Boschi Alessandra, Urso Luca, Uccelli Licia, Martini Petra, Filippi Luca
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via L. Borsari, 46, 44121, Ferrara, Italy.
Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara, 70 c/o viale Eliporto, 44121, Ferrara, Italy.
EJNMMI Radiopharm Chem. 2024 May 2;9(1):36. doi: 10.1186/s41181-024-00264-0.
In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [Tc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT).
Several approaches have been investigated for labeling FAPi-based compounds with Tc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [Tc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [Tc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [Tc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [Tc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [Tc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis.
This overview focuses on the various radiochemical strategies for obtaining [Tc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [Tc]Tc-FAPi in cancer and inflammation.
近年来，成纤维细胞激活蛋白（FAP）作为一种由癌症相关成纤维细胞过度表达的生物标志物，已成为肿瘤学中最有前景的生物标志物之一。同样，在各种成纤维细胞介导的炎症性疾病如肝硬化和特发性肺纤维化中也检测到FAP的过度表达。沿着这一轨迹，利用正电子发射体标记的FAP抑制剂（FAPi）进行FAP靶向正电子发射断层扫描（PET），已成为癌症和炎症领域一种强大的成像方法并受到关注。然而，PET是一项高成本技术，与伽马相机相比，其广泛应用仍然有限。为解决这一问题，人们已做出多项努力来探索[锝（Tc）]Tc-FAPi示踪剂作为用伽马相机和单光子发射计算机断层扫描（SPECT）成像的分子探针的潜力。
已经研究了几种用Tc标记基于FAPi的化合物的方法。具体而言，单氧代、三羰基、异腈和HYNIC策略已被用于制备[Tc]Tc-FAPi示踪剂，并已在体外和动物模型中进行了测试。总体而言，这些标记方法显示出高效率和强结合力。所得的[Tc]Tc-FAPi示踪剂在体外和动物模型研究中分别对FAP阳性细胞和异种移植瘤显示出高特异性。然而，大多数[Tc]Tc-FAPi示踪剂表现出不同程度的亲脂性，导致通过肝胆途径优先排泄以及与脂蛋白发生不良结合。因此，人们已努力合成更具亲水性的基于FAPi的化合物，以改善药代动力学性质并实现更有利的生物分布，特别是在腹部区域。用[Tc]Tc-FAPi进行SPECT成像在胃肠道肿瘤患者中取得了有前景的结果，与其他成像方式相比显示出相当或更优的诊断性能。同样，在患有神经胶质瘤、肺癌、乳腺癌和宫颈癌的受试者中也观察到了令人鼓舞的结果。除了肿瘤学应用外，基于[Tc]Tc-FAPi的成像已成功应用于心肌和特发性肺纤维化。
本综述重点关注获得[Tc]Tc-FAPi示踪剂的各种放射化学策略，突出了应用每种不同方法时遇到的主要挑战和可能的解决方案。此外，它涵盖了[Tc]Tc-FAPi在癌症和炎症方面的临床前和初步临床应用。
