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Synthesis of a 11 C‐labelled nitrated 1,4‐dihydroquinoxaline‐2,3‐dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel)
Author(s) -
Thorell JanOlov,
StoneElander Sharon,
Duelfer Tim,
Cai Sui Xiong,
Jones Lawrence,
Pfefferkorn Heidi,
Ciszewska Grazyna
Publication year - 1998
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199804)41:4<345::aid-jlcr87>3.0.co;2-s
Subject(s) - chemistry , oxalate , diamine , glycine , nitration , in vivo , medicinal chemistry , nuclear chemistry , organic chemistry , amino acid , biochemistry , microbiology and biotechnology , biology
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 drug's 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 [ 11 C]cyanide, was diethyl [1‐ 11 C]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‐ 11 C]oxalate was reacted with 4,5‐dichloro‐1,2‐ phenylenediamine to give [2‐ 11 C]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‐ 11 C]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 HNO 3 /concentrated H 2 SO 4 . Both procedures gave high conversions of [2‐ 11 C]DCQX to [ 11 C]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 [ 11 C]CN − at end of trapping). The specific activity of the no‐carrier‐added product was 15–20 GBq/μmol at end‐of‐synthesis. © 1998 John Wiley & Sons, Ltd.