摘要
成纤维细胞活化蛋白(FAP)是癌症相关成纤维细胞和活化成纤维细胞的重要生物标志物,在许多肿瘤和纤维化组织的活化成纤维细胞上高表达,而在正常组织和非恶性肿瘤中基本不表达。因此,FAP已经成为肿瘤等疾病的诊断和治疗的优良靶标。基于FAP抑制剂(FAPI)的PET显像和内放射疗法已成为包括癌症、纤维化等多种疾病在内的新型诊疗手段,以介绍FAP介导疾病发生发展的机制及其作为靶标的诊疗意义为开端,
关键词
癌症相关成纤维细胞(CAF)、免疫细胞、血管成分等构成的肿瘤微环境在肿瘤的发生、迁移、免疫抑制和治疗抵抗方面发挥重要作用。FAP是一种Ⅱ型跨膜糖蛋白,属于二肽基肽酶Ⅳ样家族,能够催化裂解脯氨酸后面的酰胺键从而实现底物活化,在细胞外基质重塑和纤维化过程中发挥重要作用,在健康组织中表达水平低,但在超过90%以上的恶性上皮肿瘤中高表达。FAP高表达已被证明是肺癌、肝细胞癌和结肠癌一种独立的不良预后的标志物。另外,FAP也参与了组织炎症、疤痕形成和纤维化过程。因此FAP靶向的分子影像[正电子发射型计算机断层显像(PET)和单光子发射计算机断层扫描(SPECT)]正在成为一种癌症、纤维化、炎症等疾病的有力诊疗手
2018年,海德堡大学医院Haberkorn研究小

图1
Haberkorn研究小

图2 基于FAPI-04的放射性探针的化学结构
为了探
Kesch
前列腺癌患者中,FAP表达随疾病进展显著上升,Kömek
Hatazawa
Wang
Fu
活化的滑膜成纤维细胞是类风湿关节炎中的关键效应细胞。Dorst
Zhou
心肌梗死后心肌细胞的大量突然丢失导致活化的成纤维细胞上调,并形成胶原瘢痕,这可以通过对活化的成纤维细胞进
Hu

图3
Ma

图4
之后,Loktev

图5 基于FAPI-21和FAPI-46的放射性探针的化学结构
Kratochwil
Liu
与PET相比,SPECT 是一种成本更低且更广泛可用的显像技术,因
Trujillo-Benítez

图6 含硼酸结构
Lindner

图7
Ruan

图8
Lin

图9 基于Alb-FAPtp-01的放射性探针的化学结构
Baum

图10 基于FAP-2286的放射性探针的化学结构
方酸二酯的酯基可在其他亲核基团存在下选择性地与胺反应,没有副反应,不发生水解,反应条件温和,在有机和水性介质都可以进行。通过控制水性条件下的pH或有机溶剂中的碱性条件,可以不对称地进行酰胺化。方酸还可能对放射性药物的药代动力学性质产生有益影响,因此,方酰胺结构可作为螯合剂和靶向部分的偶联单
Ballal

图11 含有方酰胺连接子的靶向FAP的放射性探针的化学结构
Moon
FAP已成为癌症诊断和治疗的一个有吸引力的靶点,一系列基于FAPI的放射性探针已被开发出来,并在临床应用中初步显示出良好的诊断效果。然而,它们的快速清除和肿瘤滞留不足阻碍了其在癌症治疗上的应用。因此,旨在改善其药代动力学性质的改良型的FAP靶向探针应运而生。
Wen

图12 含截短的Evans blue修饰的靶向FAP的放射性探针的化学结构
基于FAPI-04的主体结构,Xu

图13 含白蛋白结合剂偶联片段的靶向FAP的放射性探针的化学结构
Zhang

图14 长链脂肪酸修饰的靶向FAP的放射性探针的化学结构
为了增加单体FAPI小分子在肿瘤中的保留时间、降低其肾脏清除速度,Moon

图15 具备“双同弹头”的靶向FAP的放射性探针的化学结构
由于肿瘤的异质性和复杂的肿瘤-基质相互作用,目前用于肿瘤诊断和治疗的单靶向探针的效率有限。基于肿瘤细胞中的前列腺特异性膜抗原(PSMA)过表达和肿瘤基质中成纤维细胞活化蛋白(FAP)上调的药理学证据,Hu

图16 具备“双异弹头”的同时靶向FAP和PMSA的放射性探针的化学结构
近年来,基于FAPI的放射性探针的研究已经成为肿瘤显像和治疗领域的一个热点。本文从放射药物化学角度出发,以结构演进为主线,对放射性元素标记FAP靶向探针的优化、临床前和临床研究做了详尽阐述,有助于进一步理解其构效关系和明晰进一步深入改造的切入点,为未来通过化学修饰改善探针的药代动力学特性提供参考。对目前已经进入临床研究的靶向FAP放射性探针而言,通过设计方案更加合理、样本量更大的临床试验,进一步探索放射性FAPI在诊断和治疗中的临床价值是亟需开展的工作。从开发新的探针的角度而言,靶向FAP的双模态探针、同时靶向肿瘤内FAP和其他靶点的双靶点探针是未来可以探索的方向。未来基于靶向FAP治疗性探针的内放射治疗是未来核医学需要重点关注的领域。
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