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-3beta 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-3beta (GSK-3beta), was radiolabelled with carbon-11 (half-life=20.4min) for cerebral positron emission tomography (PET) studies. Reaction of desmethyl AR-A014418 with [(11)C]CH(3)I produced [(11)C]AR-A014418 in 17% decay-corrected radiochemical yield, based on [(11)C]CO(2), with 3230mCi/micromol specific activity after a 30min 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 [(11)C]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 30min post-injection, uncorrected for vascular compartment. Considering the extremely poor brain penetration of [(11)C]AR-A014418 this compound cannot be used to study GSK-3beta in cerebral PET studies. Furthermore, the specific pharmacological mechanism(s) of antidepressant-like activity attributed to AR-A014418 should be investigated.
Vasdev
Neil
N
PET Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, Ont., Canada M5T-1R8. neil.vasdev@camhpet.ca
Garcia
Armando
A
Stableford
Winston T
WT
Young
Alex B
AB
Meyer
Jeffrey H
JH
Houle
Sylvain
S
Wilson
Alan A
AA
D000818:Animals; D002250:Carbon Radioisotopes; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis* / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D007553:Isotope Labeling; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D002250:Carbon Radioisotopes; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3