[⁶⁸Ga]Ga-NYM052: Design, synthesis, preclinical characterization, and first-in-human evaluation of a novel radiotracer targeting fibroblast activation protein

Fibroblast activation protein (FAP) is abundantly expressed in cancer-associated fibroblasts across most epithelial tumors, while exhibiting minimal expression in normal tissues, making it a promising target for molecular imaging. We designed and synthesized [⁶⁸Ga]Ga-NYM052, a novel FAP-targeted PET tracer, to evaluate FAP expression in malignant tumors. In vitro studies demonstrated high affinity (IC₅₀ = 5.05 nM), rapid uptake, and efficient internalization in FAP-positive A549-hFAP cells, whereas uptake in FAP-negative A549 cells was minimal. In vivo PET/CT imaging and biodistribution confirmed significant accumulation of [⁶⁸Ga]Ga-NYM052 in A549-hFAP and U87MG xenografts, yielding favorable tumor-to-background ratios and showing clear blockage by excess unlabeled ligand (p < 0.05). The tracer showed excellent stability and rapid clearance from non-target tissues, with kidneys as the primary excretion pathway. In a first-in-human study (n = 7), [⁶⁸Ga]Ga-NYM052 demonstrated favorable biodistribution, rapid renal clearance, and sustained tumor retention. Notably, head-to-head imaging revealed superior lesion detectability compared to ¹ ⁸F-FDG in bone metastases. These results establish [⁶⁸Ga]Ga-NYM052 as a promising FAP-targeted tracer with strong potential for clinical translation and theranostic applications.