Rationale: Early discovery, accurate diagnosis, and staging of lung cancer is essential for patients to receive appropriate treatment. PET/CT has become increasingly recognized as a valuable imaging modality for these patients, but there remains room for improvement in PET tracers. We aimed to evaluate the feasibility of using [⁶⁸Ga]Ga-FAPI-RGD, a dual-targeting heterodimeric PET tracer that recognizes both fibroblast activation protein (FAP) and integrin α_vβ₃ for detecting lung neoplasms, by comparing it with [¹⁸F]FDG and single-targeting tracers [⁶⁸Ga]Ga-RGD and [⁶⁸Ga]Ga-FAPI. Methods: This was a pilot exploratory study of patients with suspected lung malignancies. All 51 participants underwent [⁶⁸Ga]Ga-FAPI-RGD PET/CT, of which: 9 participants received dynamic scans, 44 participants also underwent [¹⁸F]FDG PET/CT scan within two weeks, 9 participants underwent [⁶⁸Ga]Ga-FAPI PET/CT scan and 10 participants underwent [⁶⁸Ga]Ga-RGD PET/CT scan. The final diagnosis was made based on histopathological analyses and clinical follow-up reports. Results: Among those who underwent dynamic scans, the uptake of pulmonary lesions increased over time. The optimal timepoint for a PET/CT scan was identified to be 2 h post-injection. [⁶⁸Ga]Ga-FAPI-RGD had a higher detection rate of primary lesions than [¹⁸F]FDG (91.4% vs. 77.1%, p < 0.05), higher tumor uptake (SUVmax, 6.9 ± 5.3 vs. 5.3 ± 5.4, p < 0.001) and higher tumor-to-background ratio (10.0 ± 8.4 vs. 9.0 ± 9.1, p < 0.05), demonstrated better accuracy in mediastinal lymph node evaluation (99.7% vs. 90.9%, p < 0.001), and identified more metastases (254 vs. 220). There was also a significant difference between the uptake of [⁶⁸Ga]Ga-FAPI-RGD and [⁶⁸Ga]Ga-RGD of primary lesions (SUVmax, 5.8 ± 4.4 vs. 2.3 ± 1.3, p < 0.001). Conclusion: In our small scale cohort study, [⁶⁸Ga]Ga-FAPI-RGD PET/CT gave a higher primary tumor detection rate, higher tracer uptake, and improved detection of metastases compared with [¹⁸F]FDG PET/CT, and [⁶⁸Ga]Ga-FAPI-RGD also had advantages over [⁶⁸Ga]Ga-RGD and was non-inferior to [⁶⁸Ga]Ga-FAPI. We thus provide proof-of-concept for using [⁶⁸Ga]Ga-FAPI-RGD PET/CT for diagnosing lung cancer. With the stated advantages, the dual-targeting FAPI-RGD should also be explored for therapeutic use in future studies.

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