Journal Article

Synthesis, radiolabeling, and evaluation of a (4-quinolinoyl)glycyl-2-cyanopyrrolidine analogue for fibroblast activation protein (FAP) PET imaging

Zhang, Ni, Pan, Fei, Li, Yunchun, Pan, Lili, Qi, Zhongzhi, Huang, Rui, Yang, Bo, Zhang, Wenjie, Su, Feijing, Wu, Xiaoai, Diao, Wei

2023

Overview

Fibroblast activation protein (FAP) is regarded as a promising target for the diagnosis and treatment of tumors as it was overexpressed in cancer-associated fibroblasts. FAP inhibitors bearing a quinoline scaffold have been proven to show high affinity against FAP in vitro and in vivo , and the scaffold has been radio-labeled for the imaging and treatment of FAP-positive tumors. However, currently available FAP imaging agents both contain chelator groups to enable radio-metal labeling, making those tracers more hydrophilic and not suitable for the imaging of lesions in the brain. Herein, we report the synthesis, radio-labeling, and evaluation of a 18 F-labeled quinoline analogue ([ 18 F] 3 ) as a potential FAP-targeted PET tracer, which holds the potential to be blood–brain barrier-permeable. [ 18 F] 3 was obtained by one-step radio-synthesis via a copper-mediated S N A R reaction from a corresponding boronic ester precursor. [ 18 F] 3 showed moderate lipophilicity with a log D 7.4 value of 1.11. In cell experiments, [ 18 F] 3 showed selective accumulation in A549-FAP and U87 cell lines and can be effectively blocked by the pre-treatment of a cold reference standard. Biodistribution studies indicated that [ 18 F] 3 was mainly excreted by hepatic clearance and urinary excretion, and it may be due to its moderate lipophilicity. In vivo PET imaging studies indicated [ 18 F] 3 showed selective accumulation in FAP-positive tumors, and specific binding was confirmed by blocking studies. However, low brain uptake was observed in biodistribution and PET imaging studies. Although our preliminary data indicated that [ 18 F] 3 holds the potential to be developed as a blood–brain barrier penetrable FAP-targeted PET tracer, its low brain uptake limits its application in the detection of brain lesions. Herein, we report the synthesis and evaluation of [ 18 F] 3 as a novel small-molecule FAPI-targeted PET tracer, and our results suggest further structural optimizations would be needed to develop a BBB-permeable PET tracer with this scaffold.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 18F-labeled FAPI / Biodistribution / Bioengineering and Biotechnology / Blood-brain barrier / Brain cancer / FAP / Fibroblast activation protein / Fibroblasts / Metabolism / Neuroimaging / PET/CT imaging / Physicochemical properties / Positron emission tomography / Proteins / Radioactivity / Tumors