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bioRxiv · 10.64898/2026.10.11.758356

Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals

Zhang, C.·Gerhards, J.·Scharbert, L.·Cardinale, J.·Giesel, F.·Strodel, B.
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Abstract

Radioligands targeting fibroblast activation protein alpha (FAP) are promising tools for cancer diagnosis and therapy. However, the molecular binding mode of clinically established UAMC-1110-derived ligands such as FAPI-46 remains insufficiently characterized. To simplify synthesis while preserving key binding properties, we designed two novel derivatives - FAP-DD-101 (short aminoalkyl linker) and FAP-DD-102 (extended aminohexanoic acid spacer) - and evaluated them alongside FAPI-46 using molecular docking and all-atom molecular dynamics (MD) simulations. Across all derivatives, we identified a highly stable, energetically favorable charge-anchored binding mode, in which the 2-cyano-4,4-difluoropyrrolidine head anchors in a negatively charged subregion formed by Glu202, Glu203, and Glu204, mimicking the binding architecture observed in the FAP-linagliptin complex. MD trajectories confirmed that FAPI-46 and FAP-DD-101 maintain exceptional stability in this pose, with several non-anchored FAPI-46 trajectories spontaneously evolving toward engagement with this electrostatic subregion. For FAP-DD-102, linker elongation slightly reduced pose robustness, yet initial charge-anchored states still yielded superior average binding energies and vector stability compared to non-anchored poses. Overall, these findings elucidate the key structural determinants of FAP recognition, establishing a rational framework for designing synthetically accessible FAPI radiotracers with retained binding stability.

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Zhang, C., Gerhards, J., Scharbert, L., Cardinale, J., Giesel, F., Strodel, B.. 2026-10-12. Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals. https://doi.org/10.64898/2026.10.11.758356

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