成纤维细胞激活蛋白（FAP）最近作为一种有前景的肿瘤生物标志物在诊断和治疗应用中受到了极大的关注。一系列基于成纤维细胞活化蛋白抑制剂（FAPI）的放射性药物已被开发并转化为临床。尽管其中一些（例如放射性标记的 FAPI-04 探针）已实现了良好的体内成像性能，但仍非常需要进一步改进以获得具有高治疗诊断潜力的放射性药物。在本研究中，我们通过将FAPI-04的核心喹啉基序改为喹啉支架，创新性地设计了FAPI配体SMIC-3002。该工程分子进一步用 68Ga 进行放射性标记，生成正电子发射断层扫描 (PET) 探针 [68Ga]Ga-SMIC-3002，然后在体外和体内进行评估。 [68Ga]Ga-SMIC-3002 表现出高体外稳定性、对 FAP 的纳摩尔亲和力（对蛋白质为 8 nM，对 U87MG 细胞为 23 nM）以及在表达 FAP 的肿瘤中的特异性摄取，肿瘤/肌肉比率为 19.1， U87MG 荷瘤小鼠在 0.5 小时时肿瘤摄取为 1.48 ± 0.03 ID/g%。综上所述，喹啉支架可成功用于 FAP 靶向示踪剂的开发。 [68Ga]Ga-SMIC-3002不仅显示出临床转化的巨大潜力，而且还为设计新一代FAPI示踪剂提供了见解。

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.