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

In this study, a novel aluminium-[¹⁸F]fluoride (Al¹⁸F)-labelled 1,4,7‑triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named Al¹⁸F-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 Al¹⁸F-NOTA-FAPI was further validated in both preclinical and clinical translational studies.

The radiolabelling procedure of Al¹⁸F-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 Al¹⁸F-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al¹⁸F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al¹⁸F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients.

The radiolabelling yield of Al¹⁸F-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 Al¹⁸F-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes (⁶⁸Ga-FAPI-04, ⁶⁸Ga-FAPI-46 and ⁶⁸Ga-FAPI-74). In U87MG tumour-bearing mice, Al¹⁸F-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, Al¹⁸F-NOTA-FAPI showed a lower SUVmean than 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (2-[¹⁸F]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, Al¹⁸F-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[¹⁸F]FDG in the PET/CT imaging of several patients.

The Al¹⁸F-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.

Chinese Clinical Trial Registry ChiCTR2000038080. Registered 09 September 2020. http://www.chictr.org.cn/showproj.aspx?proj=61192.