Comparative study of [ ¹⁸ F]AlF-NOTA-FAPI-RGD and [ ¹⁸ F]FDG/[ ¹⁸ F]AlF-NOTA-FAPI-04 PET/CT in renal cell carcinoma

Renal cell carcinoma (RCC) is a significant global health concern, and the early diagnosis and accurate staging of clear cell renal cell carcinoma (ccRCC) remain major challenges. [¹⁸F]FDG PET/CT is not ideal for diagnosing ccRCC due to the low glucose metabolism potential of cancer cells. Both fibroblast activation protein (FAP) and the angiogenic integrin α_vβ₃ receptor are closely linked to the pathogenesis and progression of ccRCC. The aim of this study is to evaluate a novel radiopharmaceutical [¹⁸F]AlF-NOTA-FAPI-RGD (denoted as [¹⁸F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both FAP and integrin α_vβ₃, and to compare the diagnostic value of [¹⁸F]AlF-LNC1007 with [¹⁸F]FDG and [¹⁸F]AlF-NOTA-FAPI-04 PET/CT in RCC. <b>Materials and Methods</b>: A total of 35 participants, highly suspected to have RCC, were recruited. [¹⁸F]AlF-LNC1007 and [¹⁸F]AlF-NOTA-FAPI-04/[¹⁸F]FDG scans were performed at least one day apart, and both were completed within one week. The Wilcoxon signed-rank test or paired t-test was used to assess differences in tumor uptake and TBR (tumor-to-background ratio) between [¹⁸F]AlF-LNC1007 and the other two imaging agents. The Spearman correlation coefficient was used to evaluate the correlation between tumor uptake and the expression of FAP and α_vβ_3. <b>Results:</b> The detection rate, sensitivity, and positive predictive value (PPV) of [¹⁸F]AlF-LNC1007 for RCC primary lesions were significantly higher than those of [¹⁸F]FDG, at 91% vs. 76%, 100% vs. 85%, and 91% vs. 87%, respectively. Obvious advantages were also seen in metastatic lesions at 94% vs. 34%, 94% vs. 29%, and 100% vs. 100%. Compared to [¹⁸F]AlF-NOTA-FAPI-04, the corresponding detection rate, sensitivity, and PPV were 98% vs. 90%, 100% vs. 92%, and 98% vs. 98% for primary lesions, and 89% vs. 78%, 89% vs. 93%, and 100% vs. 82% for metastatic lesions. The uptake and TBR of [¹⁸F]AlF-LNC1007 in both primary and metastatic lesions were significantly higher than those of [¹⁸F]FDG (all P < 0.001). The uptake of [¹⁸F]AlF-LNC1007 showed a moderate to high positive correlation with the expression levels of α_vβ₃ and the combined expression of FAP and α_vβ₃ (r = 0.756, P = 0.0003; r = 0.678, P = 0.0002) and a low positive correlation with FAP expression alone (r = 0.389, P = 0.014). The uptake of [¹⁸F]AlF-NOTA-FAPI-04 showed a low to moderate positive correlation with FAP expression and the combined expression of FAP and α_vβ₃ (r = 0.570, P = 0.0002; r = 0.408, P = 0.010), and no correlation with α_vβ₃ expression alone (r = 0.262, P = 0.107). <b>Conclusion:</b> [¹⁸F]AlF-LNC1007 demonstrated significantly higher diagnostic efficacies and uptake in primary and metastatic renal cell carcinoma (RCC) compared to FDG PET/CT. Additionally, [¹⁸F]AlF-LNC1007 exhibited higher diagnostic efficacies and uptake in primary RCC than [¹⁸F]AlF-NOTA-FAPI-04 PET/CT. While these findings suggest potential diagnostic advantages, further studies are needed to fully evaluate its diagnostic efficacy compared to the standard of treatment.