Synthesis of a 11C-labelled nitrated 1,4-dihydroquinoxaline-2,3- dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel)

Article abstract of DOI:10.1002/(SICI)1099-1344(199804)41:4<345::AID-JLCR87>3.0.CO;2-S

ACEA 1021 (6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione, Licostinel) is a potent antagonist for the glycine site of the NMDA receptor. With the purpose of evaluating the drugs biodistribution in vivo as well as its potential as a PET tracer for the glycine binding sites, ACEA 1021 was labelled in the heterocyclic ring with carbon-11 in a five-step synthesis. The radiolabelling precursor, derived from [¹¹C]cyanide, was diethyl [1- ¹¹C]oxalate. Yields of its cyclization with the deactivated nitrated diamine, 4,5-dichloro-3-nitro-1,2-phenylenediamine, were too low to be reliable for the planned in vivo studies. Instead, diethyl [1-¹¹C]oxalate was reacted with 4,5-dichloro-1,2-phenylenediamine to give [2-¹¹C]6,7- dichloro-1,4-dihydroquinoxaline-2,3-dione (DCQX). Interference from the excess diamine during the subsequent nitration reaction was reduced by two methods. After formation of [2-¹¹C]DCQX, unlabelled diethyl oxalate was added and allowed to cyclize before adding the nitrating agent, giving a carrier-added product suitable for use in pharmacokinetic studies. For the non-carrier-added tracer studies, the diamine was condensed with acetic acid before adding fuming HNO₃/concentrated H₂SO₄. Both procedures gave high conversions of [2-¹¹C]DCQX to [¹¹C]ACEA 1021, which was subsequently isolated by semi-preparative liquid chromatography. The total synthesis time was 70-80 min. The conversions according to radio-analytical LC were 25-30% and isolated yields for the five-step synthesis were ? 5-10% (decay- corrected, based on [¹¹C]CN^- at end of trapping). The specific activity of the no-carrier-added product was 15-20 GBq/μmol at end-of-synthesis.