eFAP-51, a novel FAPI dimer with enhanced tumor uptake and retention for theranostic applications.
4 affiliations
- 1Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands.
- 2Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
- 3Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands. [email protected].
- 4Erasmus MC Cancer Institute, Rotterdam, The Netherlands. [email protected].
Abstract
Background
Overexpression of fibroblast activation protein (FAP) in cancer-associated fibroblasts enables a highly selective targeting strategy using FAP inhibitors. However, radiolabeled small-molecule FAP inhibitors (FAPIs) show limited tumor retention, restricting therapeutic applications. Multimerization represents a promising strategy to enhance tumor uptake and retention through polyvalent binding. Here, we report the rational design and evaluation of dimeric FAP-targeted radiopharmaceuticals for theranostic applications.Results
Based on the (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) scaffold, a series of monomeric FAPIs were assembled into dimeric radioligands using three distinct tripod-based platforms and equipped with a DOTA-GA chelator for efficient radiolabeling with indium-111 and lutetium-177; systematic in vitro and in vivo evaluation of binding affinity, stability, cellular uptake, and tumor targeting identified eFAP-51 and eFAP-52 as lead candidates, both showing high radiochemical yield and purity, favorable stability, and sub-nanomolar affinity for FAP with strong selectivity over DPP4. Further studies demonstrated superior tumor targeting and pharmacokinetics for eFAP-51 compared with the clinical reference FAPI-46, with [¹¹¹In]In-eFAP-51 exhibiting more than 4-fold higher tumor uptake at 48 h post-injection (3.2 ± 0.5 vs. 0.71 ± 0.1%ID/g) and prolonged retention. eFAP-51 was subsequently radiolabeled with lutetium-177 to yield a stable therapeutic candidate, and dose-dependent studies revealed that intermediate molar doses (0.3-0.6 nmol) provided an optimal balance between tumor uptake and tumor-to-background contrast.Conclusions
The FAPI dimer eFAP-51 showed favorable tumor targeting and pharmacokinetics, supporting its potential for clinical translation in theranostic oncology.
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BibTeX
@article{li2026efap51,
title = {{eFAP-51, a novel FAPI dimer with enhanced tumor uptake and retention for theranostic applications.}},
author = {Le Li and Hanyue Ma and Amber Piet and Corrina de Ridder and Debra Stuurman and Priciana Paraïso and Yann Seimbille},
journal = {EJNMMI radiopharmacy and chemistry},
year = {2026},
month = jul,
doi = {10.1186/s41181-026-00481-9},
url = {https://europepmc.org/article/MED/42897329},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - eFAP-51, a novel FAPI dimer with enhanced tumor uptake and retention for theranostic applications.
AU - Le Li
AU - Hanyue Ma
AU - Amber Piet
AU - Corrina de Ridder
AU - Debra Stuurman
AU - Priciana Paraïso
AU - Yann Seimbille
PY - 2026
DA - 2026/07/01
JO - EJNMMI radiopharmacy and chemistry
DO - 10.1186/s41181-026-00481-9
UR - https://europepmc.org/article/MED/42897329
AB - Background Overexpression of fibroblast activation protein (FAP) in cancer-associated fibroblasts enables a highly selective targeting strategy using FAP inhibitors. However, radiolabeled small-molecule FAP inhibitors (FAPIs) show limited tumor retention, restricting therapeutic applications. Multimerization represents a promising strategy to enhance tumor uptake and retention through polyvalent binding. Here, we report the rational design and evaluation of dimeric FAP-targeted radiopharmaceuticals for theranostic applications.Results Based on the (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) scaffold, a series of monomeric FAPIs were assembled into dimeric radioligands using three distinct tripod-based platforms and equipped with a DOTA-GA chelator for efficient radiolabeling with indium-111 and lutetium-177; systematic in vitro and in vivo evaluation of binding affinity, stability, cellular uptake, and tumor targeting identified eFAP-51 and eFAP-52 as lead candidates, both showing high radiochemical yield and purity, favorable stability, and sub-nanomolar affinity for FAP with strong selectivity over DPP4. Further studies demonstrated superior tumor targeting and pharmacokinetics for eFAP-51 compared with the clinical reference FAPI-46, with [¹¹¹In]In-eFAP-51 exhibiting more than 4-fold higher tumor uptake at 48 h post-injection (3.2 ± 0.5 vs. 0.71 ± 0.1%ID/g) and prolonged retention. eFAP-51 was subsequently radiolabeled with lutetium-177 to yield a stable therapeutic candidate, and dose-dependent studies revealed that intermediate molar doses (0.3-0.6 nmol) provided an optimal balance between tumor uptake and tumor-to-background contrast.Conclusions The FAPI dimer eFAP-51 showed favorable tumor targeting and pharmacokinetics, supporting its potential for clinical translation in theranostic oncology.
SN - 2365-421X
ER -