Scholarlink

Background <p>Enantiomeric composition may impact binding and potentially performance of a drug product but is not routinely tested and minimum acceptance criteria are not always established. Some batches of the precursors FAPI-46 and FAPI-74 used clinically contain a mixture of (<i>S</i>)- and (<i>R</i>)-enantiomers. This study investigates the in vitro pharmacodynamic characteristics of different enantiomeric compositions of FAP-targeting radioligands FAPI-46 and FAPI-74 and in vivo pharmacokinetics of FAPI-46 in naïve mice.</p> Results <p>(<i>S</i>)-, (<i>R</i>)-, and (<i>S/R</i>)-enantiomers of radiolabeled FAPI-46 and FAPI-74 were evaluated for stability in human serum, binding affinity, internalization, retention, and selectivity using HT1080-hFAP cells and HEK293-hCD26 cells. All enantiomeric compositions showed high stability in human serum with minimal serum protein adhesion. (<i>S</i>)- and (<i>S/R</i>)-enantiomers exhibited comparable binding, internalization, and retention characteristics. High selectivity for FAP over CD26/DPP4 was maintained. (<i>R</i>)-enantiomers showed no specific binding to FAP. Additionally, the same enantiomers of <sup>68</sup>Ga-labeled FAPI-46 were evaluated by dynamic positron emission tomography (PET) imaging (0–60&#xa0;min post-injection) and ex vivo organ biodistribution in naïve BALB/c mice (10, 30, and 60&#xa0;min, or 4&#xa0;h post-injection) to compare their pharmacokinetic profiles. PET imaging revealed nearly identical time-activity curves for the enantiomers of [<sup>68</sup>Ga] Ga-FAPI-46, indicating similar whole-body distribution within 1&#xa0;h post-injection, with rapid renal clearance and minimal muscle uptake. Ex vivo organ biodistribution confirmed comparable pharmacokinetic profiles between enantiomers, with no significant differences in tissue distribution.</p> Conclusion <p>These findings provide important validation that current clinical (<i>S/R</i>)-mixtures of FAPI-46/-74 exhibit pharmacokinetic and pharmacodynamic behavior comparable to pure (<i>S</i>)-enantiomers, supporting regulatory confidence and cross-trial reproducibility in the global FAPI-46/-74 imaging landscape.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Ensuring enantiomeric consistency in FAPI radiopharmaceuticals: comparative analysis of (S)- and (S/R)-FAPI-46/-74 confirms pharmacological equivalence

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月28日

查看全文
  • Magdalena Staniszewska,
  • Ralph Hübner,
  • Camilla Locatelli,
  • Douglas Howard,
  • Matilde Forni,
  • Francis Man,
  • Bent Wilhelm Schoultz,
  • Syed Nuruddin,
  • Ingrid Sofie Norberg-Schulz Hagen,
  • Sherly Mosessian,
  • Ken Herrmann,
  • Valeska von Kiedrowski,
  • Katharina Lückerath

摘要

Background

Enantiomeric composition may impact binding and potentially performance of a drug product but is not routinely tested and minimum acceptance criteria are not always established. Some batches of the precursors FAPI-46 and FAPI-74 used clinically contain a mixture of (S)- and (R)-enantiomers. This study investigates the in vitro pharmacodynamic characteristics of different enantiomeric compositions of FAP-targeting radioligands FAPI-46 and FAPI-74 and in vivo pharmacokinetics of FAPI-46 in naïve mice.

Results

(S)-, (R)-, and (S/R)-enantiomers of radiolabeled FAPI-46 and FAPI-74 were evaluated for stability in human serum, binding affinity, internalization, retention, and selectivity using HT1080-hFAP cells and HEK293-hCD26 cells. All enantiomeric compositions showed high stability in human serum with minimal serum protein adhesion. (S)- and (S/R)-enantiomers exhibited comparable binding, internalization, and retention characteristics. High selectivity for FAP over CD26/DPP4 was maintained. (R)-enantiomers showed no specific binding to FAP. Additionally, the same enantiomers of 68Ga-labeled FAPI-46 were evaluated by dynamic positron emission tomography (PET) imaging (0–60 min post-injection) and ex vivo organ biodistribution in naïve BALB/c mice (10, 30, and 60 min, or 4 h post-injection) to compare their pharmacokinetic profiles. PET imaging revealed nearly identical time-activity curves for the enantiomers of [68Ga] Ga-FAPI-46, indicating similar whole-body distribution within 1 h post-injection, with rapid renal clearance and minimal muscle uptake. Ex vivo organ biodistribution confirmed comparable pharmacokinetic profiles between enantiomers, with no significant differences in tissue distribution.

Conclusion

These findings provide important validation that current clinical (S/R)-mixtures of FAPI-46/-74 exhibit pharmacokinetic and pharmacodynamic behavior comparable to pure (S)-enantiomers, supporting regulatory confidence and cross-trial reproducibility in the global FAPI-46/-74 imaging landscape.