Development of Cysteic Acid-Modified FAP Radioligands for Enhanced Renal Clearance: From Preclinical Optimization to First-in-Human Study

Fibroblast
activation protein (FAP)-targeting radioligands hold
promise for cancer theranostics. Cyclic peptide-based DOTA-FAP-2286
radioligands have demonstrated high kidney uptake and retention, raising
concerns regarding potential nephrotoxicity. Hence, we aimed to design
three cysteic acid-modified FAP-targeting cyclic peptide ligands (DOTA-C1/C2/C3-FAP-2286)
for reducing renal retention and optimizing pharmacokinetic properties.
Competitive binding assays revealed maintained potent affinity for
FAP (IC50 < 150 nM). Following systematic preclinical
evaluation, [68Ga]Ga-C1-FAP-2286 exhibited optimal biodistribution
characteristics, reducing renal uptake by 50% (2.12 ± 0.19% ID/g, P < 0.05), while maintaining tumor accumulation (7.08
± 0.35 vs 6.26 ± 0.82% ID/g for [68Ga]Ga-FAP-2286),
yielding a significantly improved tumor-to-kidney ratio (3.34 ±
0.15 vs 1.59 ± 0.53% ID/g). First-in-human PET/CT imaging in
a metastatic gastric cancer patient demonstrated superior diagnostic
performance compared to [18F]FDG, with intense uptake in
primary lesions (SUVmax = 3.0), including [18F]FDG-negative and metastatic lesions. Thus, [68Ga]Ga-C1-FAP-2286
is a clinically translatable tracer for imaging FAP-expressing malignancies.