of a radioactive tracer composition composed of the targeted fibroblast activation protein (FAP) monomer tracer and the targeted glucose transporter metabolism monomer tracer in the preparation of a PET imaging agent for lung cancer, breast cancer, melanoma, lymphoma, glioma, digestive system tumor, neuroendocrine tumor and prostate cancer with high expression of FAP or glucose transporter protein. The invention discloses a radioactive tracer composition composed of the targeted fibroblast activation protein (FAP) monomer tracer and the targeted phosphatidylinositol proteoglycan (GPC3) monomer tracer, or the targeted somatostatin receptor (SSTR) monomer tracer, or the targeted prostate-specific membrane antigen (PSMA) monomer tracer in the preparation of a PET imaging agent for lung cancer, breast cancer, melanoma, lymphoma, brain glioma, hepatobiliary tumor, gastrointestinal tumor, neuroendocrine tumor, and prostate cancer with high expression of FAP, GPC3, SSTR, or PSMA. The invention discloses an application of a radioactive tracer composition composed of a targeted fibroblast activation protein (FAP) monomer tracer and a targeted phosphatidylinositol proteoglycan (GPC3) monomer tracer, or a targeted somatostatin receptor (SSTR) monomer tracer, or a targeted prostate-specific membrane antigen (PSMA) monomer tracer in the preparation of a SPECT imaging agent for tumors or cardiovascular and cerebrovascular diseases.

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