[en] 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 18 F-fluorination, [18 F]4 b was taken up by colorectal tumor cells and trapped through the conversion to its 18 F-labeled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [18 F]4 b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [18 F]4 b, however, was observed in vivo, which may limit the tissue penetration of this first-in-class radiotracer.
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
Pereira, Raul; Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK ; Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH, UK
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
Sanghera, Chandan; Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK ; Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH, UK
Greenwood, Hannah E; Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK ; Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH, UK
Newcombe, Joseph; Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK ; Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, UK
McCormick, Patrick N; Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK ; Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH, UK
Sander, Kerstin; Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
Topf, Maya; Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, UK
Årstad, Erik; Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
Witney, Timothy H ; Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK ; Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH, UK
Language :
English
Title :
Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-Based Approach.
Wellcome Trust [US] Royal Society [GB] EPSRC - Engineering and Physical Sciences Research Council [GB] CRUK - Cancer Research UK [GB]
Funding text :
This study was funded through a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (107610/Z/15/Z), the CRUK & EPSRC Comprehensive Cancer Imaging Centre at KCL & UCL (C1519/A16463). UCL radiochemistry is funded in-part by the Department of Health’s NIHR Biomedical Research Centres funding Scheme. We would like to thank Dr. Adam Shuhendler for his thoughtful comments during the preparation of this manuscript.
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