August 13, 2025

Synthesis and Preclinical Evaluation of Druglike

Key Points

Main finding shows that druglike FAP inhibitors [18F]5a and [18F]5b enhance tumor retention compared to previous radioligands.
Key evidence indicates that [18F]5a and [18F]5b exhibit significantly higher tumor retention at 6 hours post-injection than [18F]AlF-NOTA-FAPI-74.
Approach involved the synthesis of covalently labeled FAP inhibitors and evaluation of their pharmacokinetics in both in vitro and in vivo settings.
Significance lies in providing a new design strategy for improved radiotheranostic ligands aimed at FAP-positive tumors.

Abstract

Fibroblast activation protein (FAP) is upregulated in cancer and fibrosis, making it an ideal target for imaging and therapy. Most FAP radioligands are large, highly polar, chelator-based molecules that suffer from limited tissue penetration and rapid tumor washout. In this study, we developed two covalently 18F-labeled, druglike FAP inhibitors, 18F5a and 18F5b, featuring quaternary ammonium moieties linked via PEG chains to enhance tumor retention while maintaining high selectivity and favorable pharmacokinetics. Both radiotracers showed high affinity and specific uptake in vitro and in vivo. Compared to the clinically used 18FAlF-NOTA-FAPI-74, 18F5a and 18F5b, exhibited significantly improved tumor retention at 6 h p.i. (18F5a: 4.48 ± 0.34%IA/g; 18F5b: 6.70 ± 0.22%IA/g and 18FAlF-NOTA-FAPI-74:0.54 ± 0.08%IA/g). These findings highlight the importance of polarity tuning and the utility of quaternary ammonium groups for obtaining sustained tumor retention. They offer a valuable design strategy for novel radiotheranostic ligands that contain covalently bound radionuclides for imaging and treatment of FAP-positive tumors.

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