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DC Field | Value | Language |
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dc.contributor.author | Fraser, CR | - |
dc.contributor.author | Ajenjo, J | - |
dc.contributor.author | Veal, M | - |
dc.contributor.author | Dias, GM | - |
dc.contributor.author | Chan, C | - |
dc.contributor.author | O’Neill, E | - |
dc.contributor.author | Destro, G | - |
dc.contributor.author | Lau, D | - |
dc.contributor.author | Pacelli, A | - |
dc.contributor.author | Gouverneur, V | - |
dc.contributor.author | Hueting, R | - |
dc.contributor.author | Cornelissen, B | - |
dc.date.accessioned | 2024-07-25T15:29:38Z | - |
dc.date.available | 2024-07-25T15:29:38Z | - |
dc.date.issued | 2022-08-13 | - |
dc.identifier | ORCiD: Doreen Lau https://orcid.org/0000-0002-7623-2401 | - |
dc.identifier | ORCiD: Bart Cornelissen https://orcid.org/0000-0001-7581-3303 | - |
dc.identifier | 50 | - |
dc.identifier.citation | Fraser, C.R. et al. (2022) 'Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent', EJNMMI Research, 12 (1), 50, pp. 1 - 12. doi: 10.1186/s13550-022-00920-z. | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/29410 | - |
dc.description | Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | en_US |
dc.description | Supplementary Information is available online at: https://ejnmmires.springeropen.com/articles/10.1186/s13550-022-00920-z#Sec11 . | - |
dc.description.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 <sup>18</sup>F-labelled ATM inhibitor [<sup>18</sup>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 [<sup>18</sup>F]fluoride. Uptake of [<sup>18</sup>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 [<sup>18</sup>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 [<sup>18</sup>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 [<sup>18</sup>F]1 increased over 1 h, and retention of [18F]1 dropped to 50% over 2 h. [18F]1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [<sup>18</sup>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 <sup>18</sup>F-labelled ATM inhibitors. | en_US |
dc.description.sponsorship | This research was supported by MRC (MR/R01695X/1) and CRUK though the Oxford Institute for Radiation Oncology. | en_US |
dc.format.extent | 1 - 12 | - |
dc.format.medium | Electronic | - |
dc.language | English | - |
dc.language.iso | en | en_US |
dc.publisher | SpringerOpen (part of Springer Nature) | - |
dc.rights | Copyright © The Author(s) 2022. Rights and permissions: Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | PET | en_US |
dc.subject | ATM | en_US |
dc.subject | cancer | en_US |
dc.subject | molecular imaging | en_US |
dc.title | Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent | en_US |
dc.type | Article | en_US |
dc.date.dateAccepted | 2022-07-27 | - |
dc.identifier.doi | https://doi.org/10.1186/s13550-022-00920-z | - |
dc.relation.isPartOf | EJNMMI Research | - |
pubs.issue | 1 | - |
pubs.publication-status | Published | - |
pubs.volume | 12 | - |
dc.identifier.eissn | 2191-219X | - |
dc.rights.license | https://creativecommons.org/licenses/by/4.0/legalcode.en | - |
dc.rights.holder | The Author(s) | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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