Preclinical evaluation and first-in-human study of Al18F-FAP-NUR for PET imaging cancer-associated fibroblasts

Abstract

Background Fibroblast activation protein (FAP) has gained attention as a promising molecular target with potential utility for cancer diagnosis and therapy. 68Ga-labeled FAP-targeting peptides have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To meet the applicable demand for peptide-based FAP tracers with high patient throughput, we herein report the radiosynthesis, preclinical evaluation, and the first-in-human imaging of a novel 18F-labeled FAP-targeting peptide. Methods Al18F-FAP-NUR was radiolabeled with 18F using an Al18F complex on a modified GE TRACERlab FXFN synthesis platform. The 18F-labeled peptide was evaluated against 68Ga-FAP-2286, a 68Ga-labeled FAP-targeting peptide, in biochemical and cellular assays, ex vivo biodistribution studies, and in vivo micro-PET imaging. Additionally, successful first-in-human imaging of the 18F-labeled peptide was performed in two patients with breast cancer and lung cancer, respectively. Results Al18F-FAP-NUR was automatedly prepared within 45 min with a non-decay corrected radiochemical yield of 18.73 ± 4.25% (n = 3). Compared to 68Ga-FAP-2286, the 18F-labeled peptide demonstrated more rapid, higher levels of cellular uptake and internalization, and lower levels of cellular efflux in HT1080-FAP cells. Micro-PET imaging and biodistribution studies conducted on xenograft mice models revealed a similar distribution pattern between the two tracers. However, Al18F-FAP-NUR demonstrated significantly higher tumor-specific uptake resulting in improved Tumor-Background Ratios (TBRs). In the patients, a significant accumulation of Al18F-FAP-NUR was found in the primary tumor. High uptake of the tracer within the bladder indicated that its major route of excretion was through urine. Conclusion Based on the physical imaging properties and longer half-life of 18F, Al18F-FAP-NUR exhibited promising characteristics such as enhanced tumor-specific accumulation and elevated TBRs, which made it a viable candidate for further clinical investigation.