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Background <p>In tumor imaging and therapy, fibroblast activation protein (FAP)-targeted radiotracers remains a research hotspot. The recently reported [<sup>68</sup>Ga]Ga/[<sup>177</sup>Lu]Lu-DOTA-mFS-FAPI-04 has been demonstrated to address limitations in conventional FAP-targeted agents, such as low tumor uptake, short retention time, and suboptimal therapeutic efficacy. However, [<sup>68</sup>Ga]Ga-DOTA-mFS-FAPI-04 positron emission tomography (PET) clinical imaging revealed high uptake in salivary glands, thyroid, and pancreas, necessitating further structural optimization. To address this limitation, we developed two novel radiopharmaceuticals.</p> Results <p>[<sup>68</sup>Ga]Ga-DOTA-mFS-FAP-2286 and [<sup>68</sup>Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated favorable targeting specificity and diagnostic efficacy. [<sup>68</sup>Ga]Ga-DOTA-mFS-FAP-2286 exhibited dual excretion pathways (hepatobiliary and urinary systems), whereas [<sup>68</sup>Ga]Ga-DOTA-mFS-KERERG-FAP-2286 showed exclusive urinary excretion, demonstrating superior pharmacokinetic properties. [<sup>68</sup>Ga]Ga-DOTA-mFS-KERERG-FAP-2286 exhibited significantly enhanced tracer uptake compared to [<sup>68</sup>Ga]Ga-DOTA-FAP-2286 in primary tumors (SUVmax: 11.03 ± 1.45 vs. 5.47 ± 1.66), lymph node metastases (SUVmax: 12.13 ± 2.22 vs. 5.70 ± 1.08), and distant metastases (SUVmax: 12.03 ± 6.56 vs. 6.83 ± 0.36) (all <i>p</i> &lt; 0.05).</p> Conclusion <p>Both [<sup>68</sup>Ga]Ga-DOTA-mFS-FAP-2286 and [<sup>68</sup>Ga]Ga-DOTA-mFS-KERERG-FAP-2286 effectively overcame the drawback of high uptake in salivary glands, thyroid, and pancreas observed with [<sup>68</sup>Ga]Ga-DOTA-mFS-FAPI-04. [<sup>68</sup>Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated superior pharmacokinetic characteristics with urinary excretion and showed the potential for superior diagnostic efficacy compared with [<sup>68</sup>Ga]Ga-DOTA-FAP-2286.</p>

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Preliminary study of FAP-targeted radiopharmaceuticals based on covalent targeting strategy and pharmacokinetic characteristics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Yiheng Ai,
  • Zhongcai Jin,
  • Tongtong Wu,
  • Yi Li,
  • Yanggang Liu,
  • Jing Yang,
  • Shijie Tang,
  • Yue Chen,
  • Lin Qiu

摘要

Background

In tumor imaging and therapy, fibroblast activation protein (FAP)-targeted radiotracers remains a research hotspot. The recently reported [68Ga]Ga/[177Lu]Lu-DOTA-mFS-FAPI-04 has been demonstrated to address limitations in conventional FAP-targeted agents, such as low tumor uptake, short retention time, and suboptimal therapeutic efficacy. However, [68Ga]Ga-DOTA-mFS-FAPI-04 positron emission tomography (PET) clinical imaging revealed high uptake in salivary glands, thyroid, and pancreas, necessitating further structural optimization. To address this limitation, we developed two novel radiopharmaceuticals.

Results

[68Ga]Ga-DOTA-mFS-FAP-2286 and [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated favorable targeting specificity and diagnostic efficacy. [68Ga]Ga-DOTA-mFS-FAP-2286 exhibited dual excretion pathways (hepatobiliary and urinary systems), whereas [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 showed exclusive urinary excretion, demonstrating superior pharmacokinetic properties. [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 exhibited significantly enhanced tracer uptake compared to [68Ga]Ga-DOTA-FAP-2286 in primary tumors (SUVmax: 11.03 ± 1.45 vs. 5.47 ± 1.66), lymph node metastases (SUVmax: 12.13 ± 2.22 vs. 5.70 ± 1.08), and distant metastases (SUVmax: 12.03 ± 6.56 vs. 6.83 ± 0.36) (all p < 0.05).

Conclusion

Both [68Ga]Ga-DOTA-mFS-FAP-2286 and [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 effectively overcame the drawback of high uptake in salivary glands, thyroid, and pancreas observed with [68Ga]Ga-DOTA-mFS-FAPI-04. [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 demonstrated superior pharmacokinetic characteristics with urinary excretion and showed the potential for superior diagnostic efficacy compared with [68Ga]Ga-DOTA-FAP-2286.