SYNTHESIS OF A C-11 LABELED NITRATED 1,4-DIHYDROQUINOXALINE-2,3-DIONE, THE NMDA GLYCINE RECEPTOR ANTAGONIST ACEA-1021 (LICOSTINEL)

ACEA 1021 dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione, Licostine l) is a potent antagonist for the glycine site of the NMDA receptor. W ith the purpose of evaluating the drug's biodistribution in vivo as we ll as its potential as a PET tracer for the glycine binding sites, ACE A 1021 was labelled in the heterocyclic ring with carbon-11 in a five- step synthesis. The radiolabelling precursor, derived from [C-11]cyani de, was diethyl [1-C-11]oxalate. Yields of its cyclization with the de activated nitrated diamine, 4,5-dichloro-3-nitro-1,2-phenylenediamine, were too low to be reliable for the planned in vivo studies. Instead, diethyl [1-C-11]oxalate was reacted with 4,5-dichloro-1,2-phenylenedi amine to give C-11]6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione (DCQX ). Interference from the excess diamine during the subsequent nitratio n reaction was reduced by two methods. After formation of [2-C-11]DCQX , unlabelled diethyl oxalate was added and allowed to cyclize before a dding the nitrating agent, giving a carrier-added product suitable for use in pharmacokinetic studies. For the non-carrier-added tracer stud ies, the diamine was condensed. with acetic acid before adding fuming HNO3/concentrated H2SO4. Both procedures gave high conversions of [2-C -11]DCQX to [C-11]ACEA 1021, which was subsequently isolated by semi-p reparative liquid chromatography. The total synthesis time was 70-80 m in. The conversions according to radio-analytical LC were 25-30% and i solated yields for the five-step synthesis were approximate to 5-10% ( decay-corrected, based on [C-11]CN- at end of trapping). The specific activity of the no-carrier-added product was 15-20 GBq/mu mol at end-o f-synthesis.