纤维母细胞激活蛋白（FAP）在肿瘤中具有选择性表达，对于维持恶性肿瘤微环境非常重要。放射性同位素标记的FAP抑制剂（FAPI）已被证明在癌症诊断和放射性核素治疗中非常有用，并正在积极进行临床研究。与Ga-DOTA（log KGaL：21.3）相比，Ga-HBED复合物具有更高的体内稳定常数（log KGaL：38.5）。这种稳定性常数优势表明，它可能对于开发替代的FAPI成像试剂非常有用。本研究将早前报道的[68Ga]Ga-DOTA-FAPI-02和-04转化为相应的[68Ga]Ga-HBED-CC-FAPI-02和-04衍生物（[68Ga]Ga-4、[68Ga]Ga-5、[68Ga]Ga-6和[68Ga]Ga-7）。发现用HBED-CC替换DOTA螯合基团会导致几个独特和理想的肿瘤靶向性能：（1）强大、快速和高产率的标记─可轻松适应成套试剂盒；（2）在体外具有高稳定性；（3）优异的FAP结合亲和力（IC50范围在4至7纳摩尔之间），并且在HT1080（FAP+）细胞中的吸收和保持能力得到改善；以及（4）优异的体内肿瘤选择性吸收，在裸鼠体内携带U87MG肿瘤。似乎Ga（III）与HBED-CC螯合改善了体内动力学，有利于与相应的Ga-DOTA复合物相比更高的肿瘤吸收和保持率。在四种测试的配体中，新的[68Ga]Ga-HBED-CC-FAPI二聚体[68Ga]Ga-6显示出最佳的肿瘤定位性能，进一步研究有待证明它是癌症患者的替代性FAP成像试剂。

Fibroblast activation protein (FAP) is selectively expressed in tumors and highly important for maintaining the microenvironment in malignant tumors. Radioisotope-labeled FAP inhibitors (FAPIs) were proven to be useful for diagnosis and radionuclide therapy of cancer and are under active clinical investigations. Ga-HBED complex displays a higher in vivo stability constant (log KGaL: 38.5), compared to that of Ga-DOTA (log KGaL: 21.3). Such advantage in stability constant suggests that it may be useful for development of alternative FAPI imaging agents. In this study, previously reported [68Ga]Ga-DOTA-FAPI-02 and -04 were converted to the corresponding [68Ga]Ga-HBED-CC-FAPI-02 and -04 derivatives ([68Ga]Ga-4, [68Ga]Ga-5, [68Ga]Ga-6, and [68Ga]Ga-7). It was found that substituting the DOTA chelating group with HBED-CC led to several unique and desirable tumor-targeting properties: (1) robust, fast, and high yield labeling─readily adaptable to a kit formulation; (2) high stabilities in vitro; (3) excellent FAP binding affinities (IC50 ranging between 4 and 7 nM) and improved cell uptake and retention (in HT1080 (FAP+) cells); and (4) excellent selective in vivo tumor uptake in nude mice bearing U87MG tumor. It appeared that Ga(III) chelation with HBED-CC improved the in vivo kinetics favoring higher tumor uptake and retention compared to the corresponding Ga-DOTA complex. Out of the four tested ligands the new [68Ga]Ga-HBED-CC-FAPI dimer, [68Ga]Ga-6, displayed the best tumor localization properties, and further studies are warranted to demonstrate that it is an alternative FAP imaging agent for cancer patients.