Development of novel ¹⁸F-labelled FAP-targeting tracers with improved pharmacokinetics: From preclinical optimization...

Fibroblast activation protein (FAP) has emerged as a promising theranostic target in malignancies. Although numerous radiolabelled FAP-targeting tracers have been clinically used for tumour imaging, the development of ¹⁸F-labelled tracers remains an unmet clinical need. This study synthesized two NOTA-conjugated FAP-2286 derivatives, modified with cysteic acid (C1) and/or tranexamic acid (C2) moieties. Both tracers exhibited >96 % radiochemical purity with molar activities >14.3 GBq/μmol. High stability and FAP specificity were demonstrated in vitro. [¹⁸F]AlF-C1-FAP-2286 demonstrated superior pharmacokinetics with higher tumour-to-kidney (2.19 ± 0.74 vs 1.54 ± 0.72) and tumour-to-liver ratios (18.32 ± 6.32 vs 13.74 ± 4.61) compared to [¹⁸F]AlF-FAP-2286. Clinical PET imaging with [¹⁸F]AlF-C1-FAP-2286 enabled the clear delineation of the recurrent lesion at the surgical site and metastatic tumours, demonstrating favourable imaging characteristics, high tumour uptake, and contrast quality. Overall, [¹⁸F]AlF-C1-FAP-2286 exhibited optimized pharmacokinetic properties and enhanced tumour contrast. The above findings support its potential as a promising ¹⁸F-labelled FAP-targeting tracer, warranting its further exploration in clinical applications. TRIAL REGISTRATION: ChiCTR2400090727. Registered October 12, 2024.