Coumarin Conjugation as an Albumin-Binding Strategy to Modulate the Pharmacokinetics of FAPI Radiotracers

Fibroblast activation protein (FAP) was a prominent target overexpressed in the stroma of various tumors. However, most current FAP-targeted radiotracers suffer from rapid systemic clearance and limited tumor retention, which limits their imaging contrast and therapeutic efficacy. In this study, we exploited diethylamino coumarin as a novel small-molecule albumin binder to optimize the pharmacokinetic profile of FAP-targeted radiopharmaceuticals. Two probes with different linker lengths, [⁶⁸Ga]-Ga-PEG2-COU and [⁶⁸Ga]-Ga-PEG6-COU, were synthesized with high purity (>95%) and stability. The PEG2 variant demonstrated superior cellular uptake (6.72 ± 1.94 IA%/10⁶ cells at 120 min) compared to PEG6 (4.73 ± 0.51 IA%/10⁶ cells). It achieved high tumor accumulation with a tumor-to-heart (T/H) ratio of 14.64 ± 7.24 at 60 min. Crucially, unlike [⁶⁸Ga]-Ga-FAPI-04, whose tumor-to-muscle ratio declined from 4.18 ± 0.14 to 2.44 ± 0.15 over 120 min, the PEG2 probe's T/M ratio continuously increased from 3.65 ± 0.18 at 30 min to 5.17 ± 0.54 at 120 min. Collectively, these findings highlight the potential of the coumarin-based albumin-binding platform to enhance the pharmacokinetics of FAP-targeted radiopharmaceuticals.