Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 42; no. 13; pp. 1301 - 1312
• Main Authors: Zessin, J., Gucker, P., Ametamey, S. M., Steinbach, J., Brust, P., Vollenweider, F. X., Johannsen, B., Schubiger, P. A.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 30.12.1999; Wiley
• Subjects: [11C]-labelling; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Contrast media. Radiopharmaceuticals; Life Sciences & Biomedicine; Medical sciences; PET; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Science & Technology; serotonin uptake sites; [C-11]-labelling; serotonin uptake sites; PURITY; RADIOTRACER; POSITRON EMISSION TOMOGRAPHY; PET; PYRROLOISOQUINOLINE ANTIDEPRESSANTS; Separation; Radiolabelling; Serotonin; Angular nitrogen heterocycle; Carbon Isotopes; Tricyclic compound; Uptake; Optical resolution; Thioester; Scintigraphic agent; Enantiomer; Carbon 11; Aromatic compound; Iodomethane; Chemical synthesis; Carrier protein
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/(SICI)1099-1344(19991230)42:13<1301::AID-JLCR298>3.0.CO;2-2

An improved synthesis of the anantiomerically pure thioester precursors of [11C](+)‐McN‐5652 ([11C](+)−1]), and [11C](−)‐McN5652 ([11C](−)−1]) starting from racemic McN‐5652 ((±)−1) is described. The synthetic method includes the resolution of (±)−1 by repeated crystallization of the (+)‐ and (−)‐di‐p‐toluoyltartrates yielding (+)‐McN‐5652 ((+)−1) and (−)‐McN‐5652 ((−)‐1), each with >98% enantiomeric purity. S‐Demethylation of (±)−1, (+)−1, and (−)‐1, respectively was achieved by treatment with sodium amide at low temperatures (−78°C) followed by conversion of the intermediate thiols 2 with acetyl chloride to give the corresponding thioester precursors (±)−3, (+)−3 or (−)−3. This demethylation method almost completely suppressed the isomerization of the pharmacologically active trans diastereomer into the inactive cis form. Chiral HPLC analyses confirmed that the S‐demethylation proceeded without any racemization. 11C‐Labelling of (+)−3 or (−)−3, yields enantiomerically pure [11C](+)‐McN‐5652 or [11C](−)‐McN5652, each in 22% radiochemical yield (decay‐corrected, related to [11C]CO2) and a specific radioactivity of 74 GBq/μmol (2 Ci/μmol) at the end of synthesis (EOS) Copyright © 1999 John Wiley & Sons, Ltd.