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Mapping Aldehyde Dehydrogenase 1A1 Activity using an [ 18 F]Substrate‐Based Approach
Author(s) -
Pereira Raul,
Gendron Thibault,
Sanghera Chandan,
Greenwood Hannah E.,
Newcombe Joseph,
McCormick Patrick N.,
Sander Kerstin,
Topf Maya,
Årstad Erik,
Witney Timothy H.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201805473
Subject(s) - aldehyde dehydrogenase , in vivo , aldehyde , chemistry , benzaldehyde , stereochemistry , cofactor , amide , enzyme , biochemistry , biology , catalysis , microbiology and biotechnology
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.