Evaluation of Astatine-211-Labeled Fibroblast Activation Protein Inhibitor (FAPI): Comparison of Different Linkers with Polyethylene Glycol and Piperazine

Abstract

Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives

“…However, in vivo studies have not successfully proven these approaches adequate yet for further (pre)clinical applications [ 68 ]. Softer metal cations like Rh + could improve the in vivo stability when N -heterocyclic carbenes are used as ligands [ 64 , 69 ].…”

“…Further improvements to raise the radioconjugate stability were made using guanidine-based building blocks like [ 211 At]At-SAGMB [63] (Figure 4). Recently, four new 211 At-containing small-molecule radiotherapeutics based on the FAPI binding motif with different linkers (PEG, piperazine) were developed [64]. Cell uptake was performed using FAP-transfected HEK293/FAPα and A549/FAPα cell lines, and biodistribution on PANC-1-cell-bearing mice.…”

“…The bond enthalpy is estimated to be approximately 50% higher than the aryl-At bond [66]. This Recently, four new 211 At-containing small-molecule radiotherapeutics based on the FAPI binding motif with different linkers (PEG, piperazine) were developed [64]. Cell uptake was performed using FAP-transfected HEK293/FAPα and A549/FAPα cell lines, and biodistribution on PANC-1-cell-bearing mice.…”

Recent advances in the development of 225Ac- and 211At-labeled radioligands for radiotheranostics

“…Other 211 At-labeled FAPIs ([ 211 At]At-FAPI1, [ 211 At]At-FAPI2, [ 211 At]At-FAPI3, [ 211 At]At-FAPI4, and [ 211 At]At-FAPI5, Fig. 14 b–f) with different linkers, polyethylene glycol and piperazine, were reported in 2023 [ 117 ]. Among these compounds, [ 211 At]At-FAPI1 with a simple PEG linker showed the best properties, and showed higher therapeutic effects than [ 211 At]At-FAPI5 with a piperazine linker.…”