Abstract
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 9.3-55.5MBq/nmol. The whole body effective dose of Al18F-NOTA-FAPI was estimated to be 1.24E - 02mSv/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.
Highlights
Fibroblast activation protein (FAP) is a type II transmembrane glycoprotein consisting of 760 amino acids, which belongs to the serine protease family and is selectively expressed in the stroma fibroblasts associated with epithelial cancers [1]
68Ga-FAP inhibitor (FAPI) PET/CT imaging suffered the disadvantage of radionuclide supply, since 68Ga was usually eluted from 68Ge-68Ga generator, one single synthesis would only achieve a small amount of radiopharmaceutics avaliable to 2-4 patients
We developed the Al18F-NOTA-FAPI probe for fibroblast activation protein targted imaging
Summary
Fibroblast activation protein (FAP) is a type II transmembrane glycoprotein consisting of 760 amino acids, which belongs to the serine protease family and is selectively expressed in the stroma fibroblasts associated with epithelial cancers [1]. In recent several years, (4-Quinolinoyl)glycyl-2-cyanopyrrolidine based organic small molecules that exhibited excellent affinity with FAP [11], known as FAP inhibitor (FAPI), have been radiolabeled with different radionuclides including 68Ga, 90Y, 99mTc, 64Cu and 225Ac, and have been translated into clinical for the nuclear imaging and radionuclide therapy of various types of cancer [12,13,14,15]. The supply of 68Ga-FAPI to distant centres that requiring this probe would be restricted because of the short half-life of 68Ga (t1/2 = 68 min). Two 18F radiolabeled FAPI probes has been reported, namely 18F-FAPI-74 and [18F]FGlcFAPI, respectively [18, 19] Both of this two probes showed excellent tumour imaging efficacy, the structure of this novel Al18F-NOTA-FAPI probe was different from them
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