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    Mapping Aldehyde Dehydrogenase 1A1 activity using an [18F]Substrate-based approach

    Pereira, R. and Gendron, T. and Sanghera, C. and Greenwood, H.E. and Newcombe, J. and McCormick, P.N. and Sander, K. and Maya, Topf and Arstad, E. and Witney, T.H. (2019) Mapping Aldehyde Dehydrogenase 1A1 activity using an [18F]Substrate-based approach. Chemistry: A European Journal , ISSN 0947-6539. (In Press)

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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 transla- tional imaging agents. Presented in this report are the syn- thesis and biological evaluation of ALDH1A1-selective chemi- cal probes composed of an aromatic aldehyde derived from N,N-diethylamino benzaldehyde (DEAB) linked to a fluorinat- ed 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 excel- lent 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-la- beled 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.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): [18F]fluorination, aldehyde dehydrogenase, cancer, radiochemistry, radiolabeling
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Maya Topf
    Date Deposited: 11 Feb 2019 09:54
    Last Modified: 29 Jul 2019 01:18
    URI: http://eprints.bbk.ac.uk/id/eprint/26171

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