Ligand-Based Computational Design and Preclinical Evaluation of a Novel Cyclic Peptide Radiotracer for FGFR1-Targeted PET Imaging in Uveal Melanoma

Uveal melanoma (UM), a rare yet aggressive ocular malignancy in adults, highlights the critical need for targeted therapies to improve clinical outcomes. Elevated FGFR1 expression in UM correlates with aggressive disease progression and poor survival outcomes, underscoring its therapeutic value. This study reports the development of [⁶⁸Ga]Ga-DOTA-cHW8, an FGFR1-specific PET tracer derived from ligand-based computational design of cyclic peptide cHW8, enabling noninvasive quantification of FGFR1 expression in UM xenograft models. Bioinformatics analysis of clinical databases and immunoblotting of clinical specimens confirmed FGFR1 as an important biomarker of UM. The radiotracer [⁶⁸Ga]Ga-DOTA-cHW8 demonstrated superior pharmacokinetics with rapid tumor accumulation, high binding specificity, and rapid renal clearance. <i>In vitro</i> specificity assays demonstrated targeted accumulation of [⁶⁸Ga]Ga-DOTA-cHW8 in FGFR1-positive 92.1 cells and UM PDC cells. <i>In vivo</i> microPET imaging validated tumor-specific accumulation of [⁶⁸Ga]Ga-DOTA-cHW8 in FGFR1-positive UM xenografts (including PDX models), which was blocked by an unlabeled peptide. Furthermore, [⁶⁸Ga]Ga-DOTA-cHW8 validated FGFR1 dynamic modulation during erdafitinib treatment in CDX and PDX models, establishing its efficacy for noninvasive UM treatment response assessment. This study reports a cyclic peptide-based radiotracer, [⁶⁸Ga]Ga-DOTA-cHW8, for FGFR1 PET imaging in UM. Through rational design and preclinical validation in UM models, we establish its high specificity, favorable pharmacokinetics properties, and capability to monitor FGFR1 dynamics during targeted therapy.