New radiochemistry techniques can yield novel PET tracers for COX-2 and address the shortcomings in in vivo stability and specificity, which have held back clinical translation of tracers to image COX-2 expression. Current techniques limit radiosynthesis to analogs of the COX-2 inhibitors with fluorine-18 added via a carbon chain, or on an aromatic position which renders the radiolabeled analog less specific towards COX-2, resulting in tracers with low in vivo stability or specificity. To solve this problem, we have developed a new high affinity, 18F-labelled COX-2 inhibitor that is radiolabeled directly on a heteroaromatic ring. This molecule exhibits favorable biodistribution and increased metabolic stability. Synthesis of this molecule cannot be achieved by traditional means; consequently, we have developed an automated electrochemical radiosynthesis platform to synthesize up to 5 mCi of radiochemically pure 18F-COX-2ib in 4 hours (2% decay-corrected radiochemical yield). In vitro studies demonstrated clear correlation between COX-2 expression and uptake of the tracer. PET imaging of healthy animals confirmed that the molecule is excreted from blood within an hour, mainly through the hepatobiliary excretion pathway. In vivo metabolism data demonstrated that > 95% of the injected radioactivity remains in the form of the parent molecule 1 hour after injection.
Electrochemical fluorination of methyl(phenylthio)acetate was achieved using tetrabutylammonium fluoride (TBAF). Electrochemical fluorination was performed under potentiostatic anodic oxidation using an undivided cell in acetonitrile containing TBAF and triflic acid. The influence of several parameters including: oxidation potential, time, temperature, sonication, TBAF concentration and triflic acid concentration on fluorination efficiency were studied. It was found that the triflic acid to TBAF concentration ratio plays a key role in the fluorination efficiency. Electrochemical fluorination resulted in formation of mono-fluorinated methyl 2-fluoro-2-(phenylthio)acetate verified by gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) Spectroscopy. Under optimum conditions 44 ± 3% mono fluorination yield was obtained after a 30 min electrolysis. Electrochemical radiofluorination for the synthesis of methyl 2-[18F]fluoro-2-(phenothio) acetate was also achieved with the same optimized electrochemical cell parameters where TBAF was first passed through an anion exchange resin containing fluorine-18. A radiochemical fluorination efficiency of 7 ± 1% was achieved after 30 min of electrolysis.
A new method for rapid late-stage fluorination using the cation pool technique is presented. Fluorination and no-carrier-added radiofluorination of methyl (phenylthio) acetate, methyl 2-(methylthio) acetate, and methyl 2-(ethylthio) acetate were performed. The carbocations formed through electrochemical oxidation were stabilized by using a divided electrochemical cell and 2,2,2-trifluoroethanol (TFE) as the solvent at −20 °C. At the end of electrolysis, either stable-isotope [19F]fluoride or no-carrier-added radioactive [18F]fluoride was added to the reaction mixture to form the fluorinated or radiofluorinated product.
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