Preparation of 18F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [18F]Fluoride Exchange Reaction

Abstract

Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule 18F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC50 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [18F]fluoride exchange ([18F]SuFEx) reaction to furnish [18F]12 and [18F]13 in high activity yields (AY) of 39–56% and molar activities (Am) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and 18F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either 18F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [18F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development.

Synthesis and evaluation of [18F]FBNAF, a STAT3-targeting probe, for PET imaging of tumor microenvironment

“…Concern could also be raised about the in vivo stability of [ 18 F]FBNAF owing to some accumulation of radioactivity in bone, where [ 18 F]F − physiologically accumulates, whereas high stability is exhibited in vitro. However, bone radioactivity was not high over the experimental period relative to the literature describing in vivo defluorination (Craig et al 2023 ; Lütje et al 2019 ). This might not indicate the defluorination of [ 18 F]FBNAF; instead, it reflects STAT3 expression in bone tissue and bone-derived cells involved in bone formation (Jo et al 2018 ).…”

PET/CT Imaging of Infectious Diseases: Overview of Novel Radiopharmaceuticals

“…The half-life of 18 F (110 min), the most predominant radionuclide used in PET imaging, permits multi-step radiosynthetic protocols and tracer transport between clinical facilities. Moreover, the high positron (>97% β + ) branching and low positron energy (0.635 MeV) of 18 F provide high-resolution PET images [92].…”