LAUSR

Fibroblast activation protein (FAP) and its inhibitors (FAPI) have attracted tremendous attention worldwide over the last several years [1–4]. A number of radiolabeled FAPI have been designed, synthesized, and evaluated in preclinical models, and many of which have entered clinical trials. Radiolabeled FAPI has been investigated in a variety of diseases such as cancer, cardiovascular disease, arthritis, fibrosis, and thyroiditis [1, 2]. In non-cancerous diseases, positron emission tomography (PET) and/or single-photon emission computed tomography (SPECT) imaging with radiolabeled FAPI is usually used for diagnosis and prognosis, as well as treatment monitoring of various targeted therapies. In solid tumors, in addition to these imaging-based applications, radiolabeled FAPI can potentially also be used for targeted radionuclide therapy (TRT) applications, similar to those radiopharmaceuticals that target the prostate specific membrane antigen (PSMA) [5, 6]. Although radiolabeled FAPI have been shown to provide good image contrast in a variety of cancer types, in many cases outperforming [18F]FDG [1, 4], their absolute tumor uptake value is usually not high enough for therapeutic applications with TRT. In addition, there could also be significant clearance of radiolabeled FAPI from tumor tissues over time, which further diminishes their therapeutic potential. A few radiolabeled FAPI have been evaluated for therapeutic applications, mostly in small animal tumor models, and not surprisingly, their therapeutic efficacy is usually not ideal [1, 7, 8]. Therefore, many research groups around the world have devoted significant efforts towards improving tumor uptake and retention of radiolabeled FAPI, in order to enhance their therapeutic efficacy in solid tumors. Various approaches have been adopted and investigated. Over the last decade, a large number of studies have shown that prolonging the blood circulation of small molecules or radiopharmaceuticals via conjugation of various albumin binders, such as Evans blue (EB) and 4-(p-iodophenyl)butyric acid, can significantly improve their therapeutic dose delivery and enhance their anti-cancer efficacy [9]. Therefore, it is likely that albumin binding could also be a promising method for the enhancement of TRT with radiolabeled FAPI. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Zhang, Xu, Ding et al. reported a proof-of-concept study which suggests that conjugation of albumin binders may improve the cancer therapeutic efficacy of FAPI-based radiopharmaceuticals [10], which may become a general strategy to convert the diagnostic FAP-targeted radiopharmaceuticals into their therapeutic pairs and enable cancer TRT and/or theranostics. The albumin-binding moieties used in this study are simple fatty acid chains. Two fatty acids, lauric acid (C12) and palmitic acid (C16), were conjugated to FAPI-04 to give two albumin-binding FAPI: FAPI-C12 and FAPI-C16, respectively (Fig. 1). These two molecules were radiolabeled with either 68 Ga, 86Y, or 177Lu, and comprehensively studied in vitro and in vivo, not only for PET (68 Ga and 86Y) and SPECT (177Lu) imaging but also for TRT (177Lu) in mouse tumor models. Importantly, radiolabeling was achieved with high yield and good radiochemical purity. In addition, the stability of these radiopharmaceuticals was also excellent in serum, which makes them This article is part of the Topical Collection on Oncology General