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

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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