Preclinical study and first-in-human imaging of [¹⁸F]FAP-2286, and comparison with 2-[¹⁸F]FDG PET/CT in various cancer patients.

Abstract

Fibroblast-activated protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of many solid cancers, but low or absent in normal tissues. Our study aimed to develop a novel FAP-specific tracer, namely [¹⁸F]FAP-2286, and evaluated its performance in comparison with well-established agents such as [¹⁸F]FAPI-42 and [⁶⁸Ga]Ga-FAP-2286 in preclinical research, as well as 2-[¹⁸F]FDG in pilot clinical study. [¹⁸F]FAP-2286 was manually synthesized in accordance with Good Manufacturing Practice (GMP). Subsequent investigations encompassed cell uptake, competitive binding affinity, internalization and efflux assays using HT-1080hFAP cell lines. PET imaging and biodistribution studies were conducted in HEK-293ThFAP, A549hFAP, HT-1080hFAP tumor-bearing mice as well as HEK-293T, A549 and HT-1080 control groups. Furthermore, clinical evaluation of [¹⁸F]FAP-2286 was performed in fifteen patients with various cancers compared to 2-[¹⁸F]FDG PET. The radiolabeling yield of [¹⁸F]FAP-2286 was 30.53 ± 5.20%, with a radiochemical purity exceeding 97%. In cell assays, [¹⁸F]FAP-2286 showed specific uptake, high internalization fraction and low cellular efflux. Rapid tumor uptake and satisfactory tumor retention was observed on micro-PET imaging and cancer patients. Meanwhile, the clinical research demonstrated that [¹⁸F]FAP-2286 may represent an alternative for low glucose-metabolism malignant tumors PET imaging such as gastric cancers. [¹⁸F]FAP-2286 showed superior imaging quality including rapid and high target uptake and satisfactory retention in both tumor-bearing mice and cancer patients. It may emerge as a promising candidate for early or delayed phase imaging and 2-[¹⁸F]FDG non-avid cancers PET scan.