WO2023098920A1 - 一种双重靶向化合物及其制备方法和应用 - Google Patents

一种双重靶向化合物及其制备方法和应用 Download PDF

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WO2023098920A1
WO2023098920A1 PCT/CN2022/137823 CN2022137823W WO2023098920A1 WO 2023098920 A1 WO2023098920 A1 WO 2023098920A1 CN 2022137823 W CN2022137823 W CN 2022137823W WO 2023098920 A1 WO2023098920 A1 WO 2023098920A1
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radionuclide
compound
labeled
targeting compound
cancer
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French (fr)
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陈小元
徐鹏飞
吴晓明
郭志德
杨清宝
文雪君
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Yantai Lannacheng Biotechnology Co Ltd
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Yantai Lannacheng Biotechnology Co Ltd
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Priority to CA3232196A priority Critical patent/CA3232196A1/en
Priority to US18/546,989 priority patent/US11992536B2/en
Priority to KR1020237020530A priority patent/KR102658933B1/ko
Priority to AU2022402959A priority patent/AU2022402959B2/en
Priority to JP2023536546A priority patent/JP7515023B2/ja
Priority to EP22900722.4A priority patent/EP4253402A4/en
Publication of WO2023098920A1 publication Critical patent/WO2023098920A1/zh
Priority to ZA2024/02726A priority patent/ZA202402726B/en
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Definitions

  • the invention relates to the fields of nuclear medicine and molecular imaging, in particular to a radionuclide-labeled fibroblast activation protein FAP and integrin ⁇ v ⁇ 3 dual targeting compound, a preparation method and the use of the compound in diagnosis or treatment Use in diseases characterized by overexpression of FAP and/or integrin ⁇ v ⁇ 3 .
  • Fibroblast activation protein is a membrane serine peptidase expressed on the surface of activated fibroblasts in the tumor stroma and plays an important role in the development of tumors.
  • FAP Fibroblast activation protein
  • Previous studies have shown that FAP is generally not expressed in normal human tissues, but it is selectively highly expressed on the surface of stromal fibroblasts in more than 90% of epithelial malignant tumors, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer and Pancreatic cancer, etc.
  • Integrin ⁇ v ⁇ 3 is a heterodimeric receptor located on the cell surface.
  • integrin ⁇ v ⁇ 3 Plays a key role in tumor growth, invasion and metastasis.
  • the polypeptide containing arginine-glycine-aspartic acid (RGD) sequence can specifically bind to integrin ⁇ v ⁇ 3 .
  • FAP and integrin ⁇ v ⁇ 3 have become important targets for tumor imaging and treatment.
  • FAP and integrin ⁇ v ⁇ 3 are mainly distributed in tumor stromal cells and new blood vessels, they are highly expressed in multiple tumor types at the same time, and are ideal targets for the development of "pan-tumor" dual targeting probes. Considering the heterogeneity of tumors, in order to further improve the efficiency of tumor diagnosis and treatment, it is necessary to develop a targeted compound that can play a targeting role against both FAP and integrin ⁇ v ⁇ 3 targets.
  • This dual-targeting compound needs to have high affinity for the two targets at the same time to achieve synergistic targeting of the FAP target and the integrin ⁇ v ⁇ 3 target in the tumor, and at the same time it needs to have excellent pharmacokinetic properties in vivo, Increased tumor uptake and tumor residence time.
  • the radionuclide-labeled dual targeting compound based on this dual targeting compound can simultaneously use the FAP target and the integrin ⁇ v ⁇ 3 target to increase the number and utilization efficiency of effective receptors in the tumor, thereby solving the problem of increasing the positive Issues with tumor detection efficiency and/or treatment efficiency.
  • the primary purpose of the present invention is to develop a new compound structure that can synergistically target the FAP target and the integrin ⁇ v ⁇ 3 target in the tumor, so as to improve the uptake and residence time of the drug in the tumor .
  • Another object of the present invention is to provide a method for preparing the new compound, so as to synthesize a compound that can synergistically target the FAP target and the integrin ⁇ v ⁇ 3 target in tumors through a convenient and easy-to-obtain synthetic route.
  • Another object of the present invention is to provide the use of the compound in the diagnosis or treatment of diseases characterized by the overexpression of FAP and/or integrin ⁇ v ⁇ 3 .
  • the present invention provides a dual targeting compound that can target FAP and integrin ⁇ v ⁇ 3 , the structure of which contains the specific binding ligand structure of FAP and integrin ⁇ v ⁇ 3 at the same time, said The compound structure is shown in the following formula (I):
  • the present invention also provides a dual targeting compound of FAP and integrin ⁇ v ⁇ 3 that can be labeled with radionuclides, and its structure contains the specific binding ligand structure of FAP and integrin ⁇ v ⁇ 3 at the same time
  • nuclide chelation structure the present invention records this structure as FAPI-RGD structure, and described compound structure is shown in following formula (I-1) or formula (I-2),
  • the present invention provides a radionuclide-labeled FAP and integrin ⁇ v ⁇ 3 dual-targeting compound, which is obtained by labeling the compound described in the second aspect of the present invention with a radionuclide.
  • the radionuclide can be selected from isotopes emitting alpha rays, isotopes emitting beta rays, isotopes emitting gamma rays, isotopes emitting Auger electrons or isotopes emitting X-rays, etc., for example 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y, 90 Y, 149 Pm, 165 Dy , 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201
  • the present invention provides a method for preparing the dual targeting compound described in the second aspect and its radionuclide-labeled compound (that is, the dual targeting compound described in the third aspect of the present invention), the preparation provided by the present invention
  • the method comprises: 1 the carboxyl group of 6-hydroxyquinoline-4-carboxylic acid first undergoes amide condensation reaction with the amino group of glycine tert-butyl ester; then connects the Boc-protected piperazinyl group at the hydroxyl position of the amide condensation product through an alkyl chain; under acidic conditions Remove the Boc and tert-butyl protecting groups, then introduce the Boc protecting group at the piperazine ring; then undergo amide condensation reaction with (S)-pyrrolidine-2-formonitrile hydrochloride; remove the Boc protecting group and N- Condensation reaction of Boc-3-[2-(2-aminoethoxy) ethoxy] propionic acid; then remove Boc protecting group, react with Fmoc-O-ter
  • the present invention provides a pharmaceutical composition, which comprises the dual targeting compound capable of targeting FAP and integrin ⁇ v ⁇ 3 described in the first aspect of the present invention, and the compound described in the second aspect of the present invention.
  • the present invention also provides the dual targeting compound that can target FAP and integrin ⁇ v ⁇ 3 described in the first aspect of the present invention, and the radionuclide-labeled FAP and integrin ⁇ v described in the second aspect
  • the dual targeting compound of ⁇ 3 , the dual targeting compound of radionuclide-labeled FAP and integrin ⁇ v ⁇ 3 described in the third aspect, or the pharmaceutical composition described in the fifth aspect is used in the preparation for diagnosis or treatment of animals or in the medicine of diseases characterized by overexpression of FAP and/or integrin ⁇ v ⁇ 3 in human subjects.
  • the diseases characterized by the overexpression of FAP and/or integrin ⁇ v ⁇ 3 include but are not limited to: cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and Scar disease; preferably, the cancer is further selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer , laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, glioma, glia glioma, astrocytoma, cervical or prostate cancer.
  • cancer is further selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer
  • the FAPI-RGD compound structure provided by the present invention has a high affinity for the FAP target and the integrin ⁇ v ⁇ 3 target, and can synergistically target the FAP target and the integrin ⁇ v ⁇ 3 target in the tumor dots, exhibited high tumor uptake and tumor residence time, and are expected to be applied in the diagnosis or treatment of diseases characterized by overexpression of FAP and/or integrin ⁇ v ⁇ 3 .
  • the preparation method of the FAPI-RGD compound provided by the present invention has simple reaction route, simple operation, cheap and easy-to-obtain preparation raw materials, low production cost, and is suitable for industrial production.
  • Figure 1 is the H NMR spectrum of compound 7.
  • Figure 2 is the carbon NMR spectrum of compound 7.
  • Figure 3 is the mass spectrum of compound 7.
  • Figure 4 is the mass spectrum of compound 8.
  • Figure 5 is the mass spectrum of compound 9.
  • Figure 6 is the mass spectrum of compound 12.
  • Figure 7 is the mass spectrum of compound 13.
  • Figure 8 is the mass spectrum of compound 14.
  • Figure 9 is the mass spectrum of compound 15.
  • Fig. 10 is a diagram showing the stability experiment results of 68 Ga-labeled FAPI-RGD (formula I-1) complex in physiological saline in the present invention.
  • Fig. 11 is a graph showing the results of cell uptake and cell binding experiments of 68 Ga-labeled FAPI-RGD (formula I-1) complexes in the present invention.
  • Figure 12 is the MicroPET images of 68 Ga-labeled FAPI-RGD (formula I-1) complexes and monomers 68 Ga-FAPI-02 and 68 Ga-C (RGDfK) in HT1080-FAP tumor-bearing mice of the present invention. like the resulting graph.
  • Fig. 13 is a statistical chart of MicroPET imaging results and uptake results of tumors and vital organs after co-injection of 68 Ga-labeled FAPI-RGD (Formula I-1) complex with C (RGDfK) or/and FAPI-02 in the present invention for 30 minutes.
  • Fig. 14 is a picture of the SPECT imaging results of the 177 Lu-FAPI-RGD complex prepared in Example 4 of the present invention in HT1080-FAP tumor-bearing mice.
  • Figure 15 shows the molecular structure of the 68 Ga-labeled control compound FAPI-RGD complex, as well as the MicroPET imaging results of the control compound injected in HT1080-FAP tumor-bearing mice for 30 minutes and 2 hours, and the uptake by tumors and vital organs Result chart.
  • Fig. 16 is the 68 Ga-labeled FAPI-RGD (formula I-1) complex, 18 F-FDG and 68 Ga-FAPI46 of the present invention in patients with pancreatic cancer, non-small cell lung cancer, small cell lung cancer and nasopharyngeal cancer treated intravenously PET/CT imaging results 3 hours after injection.
  • Embodiment 1 the preparation of compound I-1
  • compound 4 (0.52 g, 1.0 mmol) was dissolved in 10 mL of a mixed solution of dichloromethane and trifluoroacetic acid (volume ratio 9:1), and the system was warmed up to room temperature for 2 h, and the pressure was reduced after the reaction The solvent was distilled off and dissolved in 10 mL of N,N-dimethylformamide to obtain compound 5, which was set aside.
  • Example 1 for the preparation method of Example 2, replace NOTA-2 tert-butyl ester-NHS activated ester in the above example with DOTA-3 tert-butyl ester-NHS activated ester to obtain the following structure:
  • Freeze-drying method add about 18.5 ⁇ 1850 megabeq (MBq) 68 GaCl 3 hydrochloric acid solution (leached from the germanium-gallium generator) into the freeze-dried kit containing the compound of formula (I-1), after mixing evenly for 37 Reaction at °C for 20min. Take a C18 separation column, wash it slowly with 10mL of absolute ethanol, and then with 10mL of water. After diluting the labeling solution with 10mL water, load the sample onto the separation column, first remove unlabeled 68 Ga ions with 10mL water, and then rinse with 0.3mL 10mM HCl ethanol solution to obtain the complex eluent. The eluent was diluted with physiological saline, and sterile filtered to obtain the injection solution of 68 Ga-labeled FAPI-RGD complex.
  • the cell uptake experiment of 68 Ga-FAPI-RGD was carried out in HT1080-FAP tumor cells.
  • the test results are shown in part A of Figure 11.
  • 68 Ga-FAPI-RGD has rapid cell uptake. When incubated for 30 minutes, the uptake Reach maximum and maintain similar intake levels for up to 2 hours.
  • blocking experiments confirmed that the cellular uptake of 68 Ga-FAPI-RGD could be partially inhibited by C(RGDfK) or FAPI-02, and completely blocked by FAPI-RGD (see part A in FIG. 11 ).
  • Cell binding experiments were carried out in HT1080-FAP and U87MG tumor cells, and the test results are shown in Figure 11 B and C, respectively.
  • 68Ga -FAPI-RGD was prepared according to the method of Example 3.
  • 7.4MBq of 68Ga -FAPI-RGD and 68Ga -FAPI were injected through the tail vein of the randomly grouped mice, respectively.
  • -02 and 68 Ga-C(RGDfK) were injected through the tail vein of the randomly grouped mice, respectively.
  • MicroPET imaging was performed at 0-240 min after administration in the 68 Ga-FAPI-RGD group, and in the other groups at 0-120 min after administration. MicroPET imaging, the results are shown in Figure 12.
  • Figure 12 shows that at the time point when the imaging was acquired, the tumor was clearly visible and the tumor uptake of 68 Ga-FAPI-RGD was higher than that of monomeric 68 Ga-FAPI-02 and 68 Ga-C(RGDfK).
  • the four images of A from left to right correspond to single injection of 68 Ga-FAPI-RGD, co-injection of 68 Ga-FAPI-RGD and C(RGDfK), co-injection of 68 Ga-FAPI-RGD and FAPI-02 , 68 Ga-FAPI-RGD co-injected with C(RGDfK) and FAPI-02;
  • B and C respectively reflect the organs or tissues (blood, liver, kidney, tumor) of the above four groups of mice injected with different injection methods and muscle) to 68 Ga-FAPI-RGD uptake and target/non-target ratio
  • the four columnar graphs in each organ or tissue in B and C correspond to the four injection methods in A from left to right.
  • 177Lu -FAPI-RGD was prepared according to the method of Example 4.
  • 37MBq of 177Lu -FAPI-RGD were injected through the tail vein, and then under isoflurane anesthesia, after administration SPECT imaging was carried out at 4 hours, and the results are shown in Figure 14. It can be seen that the tumor was clearly visible at 4 hours after administration.
  • Figure 15A shows that at the time point when the imaging was acquired, the main radioactive signal was concentrated in the liver and kidney, with less tumor uptake.
  • Figure 15C also demonstrates high uptake in liver and kidney and low uptake in tumors.
  • the sulfosuccinimide bond as the connecting structure may lead to a decrease in the affinity of the targeting group and the targeting receptor, resulting in a decrease in the uptake of the target organ, and at the same time, the uptake of the non-target tissue is too high, resulting in a decrease in the target/non-target ratio.
  • the decline is more likely to cause adverse reactions.
  • the specific linking structure in the present invention can not only ensure high affinity with the receptor but also provide suitable pharmacokinetic properties, thereby ensuring higher absolute tumor uptake and target/non-target ratio.
  • the clinical trial of 68 Ga-FAPI-RGD was approved by the Clinical Research Ethics Committee of the First affiliated Hospital of Xiamen University, and all subjects signed a written informed consent, including a patient with pancreatic cancer, a patient with non-small cell lung cancer, and a patient with non-small cell lung cancer.
  • the dose of intravenous injection of 68 Ga-FAPI-RGD (1.8-2.2MBq [0.05-0.06mCi]/kg) was calculated according to the body weight of the subjects.
  • the hybrid PET/CT scanner (Discovery MI, GE Healthcare, Milwaukee, WI, USA) was used to acquire data, and the imaging results are shown in Figure 16 .
  • the maximum standardized uptake value (SUV max ) was automatically calculated using a region of interest (ROI) drawn on the axial image.
  • the SUV max of dual-targeted 68 Ga-FAPI-RGD in different types of tumors is higher than that of FAP protein single-targeted 68 Ga-FAPI-46, and the SUV max is increased by about 30-50%, confirming the double-targeted
  • the point-targeted design can increase the number and utilization efficiency of effective receptors in the tumor, thereby improving tumor uptake.
  • the present invention has developed the FAPI-RGD structure, which has a high affinity for both the FAP target and the integrin ⁇ v ⁇ 3 target, and can synergistically target the FAP target and integrin ⁇ v ⁇ in tumors 3 targets, exhibiting excellent metabolic kinetics, high tumor uptake and tumor residence time, are expected to be applied in the diagnosis or treatment of diseases characterized by overexpression of FAP and/or integrin ⁇ v ⁇ 3 .

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Abstract

一种双重靶向化合物及其制备方法和应用，涉及核医学与分子影像学领域。一种被放射性核素标记的双重靶向化合物，其结构如下式（I-1）或式（I-2）所示。所述的双重靶向化合物，对于FAP靶点及整合素αvβ3靶点均具有较高的亲和力，能够协同靶向肿瘤中的FAP靶点及整合素αvβ3靶点，表现出较高的肿瘤摄取和肿瘤滞留时间。提供基于所述双重靶向化合物的放射性核素标记的双重靶向化合物，及其制备方法和在制备诊断和治疗以FAP和/或整合素αvβ3过度表达为特征的疾病的药物中的应用。

Description

一种双重靶向化合物及其制备方法和应用 技术领域
本发明涉及核医学与分子影像学领域，具体地涉及一种放射性核素标记的成纤维细胞活化蛋白FAP和整合素α vβ 3双重靶向化合物，以及制备方法和所述化合物在诊断或治疗以FAP和/或整合素α vβ 3过度表达为特征的疾病中的用途。
背景技术
成纤维细胞活化蛋白(Fibroblast activation protein，FAP)是一种膜丝氨酸肽酶，表达于肿瘤间质活化的成纤维细胞表面，在肿瘤的发生发展过程中发挥重要作用。既往研究表明，FAP在正常人组织中一般无表达，但是选择性地高表达于90％以上的上皮恶性肿瘤的基质成纤维细胞表面，包括乳腺癌、卵巢癌、肺癌、结直肠癌、胃癌和胰腺癌等。整合素α vβ 3(integrinα vβ 3)是位于细胞表面的异源二聚体受体，在正常血管内皮和上皮细胞很少表达，但在肺癌、骨肉瘤、成神经细胞瘤、乳腺癌、前列腺癌、膀胱癌、胶质母细胞瘤及浸润性黑色素瘤等多种实体肿瘤细胞表面有高水平的表达，而且在所有肿瘤组织新生血管内皮细胞膜有高表达，提示整合素α vβ 3在肿瘤生长、侵袭和转移过程中起着关键作用。含精氨酸-甘氨酸-天冬氨酸(RGD)序列的多肽能与整合素α vβ 3特异性结合。鉴于FAP和整合素α vβ 3在肿瘤中的广泛表达及重要作用，FAP和整合素α vβ 3已成为肿瘤显像和治疗的重要靶点。
为了进一步提高肿瘤的诊断和治疗效率，现有技术中对两个靶点同时具备亲和力的双重靶向探针已有所开发。例如，Anna Orlova等人报道了针对前列腺特异性膜抗原(PSMA)和胃泌素释放肽受体(GRPR)同时具有亲和力的双重靶向探针。由于PSMA和GRPR同时在前列腺中高表达，因此这种双重靶向探针存在的缺点是仅应用于前列腺癌的放射诊断与治疗，无法应用于其他肿瘤。
发明内容
由于FAP和整合素α vβ 3主要分布在肿瘤基质细胞和新生血管中，因此在多种肿瘤类型中同时高表达，是开发“泛肿瘤”双重靶向探针的理想靶点。考虑到肿瘤的异质性，为了能够进一步提高肿瘤的诊断和治疗效率，有必要开发一种针对FAP和整合素α vβ 3两种靶点均可发挥靶向作用的靶向化合物。这种双重靶向化合物需要对两个靶点同时具备高亲和力，实现 协同靶向肿瘤中的FAP靶点及整合素α vβ 3靶点，同时在体内需要具有优异的药物代谢动力学性质，提升肿瘤摄取和肿瘤滞留时间。基于这种双重靶向化合物的放射性核素标记的双重靶向化合物，能够同时利用FAP靶点及整合素α vβ 3靶点，提升肿瘤中的有效受体数量和利用效率，从而解决提升阳性肿瘤检出效率和/或治疗效率的问题。
为了解决上述问题，本发明的首要目的在于：开发一种新的化合物结构可协同靶向肿瘤中的FAP靶点及整合素α vβ 3靶点，以提升药物在肿瘤中的摄取及滞留时间。
本发明的另一个目的在于：提供制备所述的新化合物的方法，以通过方便易得的合成路线合成可协同靶向肿瘤中的FAP靶点及整合素α vβ 3靶点的化合物。
本发明的再一个目的在于：提供所述化合物在诊断或治疗以FAP和/或整合素α vβ 3过度表达为特征的疾病中的应用。
本发明的上述目的通过以下技术方案实现。
第一方面，本发明提供一种可靶向FAP和整合素α vβ 3的双重靶向化合物，其结构中同时包含FAP和整合素α vβ 3的特异性结合配体结构，所述的化合物结构如下式(I)所示：
Figure PCTCN2022137823-appb-000001
第二方面，本发明还提供一种可用放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物，其结构中同时包含FAP和整合素α vβ 3的特异性结合配体结构以及核素螯合结构，本发明将该结构记作FAPI-RGD结构，所述的化合物结构如下式(I-1)或式(I-2)所示，
Figure PCTCN2022137823-appb-000002
Figure PCTCN2022137823-appb-000003
第三方面，本发明提供一种放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物，它是由本发明第二方面所述的化合物标记了放射性核素得到的。
本发明所述的方案中，所述的放射性核素可以选自发射α射线的同位素、发射β射线的同位素、发射γ射线的同位素、发射俄歇电子的同位素或发射X射线的同位素等，例如 18F、 51Cr、 67Ga、 68Ga、 111In、 99mTc、 186Re、 188Re、 139La、 140La、 175Yb、 153Sm、 166Ho、 86Y、 90Y、 149Pm、 165Dy、 169Er、 177Lu、 47Sc、 142Pr、 159Gd、 212Bi、 213Bi、 72As、 72Se、 97Ru、 109Pd、 105Rh、 101mRh、 119Sb、 128Ba、 123I、 124I、 131I、 197Hg、 211At、 151Eu、 153Eu、 169Eu、 201Tl、 203Pb、 212Pb、 64Cu、 67Cu、 198Au、 225Ac、 227Th、 89Zr或 199Ag中的任意一种；更优选的放射性核素为 18F、 64Cu、 68Ga、 89Zr、 90Y、 111In、 99mTc、 177Lu、 188Re或 225Ac。
第四方面，本发明提供一种制备第二方面所述的双重靶向化合物及其放射性核素标记化合物(即本发明第三方面所述的双重靶向化合物)的方法，本发明提供的制备方法包括：①6-羟基喹啉-4-羧酸的羧基首先与甘氨酸叔丁酯的氨基发生酰胺缩合反应；然后在酰胺缩合产物羟基位置通过烷基链连接Boc保护的哌嗪基；酸性条件下脱去Boc和叔丁基保护基，接着在哌嗪环引入Boc保护基；接着与(S)-吡咯烷-2-甲腈盐酸盐发生酰胺缩合反应；脱除Boc保护基后与N-Boc-3-[2-(2-氨基乙氧基)乙氧基]丙酸发生缩合反应；接着脱去Boc保护基，与Fmoc-O-叔丁基-L-谷氨酸反应；脱去叔丁酯后，制备成活化酯，接着与带有氨基-二聚乙二醇的c(RGDfK)反应，得到双重靶向化合物；脱去Fmoc保护后与核素螯合剂反应，所述的核素螯合剂为1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸或1,4,7-三氮杂环壬烷-1,4,7-三乙酸；接着脱除螯合基团上的叔丁酯保护后得到可被放射性核素标记的双重靶向化合物，即本发明第二方面所述的双重靶向化合物。
②将①所得可被放射性核素标记的双重靶向化合物与含放射性核素的化合物按照现有的湿法标记方法或冻干法标记法反应，即可制备得到本发明第三方面所述的放射性核素标记的 FAP和整合素α vβ 3的双重靶向化合物。
第五方面，本发明提供一种药物组合物，所述的药物组合物包含本发明第一方面所述可靶向FAP和整合素α vβ 3的双重靶向化合物、本发明第二方面所述的可用放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物、第三方面所述的放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物、或它们在药学上可接受的任意互变异构体、外消旋体、水合物、溶剂化物或盐。
第六方面，本发明还提供本发明第一方面所述可靶向FAP和整合素α vβ 3的双重靶向化合物、第二方面所述的可用放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物、第三方面所述的放射性核素标记的FAP和整合素α vβ 3的双重靶向化合物或第五方面所述的药物组合物在制备用于诊断或治疗动物或人类个体的以FAP和/或整合素α vβ 3过度表达为特征的疾病的药物中的应用。
本发明所述的应用中，所述的以FAP和/或整合素α vβ 3过度表达为特征的疾病包括但不限于：癌症、慢性炎症、动脉粥样硬化、纤维化、组织重塑和瘢痕病；优选地，所述的癌症进一步选自乳腺癌、胰腺癌、小肠癌、结肠癌、直肠癌、肺癌、头颈癌、卵巢癌、肝细胞癌、食道癌、下咽癌、鼻咽癌、喉癌、骨髓瘤细胞、膀胱癌、胆管细胞癌、透明细胞肾癌、神经内分泌肿瘤、致癌性骨软化症、肉瘤、CUP(原发性未知癌)、胸腺癌、胶质瘤、神经胶质瘤、星形细胞瘤、子宫颈癌或前列腺癌。
本发明提供的所述FAPI-RGD化合物结构，对于FAP靶点及整合素α vβ 3靶点均具有较高的亲和力，能够协同靶向肿瘤中的FAP靶点及整合素α vβ 3靶点，表现出较高的肿瘤摄取和肿瘤滞留时间，有望应用于诊断或治疗以FAP和/或整合素α vβ 3过度表达为特征的疾病。
此外，本发明提供的所述FAPI-RGD化合物的制备方法反应路线简洁，操作简单，制备原料廉价易得，生产成本低，适宜工业化生产。
附图说明
图1为化合物7的核磁氢谱图。
图2为化合物7的核磁碳谱图。
图3为化合物7的质谱图。
图4为化合物8的质谱图。
图5为化合物9的质谱图。
图6为化合物12的质谱图。
图7为化合物13的质谱图。
图8为化合物14的质谱图。
图9为化合物15的质谱图。
图10为本发明中 68Ga标记的FAPI-RGD(式I-1)配合物在生理盐水中的稳定性实验结果图。
图11为本发明中 68Ga标记的FAPI-RGD(式I-1)配合物的细胞摄取和细胞结合实验结果图。
图12为本发明中 68Ga标记的FAPI-RGD(式I-1)配合物以及单体 68Ga-FAPI-02和 68Ga-C(RGDfK)在HT1080-FAP荷瘤小鼠体内的MicroPET显像结果图。
图13为本发明中 68Ga标记的FAPI-RGD(式I-1)配合物与C(RGDfK)或/和FAPI-02共注射30min后MicroPET成像结果及肿瘤及重要器官的摄取结果统计图。
图14为本发明中实施例4制备的 177Lu-FAPI-RGD配合物在HT1080-FAP荷瘤小鼠体内的SPECT显像结果图。
图15体现了 68Ga标记的对照化合物FAPI-RGD的配合物的分子结构，以及该对照化合物在HT1080-FAP荷瘤小鼠体内注射30min和2h后的MicroPET成像结果，和肿瘤及重要器官的摄取结果统计图。
图16为本发明中 68Ga标记的FAPI-RGD(式I-1)配合物、 18F-FDG和 68Ga-FAPI46在胰腺癌、非小细胞肺癌、小细胞肺癌和鼻咽癌患者经静脉注射3小时后的PET/CT显像结果图。
具体实施方式
以下通过具体实施方式结合附图对本发明的技术方案进行进一步的说明和描述。
实施例1：化合物I-1的制备
化合物2的合成：
在100mL烧瓶中分别投入化合物1(6-羟基喹啉-4-羧酸，1.89g，10.0mmol)、甘氨酸叔丁酯(1.89g，10.0mmol)，HATU(3.8g，10.0mmol)和N,N-二异丙基乙胺(2.6g， 20.0mmol)依次投入至30mL N,N-二甲基甲酰胺。反应混合物搅拌过夜，减压蒸馏除去溶剂，得到粗产物。经硅胶柱(二氯甲烷/甲醇＝30:1)纯化得白色固体化合物2，产率87％。
化合物3的合成：
在100mL烧瓶中分别将化合物2(1.51g，5.0mmol)、1-溴-3-氯丙烷(1.55g，10.0mmol)和碳酸钾(1.38g，10.0mmol)依次投入至50mL N,N-二甲基甲酰胺中。将体系升温到60℃，保持体系60℃搅拌过夜，减压蒸馏除去溶剂，得到粗产物。经硅胶柱(二氯甲烷/甲醇＝50:1)纯化得白色固体化合物3，产率63％。
化合物4的合成：
在100mL烧瓶中分别将化合物3(0.76g，2.0mmol)、1-叔丁氧羰基哌嗪(0.55g，3.0mmol)，和碘化钾(0.49g，3.0mmol)依次投入至30mL乙腈中。将体系升温到60℃，保持体系60℃搅拌过夜，减压蒸馏除去溶剂，得到粗产物。经硅胶柱(二氯甲烷/甲醇＝30:1)纯化得白色固体化合物4，产率58％。
化合物5的合成：
在冰浴条件下，将化合物4(0.52g，1.0mmol)溶解在10mL二氯甲烷和三氟乙酸(体积比9:1)混合溶液中，将体系升温到室温反应2h，反应结束后减压蒸馏除去溶剂，用10mL的N,N-二甲基甲酰胺溶解，得到化合物5，备用。
化合物6的合成：
向化合物5的N,N-二甲基甲酰胺溶液中分别加入二碳酸二叔丁酯(0.22g，1.0mmol)和N,N-二异丙基乙胺(0.39g，3.0mmol)，室温搅拌过夜，减压蒸馏除去溶剂，得到粗产物。经硅胶柱(二氯甲烷/甲醇＝10:1)纯化得白色固体化合物6，产率72％。
化合物7的合成：
在100mL烧瓶中分别投入化合物6(0.47g，1.0mmol)、(S)-吡咯烷-2-甲腈盐酸盐(0.13g，1.0mmol)，HATU(0.38g，1.0mmol)和N,N-二异丙基乙胺(0.26g，2.0mmol)依次投入至10mL N,N-二甲基甲酰胺。反应混合物室温搅拌至反应结束，减压蒸馏除去溶剂，得到粗产物。经硅胶柱(二氯甲烷/甲醇＝50:1)纯化得白色固体化合物7，产率85％。图1为化合物7的核磁氢谱，图2为化合物7的核磁碳谱，图3为化合物7的质谱图。
化合物8的合成：
将化合物7(2.50g，4.5mmol)，对甲苯磺酸一水合物(2.58g，13.6mmol)，25mL的乙腈加入反应瓶中，65℃反应1h，TLC监测化合物7反应完全(甲醇:二氯甲烷＝5:1)，40℃减压蒸干。加入14mL的DMF、DIPEA(3.05g，23.6mmol)，25℃搅拌，反应编号(1)，即化合物7的哌嗪脱保护得到中间体。将N-叔丁氧羰基-二聚乙二醇-羧酸(1.62g，4.8mmol)，HATU(2.60g,6.8mmol)，10mL的DMF加入另一反应瓶中，25℃反应30min，反应编号(2)，将反应(2)的反应溶液体系滴加到反应(1)体系中，反应1h。40℃减压蒸干，加入50mL的纯化水，用DCM萃取两次，每次50mL，合并DCM，用无水硫酸钠干燥，过滤，蒸干，得粗品，柱层析提纯，得目标物1.68g。理论分子量709.3799，实测分子量709.38801，质谱结果与目标物一致。图4为化合物8的质谱图。
化合物9的合成：
将化合物8，对甲苯磺酸一水合物(1.61g,8.5mmol)，20mL的乙腈加入反应瓶中，65℃反应1h，40℃减压蒸干。加入20mL的DMF，DIPEA(1.83g,14.2mmol)，25℃搅拌，反应编号(1)。将Fmoc-O-叔丁基-L-谷氨酸(1.43g,3.4mmol)，HATU(1.29g,3.4mmol)，20mL的DMF加入另一反应瓶中，25℃反应30min，反应编号(2)，将反应(2)的反应溶液体系滴加到反应(1)体系中，反应1h。40℃减压蒸干，得粗品，柱层析提纯，得目标物1.19g。理论分子量1016.5008，实测分子量1016.51094，质谱结果与目标物一致。图5为化合物9的质谱图。
化合物12的合成：
将c(RGDfK)(1.00g,1.7mmol)、氨基叔丁酯-二聚乙二醇-琥珀酰亚胺酯(0.74g,1.9mmol)、DIPEA(0.44g,3.4mmol)和20mL的DMF加入反应瓶中，30℃反应20h。40℃减压蒸干，加入10mL的甲醇，滴加60mL的MTBE，析出固体，得到中间体11，抽滤，40℃真空干燥2h。将固体的中间体11加入反应瓶中，加入30mL的TFA，1.5mL的纯化水，30℃反应1h，降温至0-5℃，滴加200mL的MTBE，0-5℃搅拌30min，抽滤，用MTBE淋洗，40℃真空干燥，得产品。理论分子量762.4024，实测分子量762.40768，质谱结果与目标物一致。图6为化合物12的质谱图。
化合物13的合成：
将化合物9，对甲苯磺酸一水合物(0.34g,1.8mmol)，20mL的乙腈加入反应瓶中，65℃反应4h，40℃减压蒸干。加入20mL的DMF，DIPEA(0.36g,2.8mmol)，DCC(0.14g,0.7mmol)，NHS(0.08g，0.7mmol)，35℃反应15-20h得到中间体10，降温至25℃，加入化合物12，反应1h，40℃减压蒸干，得粗品，制备液相纯化，得目标物66.5mg。理论分子量1704.8300，实测分子量1704.84518，质谱结果与目标物一致。图7为化合物13的质谱图。
化合物14的合成：
将化合物13，0.5mL的哌啶，2mL的DMF加入反应瓶中，25℃反应1h，滴加10mL的乙酸乙酯析晶，搅拌30min，抽滤，固体40℃真空干燥2h，得产品50.8mg。将脱去Fmoc保护的化合物13溶解在2mL的DMF中，加入NOTA-2叔丁酯-NHS活化酯，DIPEA(0.010g,0.08mmol)，25℃反应1h，40℃减压蒸干，加入2mL的乙酸乙酯，2mL的MTBE析晶，搅拌20min，抽滤，固体40℃真空干燥，得产品43.2mg。理论分子量1880.0196，实测分子量1880.0369，质谱结果与目标物一致。图8为化合物14的质谱图。
化合物15的合成：
将化合物14，2mL的三氟乙酸加入反应瓶中，25℃反应1h，40℃减压蒸干，得粗品，用制备液相提纯，冻干，得产品化合物15，产率42％。理论分子量1767.8944，实测分子量1767.91036，质谱结果与目标物一致。图9为化合物15的质谱图。
上述步骤合成路线如下：
Figure PCTCN2022137823-appb-000004
Figure PCTCN2022137823-appb-000005
实施例2
实施例2的制备方法参考实例1，将上述实施例中NOTA-2叔丁酯-NHS活化酯替换为DOTA-3叔丁酯-NHS活化酯，得到如下的结构：
Figure PCTCN2022137823-appb-000006
实施例3.放射性Ga-68标记FAPI-RGD式(I-1)配合物( 68Ga-FAPI-RGD)的制备：
湿法：将约18.5～1850兆贝可(MBq) 68GaCl 3盐酸溶液(淋洗自锗镓发生器)加入到含0.5mL实施例1制备的结构如式(I-1)的化合物的醋酸-醋酸盐溶液(1.0g/L)的离心管中，置于37℃下反应20min。取一C18分离小柱，先用10mL无水乙醇缓慢淋洗，再用10mL水淋洗。用10mL水将标记液稀释后，上样到分离柱上，先用10mL水除去未标记的 68Ga离子，再用0.3mL 10mM的HCl的乙醇溶液淋洗得到 68Ga标记的FAPI-RGD配合物。该淋洗液经生理盐水稀释，并经无菌过滤后即得 68Ga标记的FAPI-RGD配合物的注射液。
冻干法：将约18.5～1850兆贝可(MBq) 68GaCl 3盐酸溶液(淋洗自锗镓发生器)加入到含有式(I-1)化合物的冻干药盒中，混匀后37℃下反应20min。取一C18分离小柱，先用10mL无水乙醇缓慢淋洗，再用10mL水淋洗。用10mL水将标记液稀释后，上样到分离柱上，先用10mL水除去未标记的 68Ga离子，再用0.3mL 10mM的HCl的乙醇溶液淋洗得到配合物淋洗液。该淋洗液经生理盐水稀释，并经无菌过滤后即得 68Ga标记的FAPI-RGD配合物的注射液。
实施例4.放射性Lu-177标记FAPI-RGD式(I-2)配合物( 177Lu-FAPI-RGD)的制备：
配置pH＝5.5的缓冲溶液：称取57.6毫克醋酸、189毫克龙胆酸和525毫克三水合醋酸钠，用48毫升纯水溶解，用氢氧化钠溶液调节pH＝5.5。用200μL缓冲液(pH＝5.5)充分溶解200μg实施例2制备的结构如式(I-2)的化合物，然后加入5毫升缓冲液(pH＝5.5)以及150mCi左右 177LuCl 3的盐酸溶液。混合物摇匀后80℃加热反应20min。反应结束后冷却至 室温。该反应液经生理盐水稀释，并经无菌过滤后即得10mCi/mL的 177Lu标记的FAPI-RGD配合物的注射液。
实验例分析及应用效果
1、 68Ga标记的式(I-1)FAPI-RGD的配合物的稳定性分析
移取20μL实施例3制备的 68Ga-FAPI-RGD(3.7MBq活度/20μL)的溶液加入到含有100μL生理盐水或PBS(pH＝7.4)的离心管中，在37℃条件下共孵育0.5h、1h和4h，共孵育溶液。取20μL共孵育溶液，过0.22μm针式滤膜，采用HPLC分析放射化学纯度。测试结果如图10所示， 68Ga-FAPI-RGD在生理盐水中孵育后，未见明显分解，放射化学纯度均大于99％，说明本发明制备的 68Ga-FAPI-RGD稳定性优异。
2、 68Ga标记的式(I-1)FAPI-RGD的配合物细胞实验分析
在HT1080-FAP肿瘤细胞中进行 68Ga-FAPI-RGD的细胞摄取实验，测试结果如图11中的A部分所示， 68Ga-FAPI-RGD具有快速的细胞摄取，在孵育30分钟时，摄取达到最大并保持在相似摄取水平长达2小时。此外，阻断实验证实， 68Ga-FAPI-RGD的细胞摄取可以被C(RGDfK)或FAPI-02部分抑制，可以被FAPI-RGD完全阻断(参见图11中的A部分)。在HT1080-FAP和U87MG肿瘤细胞中进行了细胞结合实验，测试结果分别如图11中的B和C所示，在HT1080-FAP细胞实验中，测得 68Ga-FAPI-RGD和 68Ga-FAPI-02的IC 50两分别为11.17nM和4.14nM。HT1080-FAP细胞实验中，测得 68Ga-FAPI-RGD和 68Ga-C(RGDfK)的IC 50两分别为18.93nM和11.49nM组。实验结果表明FAPI-RGD与相应的单体相比，与其相应受体FAP和整合素α vβ 3具有相似的亲和力。
3、 68Ga标记的式(I)FAPI-RGD的配合物在荷瘤小鼠体内的MicroPET显像
按实施例3的方法制备 68Ga-FAPI-RGD，在HT1080-FAP荷瘤小鼠中，针对随机分组的小鼠，分别经尾静脉注射7.4MBq的 68Ga-FAPI-RGD、 68Ga-FAPI-02和 68Ga-C(RGDfK)，然后在异氟烷麻醉下， 68Ga-FAPI-RGD组分别于给药后0～240min进行MicroPET显像，其余组分别于给药后0～120min进行MicroPET显像，结果见图12。图12中A、C和E分别显示了上述三组小鼠静脉注射后不同时间的HT1080-FAP荷瘤小鼠(n＝3)的MicroPET最大密度投影图像，B、D和F分别体现了上述三组小鼠注射后各器官或组织(血、肝、肾、肿瘤和肌肉)在不同时间点的摄取，每组中三个摄取量从左至右分别对应注射后0.5h、1h和 2h。图12显示了在采集成像的时间点，肿瘤清晰可见，并且 68Ga-FAPI-RGD的肿瘤摄取高于单体 68Ga-FAPI-02和 68Ga-C(RGDfK)的肿瘤摄取。 68Ga-FAPI-RGD在体内特异性结合整合素α vβ 3和FAP的性能通过阻断实验得到证实。将上述 68Ga-FAPI-RGD与C(RGDfK)或FAPI-02共注射到HT1080-FAP荷瘤小鼠体内，其MicroPET显像结果图及器官摄取结果如图13所示。图13中，A的四个影像从左至右分别对应单独注射 68Ga-FAPI-RGD、 68Ga-FAPI-RGD与C(RGDfK)共注射、 68Ga-FAPI-RGD与FAPI-02共注射、 68Ga-FAPI-RGD与C(RGDfK)和FAPI-02共注射得到的影像；B和C分别体现了上述四组不同注射方式注射后小鼠各器官或组织(血、肝、肾、肿瘤和肌肉)对 68Ga-FAPI-RGD的摄取和靶/非靶比值，B和C中的每种器官或组织中四个柱状图形从左至右分别对应A中的四种注射方式。从图13中可以看到，与 68Ga-FAPI-RGD共注射RGD或FAPI-02均能降低肿瘤对 68Ga-FAPI-RGD的摄取，与 68Ga-FAPI-RGD共注射C(RGDfK)+FAPI-02则进一步降低肿瘤对 68Ga-FAPI-RGD的摄取，阻断实验证实 68Ga-FAPI-RGD在体内能够通过结合整合素α vβ 3和FAP实现肿瘤特异性靶向。
4、 177Lu标记的式(II)FAPI-RGD的配合物在荷瘤小鼠体内的SEPCT显像
按实施例4的方法制备 177Lu-FAPI-RGD，在HT1080-FAP荷瘤小鼠中，分别经尾静脉注射37MBq的 177Lu-FAPI-RGD，然后在异氟烷麻醉下，于给药后4h进行SPECT显像，结果见图14，可以看到，在给药4h时肿瘤清晰可见。
5、 68Ga标记的FAPI-RGD(对照化合物)的配合物在荷瘤小鼠体内的MicroPET显像
作为对照，采用了马来酰亚胺-硫醇形成的硫代琥珀酰亚胺键作为连接结构，制备了图15B化合物，按实施例3的方法进行 68Ga标记，在HT1080-FAP荷瘤小鼠中进行MicroPET显像研究，结果见图15。图15A显示了在采集成像的时间点，主要放射性信号集中在肝脏和肾脏，肿瘤摄取较少。图15C也表明在肝脏和肾脏的高摄取以及肿瘤的低摄取。因此，硫代琥珀酰亚胺键作为连接结构，可能会导致靶向基团与靶向受体的亲和力下降，致使靶器官的摄取下降，同时非靶组织摄取过高，导致靶/非靶比值的下降，更容易造成不良反应。本发明中的特定连接结构既能保证与受体的高亲和力又能提供适宜的药代动力学性质，从而保证了较高的肿瘤绝对摄取以及靶/非靶比值。
4、 68Ga标记的式(I-1)FAPI-RGD的配合物在肿瘤病人上的PET/CT显像
经厦门大学第一附属医院临床研究伦理委员会批进行 68Ga-FAPI-RGD的临床试验，所有受试者均签署书面知情同意书，包括一名胰腺癌患者，一名非小细胞肺癌患者，一名小细胞肺癌患者和一名鼻咽癌患者。根据受试者体重计算静脉注射 68Ga-FAPI-RGD的剂量(1.8～2.2MBq[0.05～0.06mCi]/kg)。在静脉注射3小时后，使用混合PET/CT扫描仪(Discovery MI，GE Healthcare，Milwaukee，WI，USA)获取数据，显像结果如图16。使用在经轴图像上绘制的感兴趣区域(ROI)自动计算最大标准摄取值(SUV max)。双靶点靶向的 68Ga-FAPI-RGD在不同类型肿瘤中的SUV max均高于FAP蛋白单靶向的 68Ga-FAPI-46，SUV max升高约30-50％，证实了双靶点靶向的设计可以提升肿瘤中的有效受体数量和利用效率进而提升肿瘤摄取。
综上所述，本发明开发了FAPI-RGD结构，对于FAP靶点及整合素α vβ 3靶点均具有较高的亲和力，能够协同靶向肿瘤中的FAP靶点及整合素α vβ 3靶点，表现出优异的代谢动力学、较高的肿瘤摄取和肿瘤滞留时间，有望应用于诊断或治疗以FAP和/或整合素α vβ 3过度表达为特征的疾病。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (11)

  1. 一种双重靶向化合物，其特征在于，结构中同时包含FAP和整合素α vβ 3的特异性结合配体结构，所述的化合物结构如下式(I)所示：
    Figure PCTCN2022137823-appb-100001
  2. 一种可被放射性核素标记的双重靶向化合物，其特征在于，结构中同时包含FAP和整合素α vβ 3的特异性结合配体及核素螯合结构，所述的化合物结构如下式(I-1)或式(I-2)所示，
    Figure PCTCN2022137823-appb-100002
  3. 制备权利要求2所述的可被放射性核素标记的双重靶向化合物的方法，其特征在于，包括以下步骤：6-羟基喹啉-4-羧酸的羧基首先与甘氨酸叔丁酯的氨基发生酰胺缩合反应；然后在酰胺缩合产物羟基位置通过烷基链连接Boc保护的哌嗪基；酸性条件下脱去Boc和叔丁基保护基，接着在哌嗪环引入Boc保护基；接着与(S)-吡咯烷-2-甲腈盐酸盐发生酰胺缩合反应；脱除Boc保护基后与N-Boc-3-[2-(2-氨基乙氧基)乙氧基]丙酸发生缩合反应；接着脱去 Boc保护基，与Fmoc-O-叔丁基-L-谷氨酸反应；脱去叔丁酯后，制备成活化酯，接着与带有氨基-二聚乙二醇的c(RGDfK)反应，得到双重靶向化合物；脱去Fmoc保护后与核素螯合剂反应，所述的核素螯合剂为1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸或1,4,7-三氮杂环壬烷-1,4,7-三乙酸；接着脱除螯合基团上的叔丁酯保护后得到一种可被放射性核素标记的双重靶向化合物。
  4. 一种放射性核素标记的双重靶向化合物，其特征在于：它是权利要求2所述的任意一种可被放射性核素标记的双重靶向化合物标记了放射性核素得到的；所述的放射性核素选自发射α射线的同位素、发射β射线的同位素、发射γ射线的同位素、发射俄歇电子的同位素或发射X射线的同位素。
  5. 如权利要求4所述的放射性核素标记的双重靶向化合物，其特征在于：所述的放射性核素选自 18F、 51Cr、 64Cu、 67Cu、 67Ga、 68Ga、 89Zr、 111In、 99mTc、 186Re、 188Re、 139La、 140La、 175Yb、 153Sm、 166Ho、 86Y、 90Y、 149Pm、 165Dy、 169Er、 177Lu、 47Sc、 142Pr、 159Gd、 212Bi、 213Bi、 72As、 72Se、 97Ru、 109Pd、 105Rh、 101mRh、 119Sb、 128Ba、 123I、 124I、 131I、 197Hg、 211At、 151Eu、 153Eu、 169Eu、 201Tl、 203Pb、 212Pb、 198Au、 225Ac、 227Th或 199Ag中的任意一种。
  6. 如权利要求4所述的放射性核素标记的双重靶向化合物，其特征在于：所述的放射性核素选自 18F、 64Cu、 68Ga、 89Zr、 90Y、 111In、 99mTc、 177Lu、 188Re或 225Ac。
  7. 制备权利要求4所述放射性核素标记的双重靶向化合物的方法，其特征在于，包括：将权利要求2所述的可被放射性核素标记的双重靶向化合物与含放射性核素的化合物按照湿法标记方法或冻干法标记法反应，即可制备得到所述的放射性核素标记的双重靶向化合物。
  8. 一种药物组合物，其特征在于：包含权利要求1所述的双重靶向化合物、权利要求2所述的可被放射性核素标记的双重靶向化合物、权利要求4所述的放射性核素标记的双重靶向化合物、或它们在药学上可接受的水合物、溶剂化物或盐。
  9. 权利要求1所述的双重靶向化合物、权利要求2所述的可被放射性核素标记的双重靶向化合物、权利要求4所述的放射性核素标记的双重靶向化合物、或它们在药学上可接受的水合物、溶剂化物或盐、或权利要求8所述的药物组合物中的任意一种在制备用于诊断或治疗 动物或人类个体的以FAP和/或整合素α vβ 3过度表达为特征的疾病的药物中的应用。
  10. 如权利要求9所述的应用，其特征在于：所述的以FAP和/或整合素α vβ 3过度表达为特征的疾病包括：癌症、慢性炎症、动脉粥样硬化或瘢痕病。
  11. 如权利要求10所述的应用，其特征在于：所述的癌症选自乳腺癌、胰腺癌、小肠癌、结肠癌、直肠癌、肺癌、头颈癌、卵巢癌、肝细胞癌、食道癌、下咽癌、鼻咽癌、喉癌、骨髓瘤细胞、膀胱癌、胆管细胞癌、透明细胞肾癌、神经内分泌肿瘤、致癌性骨软化症、肉瘤、原发性未知癌、胸腺癌、胶质瘤、神经胶质瘤、星形细胞瘤、子宫颈癌或前列腺癌。
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CN118271393B (zh) * 2024-05-31 2024-09-03 中国药科大学 一种靶向fap的二聚化合物及其探针和应用
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CN119587726B (zh) * 2024-12-04 2025-10-17 南方医科大学南方医院 靶向复方双分子探针及其制备方法与应用
CN120192362B (zh) * 2025-05-26 2025-10-21 原子高科股份有限公司 一种靶向趋化因子受体4的化合物及其应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
CN113164630A (zh) * 2018-10-24 2021-07-23 Scv-特种化学品销售有限公司 具有方酸连接的标记前体
WO2021168567A1 (en) * 2020-02-25 2021-09-02 Triumf Chelator compositions for radiometals and methods of using same
WO2021207449A1 (en) * 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
CN113880810A (zh) * 2021-09-24 2022-01-04 厦门大学 一种核素标记的配合物及其制备方法和应用
WO2022040607A1 (en) * 2020-08-20 2022-02-24 Oregon Health & Science University Small molecule albumin binders
CN115286697A (zh) * 2022-09-29 2022-11-04 烟台蓝纳成生物技术有限公司 一种双重靶向化合物及其制备方法和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770565A (en) * 1994-04-13 1998-06-23 La Jolla Cancer Research Center Peptides for reducing or inhibiting bone resorption
US11873511B2 (en) * 2016-10-19 2024-01-16 Cellectis Targeted gene insertion for improved immune cells therapy
AU2020359530A1 (en) * 2019-09-30 2022-05-19 2Seventy Bio, Inc. Dimerizing agent regulated immunoreceptor complexes
CN114874335B (zh) * 2022-05-06 2024-04-19 北京大学深圳研究生院 三靶点可调控car免疫细胞的组合物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
CN113164630A (zh) * 2018-10-24 2021-07-23 Scv-特种化学品销售有限公司 具有方酸连接的标记前体
WO2021168567A1 (en) * 2020-02-25 2021-09-02 Triumf Chelator compositions for radiometals and methods of using same
WO2021207449A1 (en) * 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
WO2022040607A1 (en) * 2020-08-20 2022-02-24 Oregon Health & Science University Small molecule albumin binders
CN113880810A (zh) * 2021-09-24 2022-01-04 厦门大学 一种核素标记的配合物及其制备方法和应用
CN115286697A (zh) * 2022-09-29 2022-11-04 烟台蓝纳成生物技术有限公司 一种双重靶向化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4253402A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024067531A1 (zh) * 2022-09-29 2024-04-04 烟台蓝纳成生物技术有限公司 一种成纤维细胞活化蛋白FAP和整合素αvβ3双重靶向化合物及其制备方法和应用
WO2025076679A1 (zh) * 2023-10-10 2025-04-17 烟台蓝纳成生物技术有限公司 一种利用异二聚体放射性化合物诊断或成像肾细胞癌的方法
WO2025124414A1 (zh) * 2023-12-11 2025-06-19 中国科学院上海药物研究所 一种靶向多聚adp核糖聚合酶的分子影像探针、制备方法及其应用
WO2025218677A1 (zh) * 2024-04-16 2025-10-23 中山医诺维申新药研发有限公司 双重靶向成纤维细胞激活蛋白和整合素亚型的化合物及其制备和应用

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