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Background <p>Understanding the interaction between radiopharmaceuticals and human serum albumin (HSA) is essential for optimizing pharmacokinetics and therapeutic efficacy. This study evaluated the binding properties of <sup>nat</sup>Lu-FAPi-46 and <sup>nat</sup>Lu-FAP-2286 to HSA using theoretical and experimental techniques.</p> Results <p>Docking results revealed moderate affinities for <sup>nat</sup>Lu-FAPi-46 (− 9.7&#xa0;kcal/mol) and <sup>nat</sup>Lu-FAP-2286 (− 7.8&#xa0;kcal/mol), correlating with their lower blood retention (0.43% and 0.03% I.A./g at 4&#xa0;h p.i.). Comparative docking of albumin-binding derivatives of FAPi-46 showed stronger binding, consistent with increased blood retention. Experimental analyses (fluorescence quenching, circular dichroism, and cyclic voltammetry) confirmed complex formation and conformational changes in HSA, validating the computational findings.</p> Conclusions <p>Together, the computational and experimental results underscore the importance of albumin-binding in shaping the pharmacokinetic properties of FAP-targeted radiopharmaceuticals. Strategic optimization of albumin-binding linkers may improve stability, circulation time, and overall therapeutic performance in next-generation FAP-based agents.</p> Graphical abstract <p></p>

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Feasibility of albumin binding modulation in FAP-targeting radiopharmaceuticals: insights from molecular docking and experimental analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Sudabeh Shokrollahi,
  • Ahmad Amiri

摘要

Background

Understanding the interaction between radiopharmaceuticals and human serum albumin (HSA) is essential for optimizing pharmacokinetics and therapeutic efficacy. This study evaluated the binding properties of natLu-FAPi-46 and natLu-FAP-2286 to HSA using theoretical and experimental techniques.

Results

Docking results revealed moderate affinities for natLu-FAPi-46 (− 9.7 kcal/mol) and natLu-FAP-2286 (− 7.8 kcal/mol), correlating with their lower blood retention (0.43% and 0.03% I.A./g at 4 h p.i.). Comparative docking of albumin-binding derivatives of FAPi-46 showed stronger binding, consistent with increased blood retention. Experimental analyses (fluorescence quenching, circular dichroism, and cyclic voltammetry) confirmed complex formation and conformational changes in HSA, validating the computational findings.

Conclusions

Together, the computational and experimental results underscore the importance of albumin-binding in shaping the pharmacokinetic properties of FAP-targeted radiopharmaceuticals. Strategic optimization of albumin-binding linkers may improve stability, circulation time, and overall therapeutic performance in next-generation FAP-based agents.

Graphical abstract