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Mapping Aldehyde Dehydrogenase 1A1 Activity using an [¹⁸F]Substrate-based Approach

Pereira, R; Gendron, T; Sanghera, C; Greenwood, HE; Newcombe, J; McCormick, P; Sander, K; ... Witney, TH; + view all (2019) Mapping Aldehyde Dehydrogenase 1A1 Activity using an [¹⁸F]Substrate-based Approach. Chemistry & A European Journal , 25 (9) pp. 2345-2351. 10.1002/chem.201805473. Green open access

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Abstract

Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids. Elevated ALDH expression in human cancers is linked to metastases and poor overall survival. Despite ALDH being a poor prognostic factor, the non‐invasive assessment of ALDH activity in vivo has not been possible due to a lack of sensitive and translational imaging agents. Presented in this report are the synthesis and biological evaluation of ALDH1A1‐selective chemical probes composed of an aromatic aldehyde derived from N,N‐diethylamino benzaldehyde (DEAB) linked to a fluorinated pyridine ring either via an amide or amine linkage. Of the focused library of compounds evaluated, N‐ethyl‐6‐(fluoro)‐N‐(4‐formylbenzyl)nicotinamide 4 b was found to have excellent affinity and isozyme selectivity for ALDH1A1 in vitro. Following ¹⁸F‐fluorination, [¹⁸F]4 b was taken up by colorectal tumor cells and trapped through the conversion to its ¹⁸F‐labeled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [¹⁸F]4 b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [¹⁸F]4 b, however, was observed in vivo, which may limit the tissue penetration of this first‐in‐class radiotracer.

Type: Article
Title: Mapping Aldehyde Dehydrogenase 1A1 Activity using an [¹⁸F]Substrate-based Approach
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/chem.201805473
Publisher version: https://doi.org/10.1002/chem.201805473
Language: English
Additional information: © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: ¹⁸F, ALDH, Cancer, PET, Radiochemistry
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10064369
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