Exploring Covalent C-18F Bonding Strategies in the Design of FAP-Targeted Radiotracers

  • J Med Chem. 2026 Feb 12;69(3):2938-2953. doi: 10.1021/acs.jmedchem.5c02795.
Xi Gao  1  2 ,  Yimin Chen  1 ,  Zehua Li  1  2 ,  Xiaojun Zhang  3 ,  Yuying Li  1 ,  Hualong Fu  1 ,  Jinming Zhang  3 ,  Mengchao Cui  1  2
Affiliations
  • 1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China.
  • 2. Center for Advanced Materials Research, Beijing Normal University at Zhuhai, Zhuhai 519087, China.
  • 3. Department of Nuclear Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China.
PMID: 41591275 DOI: 10.1021/acs.jmedchem.5c02795
Abstract

Quinoline-based fibroblast activation protein inhibitors (FAPIs) have shown great potential for tumor diagnosis and therapy. To address the instability and limited applicability of [18F]AlF coordination chemistry, we designed nine fluorinated FAPIs incorporating the UAMC-1110 pharmacophore, enabling 18F-labeling through the formation of stable C-18F covalent bonds. All compounds exhibited high fibroblast activation protein affinities (Ki = 0.092-1.22 nM). Among them, [18F]54, synthesized via copper-catalyzed click chemistry, demonstrated excellent in vivo performance, achieving a high tumor-to-muscle ratio (TMR = 11 ± 3.1) at 60 min postinjection (p.i.) and sustained tumor retention, with only a 19% decrease from 30 to 120 min p.i. These findings support [18F]54 as a promising candidate for FAP-targeted imaging and highlight C-18F bond formation as a compelling alternative to [18F]AlF methods for developing next-generation FAP-targeted positron emission tomography tracers.

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