FGF2-Based Cyclic Peptide PET Tracer for Noninvasive Detection of FGFR1 Expression in Non-Small Cell Lung Cancer

FGFR1 overexpression is strongly correlated with tumorigenesis, malignant progression, and poor clinical outcomes of nonsmall cell lung cancer (NSCLC). The development of PET radiotracers specifically targeting FGFR1 holds significant clinical value for guiding FGFR1-targeted therapy, evaluating treatment efficacy, and monitoring drug resistance. In this study, we used computational simulation approaches to develop linear peptide RY9 along with cyclic peptides cRY9 and cRY9M, derived from FGF2, a particular ligand of FGFR1, and designed FGFR1-targeting radiotracers [⁶⁸Ga]Ga-NOTA-RY9, [⁶⁸Ga]Ga-NOTA-cRY9 and [⁶⁸Ga]Ga-NOTA-cRY9M for detecting the FGFR1 expression. In comparison to [⁶⁸Ga]Ga-NOTA-RY9 and [⁶⁸Ga]Ga-NOTA-cRY9, [⁶⁸Ga]Ga-NOTA-cRY9M demonstrated superior FGFR1-binding affinity, enhanced in vivo stability, and a significantly improved tumor-to-background ratio (TBR). Notably, PET imaging revealed that [⁶⁸Ga]Ga-NOTA-cRY9M exhibited significant and specific tumor uptake in FGFR1-positive NSCLC cell-derived xenograft (CDX) models and patient-derived xenograft (PDX) models. These results demonstrate that the cyclic peptide-based radiotracer [⁶⁸Ga]Ga-NOTA-cRY9M serves as a potential diagnostic agent for FGFR1-expressing tumors.