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

doi:10.1002/chem.201805473

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

UCL University College London

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

53 Downloads (Pure)

Abstract

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 language	English
Article number	25
Pages (from-to)	2345-2351
Number of pages	7
Journal	Chemistry - A European Journal
Volume	25
Issue number	9
DOIs	https://doi.org/10.1002/chem.201805473
Publication status	Published - 12 Feb 2019

Keywords

[ F]fluorination
aldehyde dehydrogenase
cancer
radiochemistry
radiolabeling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/chem.201805473Licence: Unspecified

ManuscriptAccepted author manuscript, 6.03 MBLicence: Unspecified

Cite this

@article{eef989b6d823415c903a6809106d7547,

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

abstract = "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.",

keywords = "[ F]fluorination, aldehyde dehydrogenase, cancer, radiochemistry, radiolabeling",

author = "Pereira, {Raul Geraldo} and Thibault Gendron and Chandan Sanghera and Greenwood, {Hannah E.} and Joseph Newcombe and Patrick McCormick and Kerstin Sander and Maya Topf and E {\AA}rstad and Witney, {Timothy Howard}",

year = "2019",

month = feb,

day = "12",

doi = "10.1002/chem.201805473",

language = "English",

volume = "25",

pages = "2345--2351",

journal = "Chemistry - A European Journal",

number = "9",

}

TY - JOUR

T1 - Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-based Approach

AU - Pereira, Raul Geraldo

AU - Gendron, Thibault

AU - Sanghera, Chandan

AU - Greenwood, Hannah E.

AU - Newcombe, Joseph

AU - McCormick, Patrick

AU - Sander, Kerstin

AU - Topf, Maya

AU - Årstad, E

AU - Witney, Timothy Howard

PY - 2019/2/12

Y1 - 2019/2/12

N2 - 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.

AB - 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.

KW - [ F]fluorination

KW - aldehyde dehydrogenase

KW - cancer

KW - radiochemistry

KW - radiolabeling

UR - http://www.scopus.com/inward/record.url?scp=85059932472&partnerID=8YFLogxK

U2 - 10.1002/chem.201805473

DO - 10.1002/chem.201805473

M3 - Article

VL - 25

SP - 2345

EP - 2351

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 9

M1 - 25

ER -