Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent

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 79.5 GBq/μmol ( n = 11). In vitro, cell-associated activity of [ 18 F] 1 increased over 1 h, and retention of [ 18 F] 1 dropped to 50% over 2 h. [ 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 1 h. 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.

Abstract licence: CC BY-NC-ND

1. 10.

   A “Proteomic Ruler” for Protein Copy Number and Concentration Estimation without Spike-in Standards · 2014

2. 13.

   An Optimized Shotgun Strategy for the Rapid Generation of Comprehensive Human Proteomes · 2017

17 more references, whose wording the paper’s licence keeps private.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.