Synthesis and evaluation of 3’-[18F]fluorothymidine-5’-squaryl as a bioisostere of 3’-[18F]fluorothymidine-5’-monophosphate

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Title: Synthesis and evaluation of 3’-[18F]fluorothymidine-5’-squaryl as a bioisostere of 3’-[18F]fluorothymidine-5’-monophosphate
Authors: Brickute, D
Beckley, A
Allott, L
Costa Braga, M
Barnes, C
Thorley, KJ
Aboagye, E
Item Type: Journal Article
Abstract: The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3′-[18F]fluorothymidine-5′-squaryl ([18F]SqFLT) as a bioisostere to 3′-[18F]fluorothymidine-5′-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluation in vitro showed low tracer uptake (<0.3% ID mg−1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK−. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK− xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.
Issue Date: 29-Mar-2021
Date of Acceptance: 14-Mar-2021
DOI: 10.1039/D1RA00205H
ISSN: 2046-2069
Publisher: Royal Society of Chemistry
Start Page: 12423
End Page: 12433
Journal / Book Title: RSC Advances: an international journal to further the chemical sciences
Volume: 11
Issue: 20
Copyright Statement: © 2021 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (
Sponsor/Funder: Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 16584
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
03 Chemical Sciences
Publication Status: Published
Online Publication Date: 2021-03-29
Appears in Collections:Department of Surgery and Cancer

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