Zang_2022_Theranostics_12_7180

To enhance tumor uptake and retention, we designed and developed bi-specific heterodimeric radiotracers targeting both FAP and alphavbeta3, [(68)Ga]Ga-FAPI-RGD. The present study aimed to evaluate the specificity, pharmacokinetics, and dosimetry of [(68)Ga]Ga-FAPI-RGD by preclinical and preliminary clinical studies. Methods: FAPI-RGD was designed and synthesized with the quinoline-based FAPI-02 and the cyclic RGDfK peptide. Preclinical pharmacokinetics were determined in Panc02 xenograft model using microPET and biodistribution experiments. The safety and effective dosimetry of [(68)Ga]Ga-FAPI-RGD was evaluated in 6 cancer patients, and compared with 2-[(18)F]FDG imaging. Results: The [(68)Ga]Ga-FAPI-RGD had good stability in saline for at least 4 h, and showed favorable binding affinity and specificity in vitro and in vivo. Compared to [(68)Ga]Ga-FAPI-02 and [(68)Ga]Ga-RGDfK, the tumor uptake and retention of [(68)Ga]Ga-FAPI-RGD were very much enhanced than its monomeric counterparts at all the time points examined by microPET imaging. A total of 6 patients with various malignant tumors were prospectively enrolled. The effective dose of [(68)Ga]Ga-FAPI-RGD was 1.94E-02 mSv/MBq. The biodistribution of [(68)Ga]Ga-FAPI-RGD from 0 to 2 h after injection demonstrated rapid and high tumor uptake, prolonged tumor retention, and high tumor-to-background ratios (TBRs) which further increased over time. No significant difference in mean SUVmax of [(68)Ga]Ga-FAPI-RGD and 2-[(18)F]FDG was present in primary tumors (8.9+/-3.2 vs. 10.3 +/- 6.9; p = 0.459). Conclusion: The dual targeting PET tracer [(68)Ga]Ga-FAPI-RGD showed significantly improved tumor uptake and retention, as well as cleaner background over (68)Ga-labeled FAPI and RGD monospecific tracers. The first-in-human biodistribution study showed high TBRs over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.