WO2022160338A1 - 成纤维细胞活化蛋白-α显像剂的放射性标记配体及其制备方法 - Google Patents

成纤维细胞活化蛋白-α显像剂的放射性标记配体及其制备方法 Download PDF

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WO2022160338A1
WO2022160338A1 PCT/CN2021/074671 CN2021074671W WO2022160338A1 WO 2022160338 A1 WO2022160338 A1 WO 2022160338A1 CN 2021074671 W CN2021074671 W CN 2021074671W WO 2022160338 A1 WO2022160338 A1 WO 2022160338A1
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imaging agent
activation protein
fibroblast activation
solution
radiolabeled ligand
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French (fr)
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孔·H.F
查智豪
普罗埃斯尔·K
崔·S.R
艾利克弗·大卫
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五一一制药股份有限公司
北京宾派生物技术有限公司
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Priority to CN202180057462.5A priority Critical patent/CN117545481A/zh
Priority to PCT/CN2021/074671 priority patent/WO2022160338A1/zh
Priority to US18/263,722 priority patent/US20240139350A1/en
Publication of WO2022160338A1 publication Critical patent/WO2022160338A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

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  • the invention relates to a novel radionuclide-labeled ligand (precursor) and a preparation method thereof, in particular to a 68Ga -labeled radiolabeled ligand targeting fibroblast activation protein- ⁇ (FAP) imaging agent and the same
  • the preparation method belongs to the field of radiolabeled compounds.
  • Fibroblast activation protein- ⁇ is a serine protease on the cell surface that acts on a variety of hormones and extracellular matrix components of cells. FAP is expressed at high levels in a variety of cancers and is often used as a marker of tumor-promoting mechanisms. In recent years, FAP has been used as a molecular target for cancer diagnosis and treatment, and a large number of FAP-targeted therapies have entered the design and testing stage.
  • Fibroblast activation protein-alpha was discovered independently in the mid-1880s and early 1890s by two groups working on different topics. FAP was first described by Retting et al. in 1986 while studying surface antigens based on its expression on fibroblasts. Another group was Aoyama et al., who discovered a gelatinase expressed on the surface of invasive melanoma cells, named "seprase,” while studying membrane-surface proteases. Until 1997, the results of gene sequencing proved that FAP and seprase were the same protein molecule and belonged to the dipeptidyl peptidase (DPP) family.
  • DPP dipeptidyl peptidase
  • FAP has post-proline exopeptidase activity, however, FAP has a unique gelatinase activity that allows it to be degraded, denatured or cleaved by matrix metalloproteinases (MMPs).
  • MMPs matrix metalloproteinases
  • FAP consists of a 6-amino acid cytoplasmic tail, a 20-amino acid transmembrane domain, and a 734-amino acid ectodomain consisting of an eight-leaf ⁇ that acts as a substrate-selective gate Propeller and an alpha/beta hydrolase domain.
  • FAP monomer is inactive, but forms active homodimers and heterodimers with its closest family member, dipeptidyl peptidase IV (DPPIV). Unlike the ubiquitous expression pattern of DPPIV, FAP is only expressed in fetal cells, stromal fibroblasts, injured tissues and fibroblasts in more than 90% of malignant tumors, but not in benign tumors or normal adult tissues.
  • DPPIV dipeptidyl peptidase IV
  • FAP is only expressed in bone marrow mesenchymal stem cells (BM-MSCs), whereas in tumors, various mesenchymal cells contain FAP, including mesenchymal stem cells (MSCs), as a cancer-associated Fibroblasts (cancer-associated fibroblasts, CAFs), sarcoma and melanoma cells.
  • MSCs mesenchymal stem cells
  • CAFs cancer-associated Fibroblasts
  • CAFs cancer-associated fibroblasts
  • activated fibroblasts are a cell type in the tumor microenvironment that contribute to tumor growth and invasion. They promote remodeling of the extracellular matrix, enhance tumor invasiveness and angiogenic capacity, and, by secreting growth factors and cytokines, induce epithelial-to-mesenchymal transition.
  • CAFs are also involved in the immune interaction between tumor and host. Based on the high expression of FAP in CAFs, many studies have used FAP as a marker of CAFs.
  • FAP-targeted PET imaging of tumors has a huge advantage because supportive stroma is formed in tumor lesions larger than 1-2 mm in size, and the volume of stromal cells is larger than that of cancer cells. Targeted PET imaging will be more sensitive than glucose metabolism PET imaging. PET imaging targeting FAP is also advantageous for the detection of tumors with low or heterogeneous glucose metabolism or tumors adjacent to highly glycolytic normal tissues. Other potential advantages include early imaging 10 minutes after injection and the absence of fasting. Last and foremost, PET imaging for FAP can serve as an accurate predictive biomarker of response to treatment against any FAP in most cancers. A limitation is that because FAP is expressed in many tissue remodeling processes, it is not cancer-specific.
  • FAP-targeted PET imaging can also be used for many non-oncological imaging, such as myocardial infarction, chronic inflammatory diseases, and lung, liver, or kidney fibrosis.
  • 68Ga -FAPI-02 and 68Ga -FAPI-04 exhibited the highest tumor uptake at 1 h after injection (SUV max of 0.88 and 1.2, respectively), with no significant decrease within 2 h (SUV of 0.71 and 1.1, respectively).
  • the targeting of 68Ga -FAPI-04 was also successfully demonstrated in a second xenograft model, SK-LMS-1.
  • target specificity was elucidated by blocking experiments on HT-1080FAP xenografts.
  • FAPI-04 was the most suitable as a theranostic tracer. Similar to its precursor FAPI-02, FAPI-04 showed rapid internalization into FAP-positive tumors and rapid clearance from the body, resulting in very rapid accumulation at the tumor site (10 min after tracer administration) and tumor-organ interaction. ratio is higher. In addition, the effective tumor uptake of FAPI-04 after 24 hours was 100% higher than that of FAPI-02, which is a great advantage for the oncology application of the tracer.
  • FAP As an emerging tumor radiological diagnosis and treatment target, FAP has attracted close attention due to its high targeting, low background interference, and wide applicability to different tumors. Although there are still many challenges, FAP has become a The next spotlight in nuclear medicine.
  • HBED 3,3'-(((2,2,13,13-Tetramethyl-4,11-dioxo-3,12-dioxa-6,9-diazatetradecane-6,9-di base)bis(methylene))bis(4-hydroxy-3,1-phenylene))dipropionic acid (HBED) is a non-macrocyclic bifunctional linker, and was not used for 68 Ga positrons in the initial stage of development In pharmaceutical research, people initially used it to coordinate with Fe 3+ and used it as soil fertilizer to cure iron deficiency fading of plants.
  • HBED is an excellent Ga 3+ bifunctional linker, and its thermodynamic stability constant is much higher than other commonly used linkers (log K ML : HBED: 38.5; DOTA: 21.3; NOTA: 31.0; AAZTA: 22.18).
  • HBED sometimes not only acts as a bifunctional linker, but also provides additional targeting groups for drugs to increase the affinity of positron drugs to targets.
  • Eder M et al. developed a positron drug for prostate cancer, they found that compared with DOTA, the imaging drug containing HBED had better tumor cell uptake value, and PET imaging of tumor mice showed that HBED had better tumor uptake value and target/non-target. ratio.
  • HBED-CC can also coordinately label F-18 with [ 18 F]AlF for PET imaging, and coordinate with carbonyl technetium 99m Tc(CO) 3 and carbonyl rhenium 188/186 Re(CO) 3 to obtain SPECT Radioactive agents for imaging and therapy.
  • One of the objectives of the present invention is to provide a radiolabeled ligand for 68Ga -labeled fibroblast activation protein- ⁇ (FAP) imaging agent, which is convenient and efficient to prepare and has better biological metabolism in vivo. It is a good tumor imaging drug.
  • FAP fibroblast activation protein- ⁇
  • Another object of the present invention is to provide a method for preparing a radiolabeled ligand of the above 68Ga -labeled fibroblast activation protein- ⁇ (FAP) imaging agent.
  • Another object of the present invention is to provide the use of the above-mentioned 68Ga -labeled fibroblast activation protein- ⁇ (FAP) imaging agent radiolabeled ligand as a tumor imaging agent.
  • FAP fibroblast activation protein- ⁇
  • the present invention provides a radiolabeled ligand for a fibroblast activation protein-alpha (FAP) imaging agent having the following structural formula:
  • the present invention provides a method for preparing a radiolabeled ligand of the above fibroblast activation protein- ⁇ (FAP) imaging agent, the steps of which are as follows: in the presence of a base and a condensing agent, make The bifunctional linker HBED-CC and the FAP inhibitor undergo condensation reaction, and then use acid to remove the protective group to obtain the fibroblast activation protein- ⁇ (FAP) imaging agent.
  • the reaction formula is as follows:
  • the radiolabeled ligand of the fibroblast activation protein-alpha (FAP) imaging agent of the present invention is used for 68 Ga positron drugs, and the imaging agent chemical structure comprises a chemical structure that is more easily compatible with 68 Ga
  • the combined bifunctional linker, HBED makes the radioactive preparation more convenient and efficient.
  • the radiolabeled ligand of the fibroblast activation protein- ⁇ (FAP) imaging agent of the present invention utilizes its biological properties of specifically targeting FAP, and can be used for early diagnosis, preoperative staging, treatment guidance, recurrence and metastasis of tumors. It has important clinical potential value in lesion detection, and it is expected to develop tumor imaging drugs with better biological properties.
  • Fig. 1 is the HPLC chromatogram of the labeled reaction solution of 68 GaAl prepared in step (3) in Example 3 of the present invention.
  • Fig. 2 is the HPLC chromatogram of the labeled reaction solution of 68 GaA2 prepared in step (3) of Example 4 of the present invention.
  • the raw materials and reagents mentioned in the examples of the present invention are conventional raw materials and reagents available on the market
  • the testing methods used are conventional methods used in the art
  • the equipment and devices used are conventional equipment in the art and device.
  • the first mobile phase is 0.1% trifluoroacetic acid aqueous solution
  • the second mobile phase is acetonitrile, gradient elution conditions, 0min, 100% of the first mobile phase; 0 ⁇ 10min , 100% ⁇ 0% of the first mobile phase; the flow rate of the mobile phase is 4ml/min.
  • the first mobile phase is 0.1% trifluoroacetic acid aqueous solution
  • the second mobile phase is acetonitrile, gradient elution conditions, 0min, 100% of the first mobile phase; 0 ⁇ 10min , 100% ⁇ 0% of the first mobile phase; the flow rate of the mobile phase is 4ml/min.
  • step (3) Add 50 ⁇ L of 0.5M sodium acetate buffer to the reaction vessel, then add 30 ⁇ L of compound A1 solution prepared in step (1), mix evenly, and then add 500 ⁇ L of 68GaCl prepared in step (2) 3 of the hydrochloric acid solution, after the mixture is shaken, react at room temperature for 10-30 min, cool to room temperature, and measure its labeling rate with a semi-preparative high performance liquid chromatography column (HPLC) to obtain 68 GaAl;
  • HPLC semi-preparative high performance liquid chromatography column
  • the first mobile phase is 0.1% trifluoroacetic acid aqueous solution
  • the second mobile phase is acetonitrile
  • gradient elution conditions 0 min, 100% first Mobile phase; 0 ⁇ 10min, 100% ⁇ 0% of the first mobile phase; the flow rate of the mobile phase is 1ml/min.
  • step (3) Add 50 ⁇ L of sodium acetate buffer with a concentration of 0.5M to the reaction vessel, then add 30 ⁇ L of compound A2 solution prepared in step (1), mix evenly, and then add 500 ⁇ L of 68GaCl prepared in step (2) 3 's hydrochloric acid solution, after the mixture is shaken, react at room temperature for 10-30 minutes, cool to room temperature, and measure its labeling rate by HPLC to obtain 68GaA2 ;
  • the first mobile phase is 0.1% trifluoroacetic acid aqueous solution
  • the second mobile phase is acetonitrile
  • gradient elution conditions 0 min, 100% first Mobile phase; 0 ⁇ 10min, 100% ⁇ 0% of the first mobile phase; the flow rate of the mobile phase is 1ml/min.
  • the radioactive labeling ligand of the fibroblast activation protein- ⁇ (FAP) imaging agent of the present invention has excellent 68 Ga labeling properties, rapid and efficient radioactive preparation, and high stability of the obtained preparation.
  • 68 Ga molecular probe contains (S)-N-(2-(2-cyanopyrrol-1-yl)-2-ethoxy)-6-(3-(-1-piperazin-1-yl) Propoxy)quinoline-4-carboxamide group, this group has good affinity for FAP, we expect 68GaA1 and 68GaA2 to have better affinity for FAP tumors; therefore, the 68Ga -labeled of the present invention
  • Molecular probes made from radiolabeled ligands of fibroblast activation protein- ⁇ (FAP) targeting molecular probes can be used as tumor positron molecular probes.

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Abstract

涉及一种成纤维细胞活化蛋白-α显像剂的放射性标记配体及其制备方法，属于放射性药物化学领域，成纤维细胞活化蛋白-α显像剂的放射性标记配体具有结构式（I）。该类化合物具备优良的 68Ga标记性质，稳定性高，对FAP肿瘤亲和性好。因此，该类 68Ga标记的FAPi放射性标记配体可作为肿瘤正电子显像剂。

Description

成纤维细胞活化蛋白-α显像剂的放射性标记配体及其制备方法 技术领域
本发明涉及新型的放射性核素标记配体(前体)及其制备方法，具体为一种 68Ga标记的靶向成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体及其制备方法，属于放射性标记化合物领域。
背景技术
成纤维细胞活化蛋白-α(Fibroblast activation protein，FAP)是一种细胞表面的丝氨酸蛋白酶，作用于多种激素和细胞的外基质成分。FAP在多种癌症中均有较高水平的表达，通常被用作促肿瘤原性机制的标志物。近年来FAP被用作癌症诊断治疗的分子靶标，大量以FAP为靶标的疗法进入设计测试阶段。
成纤维细胞活化蛋白-α(FAP)是在19世纪80年代中期和90年代初由两个研究不同课题的小组分别独立发现的。Retting等人于1986年在研究表面抗原之时，基于其在成纤维细胞上表达，首次描述命名了FAP。另一组是Aoyama等人在研究与膜表面的蛋白酶之时，发现了一种在侵入性黑色素瘤细胞表面表达的明胶酶，命名为“seprase”。直到1997年，基因测序结果证明FAP和seprase是同一蛋白分子，属于二肽基肽酶(dipeptidyl peptidase,DPP)家族。FAP与其他DPP酶一样，具有脯氨酸后肽外切酶活性，但是，FAP有独特的明胶酶活性，使其可以降解变性或被基质金属蛋白酶(MMP)裂解。在结构上，FAP由一个6个氨基酸的胞质尾，一个20个氨基酸的跨膜结构域和一个734个氨基酸的胞外结构域组成，外结构域由充当底物选择性门的八叶β螺旋桨和一个α/β水解酶结构域组成。FAP单体没有活性，但与其最相近的家族成员二肽基肽酶IV(DPPIV)形成活性同二聚体和异二聚体。与DPPIV的普遍表达方式不同，FAP仅在胎儿细胞，基质成纤维细胞，受伤的组织和90％以上的恶性肿瘤的成纤维细胞中表达，而在良性肿瘤或正常成人组织中不表达。在正常的成人组织中，FAP仅在骨髓间充质干细胞(BM-MSC)中表达，而在肿瘤中，各种间充质细胞均含有FAP，包括间充质干细胞(MSCs)、作为癌症相关成纤维细胞(cancer-associated fibroblasts,CAFs)、肉瘤和黑色素瘤细胞。CAFs，也称为肿瘤相关的成纤维细胞，活化的成纤维细胞，是肿瘤微环境中的一种细胞类型，对肿瘤的生长和侵袭具有辅助作用。它们促进细胞外基质的重塑，增强肿瘤的侵袭性和血管生成能力，并且通过分泌生长因子和细胞因子，可以诱导上皮向间质的转化。此外，CAFs也参与肿瘤与宿主之间的免疫相互作用。基于FAP在CAFs中的高表达，许多研究将FAP作为CAFs的标志物。
以FAP为靶点的肿瘤PET成像具有巨大的优势，因为大小超过1-2mm的肿瘤病变时，有支持性基质形成，基质细胞的体积大于癌细胞的体积，因此，如果FAP足够表达，以基质为目标的PET成像将比葡萄糖代谢PET成像更灵敏。以FAP为靶点的PET成像对于检测低或异质葡萄糖代谢的肿瘤或高度糖酵解正常组织附近的肿瘤也有较大优势。其他潜在优势包括注射后10分钟进行早期成像以及无需禁食等。最后也是最重要的是，针对FAP的PET成像可以作为对大多数癌症中针对任何FAP的治疗的反应的精确预测生物标记。局限性是，由于FAP在许多组织重塑过程中的表达，因此，它不是癌症特异性的。例如，这可能使慢性胰腺炎和胰腺导管腺癌之间的区分变得困难。相反地，FAP靶向PET成像也可用于许多非肿瘤学成像，例如心肌梗死，慢性炎症性疾病，肺，肝或肾纤维化。
基于已有的FAP抑制剂(FAPI)，Thomas Lindner等人于2018年报道了以FAP为靶点的放射性分子探针。合成了一系列以喹啉为基础结构的衍生物，并对其使用 177Lu标记，使用经人或鼠FAP基因转染的HT-1080细胞以及经CD26转染的人胚胎肾细胞测定化合物的结合率与内化率。所有示踪剂均显示出超过90％的内化率。为了证实靶标特异性，还使用表达鼠FAP和二肽基肽酶4(CD26)的人胚胎肾细胞进行结合测定，这与人FAP具有高度同源性。在这些实验中，FAPI-02和FAPI-04显示出与鼠类FAP的强结合，FAPI-04的值明显更高，并且不与CD26结合。
使用(HT-1080)FAP异种移植小鼠对细胞实验结果较好的FAPI化合物进行了小动物PET研究。 68Ga-FAPI-02和 68Ga-FAPI-04在注射后1h表现出最高的肿瘤摄取(SUV max分别为0.88和1.2)，在2h内没有显着降低(SUV分别为0.71和1.1)。在第二种异种移植模型SK-LMS-1中也成功证明了 68Ga-FAPI-04的靶向性。此外，通过对HT-1080FAP异种移植物的阻断实验阐明了靶标特异性。
在乳腺癌患者的临床应用中，对2例转移性乳腺癌患者静脉注射 68Ga-FAPI-04，10分钟、1小时和3小时后，进行了诊断性PET/CT扫描。在这两名患者中，示踪剂在转移灶中的蓄积都很高(SUV max分别为7-15.5和15.3-29.9)，正常组织中的示踪剂摄取非常低。
在所有测试的衍生物中，FAPI-04最适合作为治疗诊断示踪剂。与其前体FAPI-02相似，FAPI-04显示出快速内在化为FAP阳性肿瘤并快速从体内清除，从而导致肿瘤部位非常迅速的积累(示踪剂给药10分钟后)，并且肿瘤与器官的比率较高。此外，24小时后的有效肿瘤吸收FAPI-04比FAPI-02高100％，这对于示踪剂的肿瘤学应用具有很大的优势。
基于FAPI-04的结构，Anastasia Loktev等人于2019年报道了一系列新型FAP靶向放射性分子探针，进一步提升了药物在肿瘤中的保留时间。体外竞争结合实验结果表明，所有化合物均显示出与FAP的高结合，孵育1和4小时后的结合值等于或高于FAPI-04的结合值。除FAPI-38外，所有化合物的内化率均与FAPI-04相当。尽管大多数衍生物在24小时后显示出比FAPI-04更高的结合值，但化合物FAPI-38，-39，-40和-41从表达FAP的细胞中的清除速度显着加快。
FAP作为新兴肿瘤放射性诊断和治疗靶点，以其高靶向性、低背景干扰、对于不同肿瘤的广泛的适用性，受到大家的密切关注，尽管还存在着诸多的挑战性，但FAP已成为下一个核医学关注的焦点。
3,3'-(((2,2,13,13-四甲基-4,11-二氧-3,12-二氧杂-6,9-二氮四癸烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸(HBED)属于非大环类双功能连接剂，在研制初期并不用于 68Ga正电子药物研究，人们最初利用它和Fe 3+配位，用做土壤肥料，来治愈植物的缺铁退色病。近年来，研究发现：HBED是绝佳的Ga 3+双功能连接剂，其热力学稳定常数远高于其他常用的连接剂(log K ML：HBED：38.5；DOTA：21.3；NOTA：31.0；AAZTA：22.18)。HBED与Ga 3+配位所需能量相对其他双功能连接剂较低，因此， 68Ga-HBED标记所需温度较低，时间较短。在正电子药物的研发过程中，HBED有时并不仅仅具有双功能连接剂的作用，它还能为药物提供额外的靶向基团，增加正电子药物与靶点的亲和性。Eder M等人研制前列腺癌正电子药物时发现，与DOTA相比，含有HBED显像药物肿瘤细胞摄取值更好，肿瘤小鼠PET显像表明HBED具有更好的肿瘤摄取值以及靶/非靶比值。
因此，当将HBED和FAP抑制剂结合起来作为放射性药物研究时，可能使 68Ga标记反应条件更为温和，效率更高，同时获得更适宜的体内药代动力学性质，有望满足今后临床肿瘤诊断需求。此外，HBED-CC也可以与[ 18F]AlF配位标记F-18用于PET显像、与羰基锝 99mTc(CO) 3和羰基铼 188/186Re(CO) 3配位标记得到SPECT显像和治疗的放射性制剂。
发明内容
本发明的目的之一在于提供一种 68Ga标记的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体，该放射性标记配体制备方便高效，同时具有较好的体内生物代谢性质，是较好的肿瘤显像药物。
本发明的另一目的在于提供一种上述 68Ga标记的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体的制备方法。
本发明的再一目的在于提供上述 68Ga标记的成纤维细胞活化蛋白-α(FAP)显像剂放射性标记配体作为肿瘤显像剂的用途。
根据本发明的一个方面，本发明提供结构式如下的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体：
Figure PCTCN2021074671-appb-000001
其中，R为-OH或者
Figure PCTCN2021074671-appb-000002
根据本发明的另一个方面，本发明提供一种上述成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体的制备方法，其步骤如下：在碱和缩合剂的存在下，使双功能连接剂HBED-CC和FAP抑制剂进行缩合反应，然后利用酸脱去保护基团，得到所述的成纤维细胞活化蛋白-α(FAP)显像剂，反应式如下：
Figure PCTCN2021074671-appb-000003
其中，R为-OH或者
Figure PCTCN2021074671-appb-000004
根据本发明的又一个方面，本发明的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体，用于 68Ga正电子药物，该显像剂化学结构包含更易于与 68Ga结合的双功能连接剂HBED，因而放射性制备更加方便高效。
有益效果：
本发明的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体，利用其特异性靶向FAP的生物学特性，在肿瘤的早期诊断、术前分期、治疗指导、复发和转移病灶检测方面具有重要的临床潜在价值，有望开发出生物性质较好的肿瘤显像药物。
下面通过具体实施方式结合附图对本发明的技术方案做进一步说明和描述，但并不意味着对本发明保护范围的限制。
附图说明
图1为本发明实施例3中步骤(3)制备的 68GaA1的标记反应液的HPLC图谱。
图2为本发明实施例4步骤(3)制备的 68GaA2的标记反应液的HPLC图谱。
具体实施方式
除非特别，本发明实施例中提到的原料和试剂均为市场上可购的常规原料和试剂，所用测试方法均为本领域所用的常规方法，所用的设备和装置均为本领域的常规设备和装置。
实施例1
成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体A1的合成
(S)-3-(3-((羧甲基)(2-((羧甲基)(5-(3-(4-((4-((2-(2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氨基)乙基)氨基)甲基)-4-羟基苯基)丙酸
合成反应方程式：
Figure PCTCN2021074671-appb-000005
合成方法：
将化合物3,3'-(((2,2,13,13-四甲基-4,11-二氧-3,12-二氧杂-6,9-二氮四癸烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸(64毫克，0.1毫摩尔)溶于2mL无水二甲基甲酰胺，向混合溶液中依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI，28.5毫克，0.15毫摩尔)，1-羟基苯并三唑(HOBt，25.3毫克，0.15毫摩尔)，N,N-二异丙基乙胺(DIPEA，41.3毫克，0.32毫摩尔)以及(S)-N-(2-(2-氰基吡咯-1-基)-2- 乙氧基)-6-(3-(-1-哌嗪-1-基)丙氧基)喹啉-4-甲酰胺(45毫克，0.1毫摩尔)；室温下反应过夜后，向混合溶液中加入30mL乙酸乙酯，用水(10mL×2)以及饱和食盐水(10mL)洗涤；有机相用无水硫酸镁干燥，过滤除去固体杂质；利用旋转蒸发仪减压，除去滤液中的有机相，用二氯甲烷/乙醇/氨水(v/v/v，90/10/1)过硅胶柱分离，收集组分，减压除去溶剂，得到45毫克淡黄色油状物；
将得到的淡黄色油状物溶于5毫升三氟乙酸中，室温下，搅拌3小时，利用旋转蒸发仪减压，除去溶剂，残余物利用半制备高效液相色谱柱(HPLC)分离，得到15.2毫克的产品A1(产率：10.5％)；产品经过LC/MS鉴定，为目标产物。HRMS(ESI)理论分子量C 50H 61N 8O 12(M+H) +，964.4331；实测分子量，964.4376。上述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件，0min，100％的第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为4ml/min。
实施例2
成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体A2的合成
2,2'-(乙烷-1,2-二基双((5-(3-(4-((2-((S)-2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氮杂环二乙酸
合成反应方程式：
Figure PCTCN2021074671-appb-000006
合成方法：
将化合物3,3'-(((2,2,13,13-四甲基-4,11-二氧-3,12-二氧杂-6,9-二氮四癸烷-6,9-二 基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸(128毫克，0.2毫摩尔)溶于5mL无水二甲基甲酰胺，向混合溶液中依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI，57毫克，0.3毫摩尔)，1-羟基苯并三唑(HOBt，51.3毫克，0.3毫摩尔)，N,N-二异丙基乙胺(DIPEA，82.6毫克，0.64毫摩尔)以及(S)-N-(2-(2-氰基吡咯-1-基)-2-乙氧基)-6-(3-(-1-哌嗪-1-基)丙氧基)喹啉-4-甲酰胺(45毫克，0.1毫摩尔)；室温下反应过夜后，向混合溶液中加入30mL乙酸乙酯，用水(10mL×2)以及饱和食盐水(10mL)洗涤；有机相用无水硫酸镁干燥，过滤，除去固体杂质；利用旋转蒸发仪减压，除去滤液中的有机相，用二氯甲烷/乙醇/氨水(v/v/v，90/10/1)过硅胶柱分离，收集组分，减压，除去溶剂，得到80毫克的淡黄色油状物；
将得到的淡黄色油状物溶于10毫升三氟乙酸中，室温下搅拌3小时；利用旋转蒸发仪，减压，除去溶剂，残余物利用半制备高效液相色谱柱(HPLC)分离，得到25.9毫克产品A2(产率：41％)。产品经过LC/MS鉴定，为目标产物。HRMS(ESI)理论分子量C 74H 89N 14O 14(M+H) +，1397.6683；实测分子量，1397.6746。上述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件，0min，100％的第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为4ml/min。
实施例3
放射性标记配体A1的 68Ga放射性标记
Figure PCTCN2021074671-appb-000007
(1)将1mg的化合物A1((S)-3-(3-((羧甲基)(2-((羧甲基)(5-(3-(4- ((4-((2-(2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氨基)乙基)氨基)甲基)-4-羟基苯基)丙酸)溶于1mL 0.05N的醋酸钠缓冲液，然后，加入氢氧化钠溶液，调节至pH为5，得到浓度为1mg/mL的化合物A1溶液；
(2)用4mL高纯0.05N盐酸溶液淋洗锗镓发生器，得到活度为8-10mCi的 68GaCl 3的盐酸溶液；
(3)向反应容器中加入50μL的浓度为0.5M的醋酸钠缓冲液，然后，加入步骤(1)制得的30μL化合物A1溶液，均匀混合，再加入步骤(2)制得的500μL  68GaCl 3的盐酸溶液，混合物摇匀后，室温下，反应10～30min，冷却至常温，用半制备高效液相色谱柱(HPLC)测定其标记率，得 68GaA1；
步骤(3)中所述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件：0min，100％的第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为1ml/min。
如图1所示，为本发明实施例3中步骤(3)制备的 68GaA1的标记反应液的HPLC图谱。
实施例4
放射性标记配体A2的 68Ga放射性标记
Figure PCTCN2021074671-appb-000008
(1)将1mg的化合物A2(2,2'-(乙烷-1,2-二基双((5-(3-(4-((2-((S)-2- 氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氮杂环二乙酸)溶于1mL 0.05N的醋酸钠缓冲液，然后，加入氢氧化钠溶液，调节至pH为5，得到浓度为1mg/mL的化合物A2溶液；
(2)用4mL高纯0.05N盐酸溶液淋洗锗镓发生器，得到活度为8-10mCi的 68GaCl 3的盐酸溶液；
(3)向反应容器中加入50μL的浓度为0.5M的醋酸钠缓冲液，然后，加入步骤(1)制得的30μL化合物A2溶液，均匀混合，再加入步骤(2)制得的500μL  68GaCl 3的盐酸溶液，混合物摇匀后，室温下，反应10～30min，冷却至常温，用HPLC测定其标记率，得 68GaA2；
步骤(3)中所述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件：0min，100％的第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为1ml/min。
如图2所示，为本发明实施例4中步骤(3)制备的 68GaA2的标记反应液的HPLC图谱。
本发明的成纤维细胞活化蛋白-α(FAP)显像剂的放射性标记配体，具备优良的 68Ga标记性质，放射性制备快速、高效，所得的制剂稳定性高。 68Ga分子探针含有(S)-N-(2-(2-氰基吡咯-1-基)-2-乙氧基)-6-(3-(-1-哌嗪-1-基)丙氧基)喹啉-4-甲酰胺基团，该基团具有良好的FAP亲和性，我们预期 68GaA1和 68GaA2对FAP肿瘤亲和性较好；因此，本发明的 68Ga标记的成纤维细胞活化蛋白-α(FAP)靶向分子探针的放射性标记配体制成的分子探针可作为肿瘤正电子分子探针。
以上所述，仅为本发明的较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。

Claims (10)

  1. 一种成纤维细胞活化蛋白-α显像剂的放射性标记配体，其结构式如下：
    Figure PCTCN2021074671-appb-100001
    其中，R为-OH或者
    Figure PCTCN2021074671-appb-100002
  2. 权利要求1所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的制备方法，其步骤如下：在碱和缩合剂的存在下，使双功能连接剂HBED-CC和FAP抑制剂进行缩合反应，然后利用酸脱去保护基团，得到所述的成纤维细胞活化蛋白-α(FAP)显像剂；所述双功能连接剂HBED-CC和FAP抑制剂的结构如下：
    Figure PCTCN2021074671-appb-100003
  3. 权利要求1所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的制备方法，其特征在于：所述成纤维细胞活化蛋白-α显像剂的放射性标记配体为(S) -3-(3-((羧甲基)(2-((羧甲基)(5-(3-(4-((4-((2-(2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氨基)乙基)氨基)甲基)-4-羟基苯基)丙酸，其制备步骤如下：将化合物3,3'-(((2,2,13,13-四甲基-4,11-二氧-3,12-二氧杂-6,9-二氮四癸烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸溶于无水二甲基甲酰胺，向混合溶液中依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺，1-羟基苯并三唑，N,N-二异丙基乙胺以及(S)-N-(2-(2-氰基吡咯-1-基)-2-乙氧基)-6-(3-(-1-哌嗪-1-基)丙氧基)喹啉-4-甲酰胺；室温下反应过夜后，向混合溶液中加入乙酸乙酯，用水以及饱和食盐水洗涤；有机相用无水硫酸镁干燥，过滤，除去固体杂质；利用旋转蒸发仪减压，除去滤液中的有机相，用二氯甲烷/乙醇/氨水过硅胶柱分离，收集组分，减压，除去溶剂，得到淡黄色油状物(S)-3-(3-((羧甲基)(2-((羧甲基)(5-(3-(4-((4-((2-(2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氨基)乙基)氨基)甲基)-4-羟基苯基)丙酸。
  4. 权利要求1所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的制备方法，其特征在于：所述成纤维细胞活化蛋白-α显像剂的放射性标记配体为2,2'-(乙烷-1,2-二基双((5-(3-(4-((2-((S)-2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氮杂环二乙酸，其制备步骤如下：将化合物3,3'-(((2,2,13,13-四甲基-4,11-二氧-3,12-二氧杂-6,9-二氮四癸烷-6,9-二基)二(亚甲基))二(4-羟基-3,1-亚苯基))二丙酸溶于无水二甲基甲酰胺，向混合溶液中依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺、1-羟基苯并三唑、N,N-二异丙基乙胺以及(S)-N-(2-(2-氰基吡咯-1-基)-2-乙氧基)-6-(3-(-1-哌嗪-1-基)丙氧基)喹啉-4-甲酰胺；室温下反应过夜后，向混合溶液中加入乙酸乙酯，用水以及饱和食盐水洗涤；有机相用无水硫酸镁干燥，过滤，除去固体杂质；利用旋转蒸发仪减压，除去滤液中的有机相，用二氯甲烷/乙醇/氨水过硅胶柱分离，收集组分，减压，除去溶剂，得到淡黄色油状物2,2'-(乙烷-1,2-二基双((5-(3-(4-((2-((S)-2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氮杂环二乙酸。
  5. 权利要求1所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，用于 68Ga标记正电子药物。
  6. 根据权利要求5所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，其特征在于：所述 68Ga正电子药物的结构式分别如下所示。
    Figure PCTCN2021074671-appb-100004
  7. 根据权利要求6所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，其特征在于：所述 68Ga正电子药物 68GaA1的标记方法如下：
    (1)将1mg的化合物A1((S)-3-(3-((羧甲基)(2-((羧甲基)(5-(3-(4-((4-((2-(2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氨基)乙基)氨基)甲基)-4-羟基苯基)丙酸)溶于1mL 0.05N的醋酸钠缓冲液，然后，加入氢氧化钠溶液，调节至pH为5，得到浓度为1mg/mL的化合物A1溶液；
    (2)用4mL高纯0.05N盐酸溶液淋洗锗镓发生器，得到活度为8-10mCi的 68GaCl 3的盐酸溶液；
    (3)向反应容器中加入50μL的浓度为0.5M的醋酸钠缓冲液，然后，加入步骤(1)制得的30μL化合物A1溶液，均匀混合，再加入步骤(2)制得的500μL 68GaCl 3的盐酸溶液，混合物摇匀后，室温下，反应10～30min，冷却至常温，用半制备高效液相色谱柱(HPLC)测定其标记率，得 68GaA1。
  8. 根据权利要求7所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，其特征在于：步骤(3)中所述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件：0min，100％的 第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为1ml/min。
  9. 根据权利要求6所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，其特征在于：所述 68Ga正电子药物 68GaA2的标记方法如下：
    (1)将1mg的化合物A2(2,2'-(乙烷-1,2-二基双((5-(3-(4-((2-((S)-2-氰基吡咯烷-1-基)-2-氧乙基)氨甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)-2-羟基苄基)氮杂环二乙酸)溶于1mL 0.05N的醋酸钠缓冲液，然后，加入氢氧化钠溶液，调节至pH为5，得到浓度为1mg/mL的化合物A2溶液；
    (2)用4mL高纯0.05N盐酸溶液淋洗锗镓发生器，得到活度为8-10mCi的 68GaCl 3的盐酸溶液；
    (3)向反应容器中加入50μL的浓度为0.5M的醋酸钠缓冲液，然后，加入步骤(1)制得的30μL化合物A2溶液，均匀混合，再加入步骤(2)制得的500μL 68GaCl 3的盐酸溶液，混合物摇匀后，室温下，反应10～30min，冷却至常温，用HPLC测定其标记率，得 68GaA2。
  10. 根据权利要求9所述的成纤维细胞活化蛋白-α显像剂的放射性标记配体的应用，其特征在于：步骤(3)中所述半制备高效液相色谱柱(HPLC)中，第一流动相为0.1％三氟乙酸水溶液，第二流动相为乙腈，梯度洗脱条件：0min，100％的第一流动相；0～10min，100％～0％的第一流动相；流动相的流速为1ml/min。
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