18F- or 177Lu-labeled bivalent ligand of fibroblast activation protein with high tumor uptake and retention

作者：Li, Hongsheng; Ye, Shimin; Li, Li; Zhong, Jiawei; Yan, Qingsong; Zhong, Yuhua; Feng, Pengju; Hu, Kongzhen^*

来源：European Journal of Nuclear Medicine and Molecular Imaging, 2022, 49(8): 2705-2715.

DOI：10.1007/s00259-022-05757-1

• Fibroblast activation protein (FAP)
• Bivalent ligand
• Theranostic
• Lutetium-177
• Fluorine-18

Purpose Fibroblast activation protein (FAP) has become a promising cancer-related target for diagnosis and therapy. The aim of this study was to develop a bivalent FAP ligand for both diagnostic PET imaging and endoradiotherapy. Methods We synthesized a bivalent FAP ligand (ND-bisFAP) and labeled it with F-18 or Lu-177. FAP-positive A549-FAP cells were used to study competitive binding to FAP, cellular internalization, and efflux properties in vitro. Micro-PET imaging with [F-18]AlF-ND-bisFAPI was conducted in mice bearing A549-FAP or U87MG tumors. Biodistribution and therapeutic efficacy of [Lu-177]Lu-ND-bisFAPI were conducted in mice bearing A549-FAP tumors. Results The FAP binding affinity of ND-bisFAPI is 0.25 +/- 0.05 nM, eightfold higher in potency than the monomeric DOTA-FAPI-04 (IC50 = 2.0 +/- 0.18 nM). In A549-FAP cells, ND-bisFAPI showed specific uptake, a high internalized fraction, and slow cellular efflux. Compared to the monomeric [F-18]AlF-FAPI-42, micro-PET imaging with [F-18]AlF-ND-bisFAPI showed higher specific tumor uptake and retention for at least 6 h. Biodistribution studies showed that [Lu-177]Lu-ND-bisFAPI had higher tumor uptake than [Lu-177]Lu-FAPI-04 at the 24, 72, 120, and 168 h time points (all P < 0.01). [Lu-177]Lu-ND-bisFAPI delivered fourfold higher radiation than [Lu-177]Lu-FAPI-04 to A549-FAP tumors. For the endoradiotherapy study, 37 MBq of [Lu-177]Lu-ND-bisFAPI significantly reduced tumor growth compared to the same dose of [Lu-177]Lu-FAPI-04. Half of the dose of [Lu-177]Lu-ND-bisFAPI (18.5 MBq) has comparable median survival as 37 MBq of [Lu-177]Lu-FAPI-04 (37 vs 36 days). Conclusion The novel bivalent FAP ligand was developed as a theranostic radiopharmaceutical and showed promising properties including higher tumor uptake and retention compared to the established radioligands [F-18]AlF-FAPI-42 and [Lu-177]Lu-FAPI-04. Preliminary experiments with F-18- or Lu-177-labeled ND-bisFAPI showed promising imaging properties and favorable anti-tumor responses.

• 单位
  南方医科大学