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• W4210347910 abstract "Abstract Purpose: Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18 F-labelled ATM inhibitor [ 18 F] 1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Methods: Radiofluorination of a confirmed selective ATM inhibitor ( 1 ) was achieved through substitution of a nitro-precursor with [ 18 F]fluoride. Uptake of [ 18 F] 1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [ 18 F] 1 in H1299 tumour xenografts was assessed in BALB/c nu/nu mice. Results: Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [ 18 F] 1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 80 GBq/μmol (n=11). In vitro , cell associated activity of [ 18 F] 1 increased over one hour, and retention of [ 18 F] 1 dropped to 50% over two hours. [ 18 F] 1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [ 18 F] 1 to ATM. In vivo , fast hepatobiliary clearance was observed with tumour uptake ranging 0.13-0.90%ID/g after one hour. Conclusion: Here we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18 F-labelled ATM inhibitors." @default.
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• W4210347910 date "2022-02-02" @default.
• W4210347910 modified "2023-09-27" @default.
• W4210347910 title "Radiofluorination of A Highly Potent ATM Inhibitor As A Potential PET Imaging Agent" @default.
• W4210347910 doi "https://doi.org/10.21203/rs.3.rs-1228717/v1" @default.
• W4210347910 hasPublicationYear "2022" @default.
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