Synthesis, preclinical evaluation and radiation dosimetry of a dual targeting PET tracer [Ga]Ga-FAPI-RGD.

To enhance tumor uptake and retention, we designed and developed bi-specific heterodimeric radiotracers targeting both FAP and αvβ3, [Ga]Ga-FAPI-RGD. The present study aimed to evaluate the specificity, pharmacokinetics, and dosimetry of [Ga]Ga-FAPI-RGD by preclinical and preliminary clinical studies. 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 [Ga]Ga-FAPI-RGD was evaluated in 6 cancer patients, and compared with 2-[F]FDG imaging. The [Ga]Ga-FAPI-RGD had good stability in saline for at least 4 h, and showed favorable binding affinity and specificity and . Compared to [Ga]Ga-FAPI-02 and [Ga]Ga-RGDfK, the tumor uptake and retention of [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 [Ga]Ga-FAPI-RGD was 1.94E-02 mSv/MBq. The biodistribution of [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 [Ga]Ga-FAPI-RGD and 2-[F]FDG was present in primary tumors (8.9±3.2 10.3 ± 6.9; p = 0.459). The dual targeting PET tracer [Ga]Ga-FAPI-RGD showed significantly improved tumor uptake and retention, as well as cleaner background over 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.