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

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.