Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging

Purpose In this study, a novel aluminium-[F-18]fluoride ((AlF)-F-18)-labelled 1,4,7-triazacyclononane-N,N ',N ''-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named (AlF)-F-18-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of (AlF)-F-18-NOTA-FAPI was further validated in both preclinical and clinical translational studies. Methods The radiolabelling procedure of (AlF)-F-18-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the (AlF)-F-18-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the (AlF)-F-18-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the (AlF)-F-18-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients. Results The radiolabelling yield of (AlF)-F-18-NOTA-FAPI was 33.8 +/- 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. The whole body effective dose of (AlF)-F-18-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes (Ga-68-FAPI-04, Ga-68-FAPI-46 and Ga-68-FAPI-74). In U87MG tumour-bearing mice, (AlF)-F-18-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, (AlF)-F-18-NOTA-FAPI showed a lower SUVmean than 2-[F-18]-fluoro-2-deoxy-D-glucose (2-[F-18]FDG) in most organs, especially in the liver (1.1 +/- 0.2 vs. 2.0 +/- 0.9), brain (0.1 +/- 0.0 vs. 5.9 +/- 1.3), and bone marrow (0.9 +/- 0.1 vs. 1.7 +/- 0.4). Meanwhile, (AlF)-F-18-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[F-18]FDG in the PET/CT imaging of several patients. Conclusion The (AlF)-F-18-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients.

Automated summary

A novel (AlF)-F-18-labelled NOTA-FAPI probe was developed for targeted tumour imaging, showing excellent detection efficacy in both preclinical and clinical translational studies.