Synthesis and ex vivo evaluation of carbon-11 labelled N-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea ([11C]AR-A014418): A radiolabelled glycogen synthase kinase-3β specific inhibitor for PET studies

doi:10.1016/j.bmcl.2005.08.037

Bioorganic & Medicinal Chemistry Letters

Volume 15, Issue 23, 1 December 2005, Pages 5270-5273

https://doi.org/10.1016/j.bmcl.2005.08.037 Get rights and content

Abstract

N-(4-Methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418), a highly selective inhibitor of glycogen synthase kinase-3β (GSK-3β), was radiolabelled with carbon-11 (half-life = 20.4 min) for cerebral positron emission tomography (PET) studies. Reaction of desmethyl AR-A014418 with [¹¹C]CH₃I produced [¹¹C]AR-A014418 in 17% decay-corrected radiochemical yield, based on [¹¹C]CO₂, with 3230 mCi/μmol specific activity after a 30 min synthesis time. The desmethyl precursor of AR-A014418 was synthesized in 23% yield by a novel one-pot reaction of 2-amino-5-nitrothiazole with in situ generated TMS-protected 4-hydroxybenzylisocyanate, following deprotection with acid. Ex vivo biodistribution studies were conducted after [¹¹C]AR-A014418 was administered via tail vein injection into Sprague–Dawley rats. Very low levels of radioactivity were found in all brain regions (0.08% injected dose/gram of tissue) at 5 and 30 min post-injection, uncorrected for vascular compartment. Considering the extremely poor brain penetration of [¹¹C]AR-A014418 this compound cannot be used to study GSK-3β in cerebral PET studies. Furthermore, the specific pharmacological mechanism(s) of antidepressant-like activity attributed to AR-A014418 should be investigated.

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Acknowledgments

The Faculty of Medicine at the University of Toronto is acknowledged for financial support for this work from the Dean’s Fund (N.V.). The authors thank Doug Hussey, Patrick McCormick, and Hermia Cheung for their expertise with the ex vivo evaluations.

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Citation Excerpt :
In 2004, our laboratories in Toronto reported the first GSK-3 targeting radiotracer labeled with carbon-11 (11C; t1/2 = 20.3 min), [11C]AR-A014418, and have continued efforts to develop a GSK-3 tracer for first-in-human imaging. Our laboratories in Michigan subsequently developed the first brain penetrant GSK-3 radiotracer ([11C]SB-216763) [15,16]. We have since shifted our efforts to a new series of GSK-3 targeting radiotracers based on the oxazole-4-carboxamide structural scaffold and identified [11C]PF-367 [16] as one of the most potent and selective GSK-3 inhibitors.
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Bioorganic & Medicinal Chemistry Letters

Abstract

Graphical abstract

Section snippets

Acknowledgments

References and notes (28)

Prog. Neurobiol.

Trends Pharmacol. Sci.

J. Biol. Chem.

Nucl. Med. Biol.

Nucl. Med. Biol.

J. Chem. Neuroanat.

Life Sci.

Mol. Imaging Biol.

Appl. Radiat. Isot.

Mol. Imaging Biol.

EMBO J.

J. Clin. Psychiatry

Nat. Rev. Drug Disc.

Med. Res. Rev.

Cited by (53)

Development of [<sup>18</sup>F]Thiazolylacylaminopyridine-Based Glycogen synthase Kinase-3β ligands for positron emission tomography imaging

Comparison of [<sup>18</sup>F]F-CNBI and [<sup>18</sup>F]F-CNPIFE as Positron Emission Tomography Probes for Noninvasive Imaging of Glycogen Synthase Kinase-3 in Normal Mice

Radiofluorination of oxazole-carboxamides for preclinical PET neuroimaging of GSK-3

PET Imaging of Neuroinflammation

Discovery of PET radiopharmaceuticals at the academia-industry interface

Design, synthesis and activity evaluation of pyridinylcyclopropanecarboxamides targeting GSK-3 p in brains