Preclinical characterization of FAP-targeting radioconjugates: assessing biophysical and pharmacokinetic equivalence of lutetium-177 and terbium-161
- 1Center for Radiopharmaceutical Sciences, PSI Center for Life Sciences, Villigen‑PSI, Switzerland
- 2Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
- 3Laboratory of Radiochemistry, PSI Center for Nuclear Engineering and Sciences, Villigen‑PSI, Switzerland
Abstract
Background: Radioconjugates targeting the fibroblast activation protein (FAP) have been successfully applied for nuclear imaging and are currently under investigation for radionuclide therapy. The aim of this study was to assess the biophysical properties of the 177Lu-labeled FAP inhibitors (FAPIs), FAPI-46, OncoFAP, FAP-2286 and 3BP-3940, and compare them with their 161Tb-labeled analogues. The respective 177Lu- and 161Tb-labeled FAPIs were evaluated using fibrosarcoma tumor cells in vitro and a xenograft mouse model to demonstrate pharmacokinetic equivalence.
Results: The radioconjugates (500 MBq/mL) remained ≥ 96% intact in saline over 24 h, irrespective of the employed radionuclide. The 161Tb-labeled conjugates showed similar logD values, uptake in HT1080-FAP cells and FAP-binding affinities (KD: 0.48–1.8 nM) as their 177Lu-based analogues. The in vitro binding to mouse and human blood plasma proteins was moderate with protein-bound fractions in the ranges of 39–56% and 31–61%, respectively, irrespective of the employed radionuclide. After 24 h incubation, the intact fraction of radioconjugates in mouse blood plasma was ≥ 87% while this was even ≥ 91% in human blood plasma without any differences among the same FAPIs labeled with either radionuclide. In HT1080-FAP/HT1080 tumor-bearing mice, the 161Tb-based FAP-targeting radioconjugates showed distribution profiles that corresponded well with their 177Lu-labeled analogues as demonstrated by dual-isotope SPECT/CT imaging and quantitative biodistribution data obtained at 4 h post-injection (p.i.). The radioconjugates were rapidly cleared from the blood, with < 1.5% IA/g retained at 1 h after administration. HT1080-FAP tumor accumulation reached its maximum with 8.8–20% IA/g at 1 h after injection of the radioconjugates, followed by gradual wash-out to 7.4–11% IA/g at 4 h p.i. and further to < 3% IA/g at 24 h p.i. An exception was the 3BP-3940 radioconjugate which still showed 6.4 ± 0.6% IA/g in the tumor xenograft at 24 h p.i..
Conclusion: The in vitro and in vivo properties of the 161Tb-labeled radioconjugates were similar to those of the 177Lu-labeled analogues. The accumulation of these FAP-targeting radioconjugates in HT1080-FAP tumors of mice was reasonably high, however, as the activity declined rapidly over time, repeated radioconjugate administration may be necessary to achieve therapeutic efficacy.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13550-026-01488-8.
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BibTeX
@article{mapanao2026preclinical,
title = {{Preclinical characterization of FAP-targeting radioconjugates: assessing biophysical and pharmacokinetic equivalence of lutetium-177 and terbium-161}},
author = {Ana Katrina Mapanao and Ecem Selin Adakli and Christian Vaccarin and Fan Sozzi-Guo and Anzhelika N. Moiseeva and Roger Schibli and Nicholas P. van der Meulen and Cristina Müller and Thera4Care Consortium},
journal = {EJNMMI Research},
year = {2026},
month = jul,
doi = {10.1186/s13550-026-01488-8},
url = {https://doi.org/10.1186/s13550-026-01488-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Preclinical characterization of FAP-targeting radioconjugates: assessing biophysical and pharmacokinetic equivalence of lutetium-177 and terbium-161
AU - Ana Katrina Mapanao
AU - Ecem Selin Adakli
AU - Christian Vaccarin
AU - Fan Sozzi-Guo
AU - Anzhelika N. Moiseeva
AU - Roger Schibli
AU - Nicholas P. van der Meulen
AU - Cristina Müller
AU - Thera4Care Consortium
PY - 2026
DA - 2026/07/29
JO - EJNMMI Research
DO - 10.1186/s13550-026-01488-8
UR - https://doi.org/10.1186/s13550-026-01488-8
AB - Background: Radioconjugates targeting the fibroblast activation protein (FAP) have been successfully applied for nuclear imaging and are currently under investigation for radionuclide therapy. The aim of this study was to assess the biophysical properties of the 177Lu-labeled FAP inhibitors (FAPIs), FAPI-46, OncoFAP, FAP-2286 and 3BP-3940, and compare them with their 161Tb-labeled analogues. The respective 177Lu- and 161Tb-labeled FAPIs were evaluated using fibrosarcoma tumor cells in vitro and a xenograft mouse model to demonstrate pharmacokinetic equivalence. Results: The radioconjugates (500 MBq/mL) remained ≥ 96% intact in saline over 24 h, irrespective of the employed radionuclide. The 161Tb-labeled conjugates showed similar logD values, uptake in HT1080-FAP cells and FAP-binding affinities (KD: 0.48–1.8 nM) as their 177Lu-based analogues. The in vitro binding to mouse and human blood plasma proteins was moderate with protein-bound fractions in the ranges of 39–56% and 31–61%, respectively, irrespective of the employed radionuclide. After 24 h incubation, the intact fraction of radioconjugates in mouse blood plasma was ≥ 87% while this was even ≥ 91% in human blood plasma without any differences among the same FAPIs labeled with either radionuclide. In HT1080-FAP/HT1080 tumor-bearing mice, the 161Tb-based FAP-targeting radioconjugates showed distribution profiles that corresponded well with their 177Lu-labeled analogues as demonstrated by dual-isotope SPECT/CT imaging and quantitative biodistribution data obtained at 4 h post-injection (p.i.). The radioconjugates were rapidly cleared from the blood, with < 1.5% IA/g retained at 1 h after administration. HT1080-FAP tumor accumulation reached its maximum with 8.8–20% IA/g at 1 h after injection of the radioconjugates, followed by gradual wash-out to 7.4–11% IA/g at 4 h p.i. and further to < 3% IA/g at 24 h p.i. An exception was the 3BP-3940 radioconjugate which still showed 6.4 ± 0.6% IA/g in the tumor xenograft at 24 h p.i.. Conclusion: The in vitro and in vivo properties of the 161Tb-labeled radioconjugates were similar to those of the 177Lu-labeled analogues. The accumulation of these FAP-targeting radioconjugates in HT1080-FAP tumors of mice was reasonably high, however, as the activity declined rapidly over time, repeated radioconjugate administration may be necessary to achieve therapeutic efficacy. Graphical abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13550-026-01488-8.
SN - 2191-219X
ER -