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

Raul Geraldo Pereira, Thibault Gendron, Chandan Sanghera, Hannah E. Greenwood, Joseph Newcombe, Patrick McCormick, Kerstin Sander, Maya Topf, E Årstad, Timothy Howard Witney

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Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids, with elevated ALDH expression in human cancers 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. In this report, we present 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 4b was found to have excellent affinity and isozyme selectivity for ALDH1A1 in vitro. Following 18F-fluorination, [18F]4b was taken up by colorectal tumor cells and trapped through the conversion to its 18F-labelled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [18F]4b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [18F]4b, however, was observed in vivo which may limit the tissue penetration of this first-in-class radiotracer.
Original languageEnglish
Article number25
Pages (from-to)2345-2351
Number of pages7
JournalChemistry - A European Journal
Issue number9
Publication statusPublished - 12 Feb 2019


  • [ F]fluorination
  • aldehyde dehydrogenase
  • cancer
  • radiochemistry
  • radiolabeling


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