Synthesis of tritium labelled thiorphan, an enkephalinase inhibitor

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 52; no. 1; pp. 23 - 28
• Main Authors: Wu, Shao-Yong, Masjedizadeh, Mohammad R.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2009; Wiley
• Subjects: Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Contrast media. Radiopharmaceuticals; enkephalinase; Life Sciences & Biomedicine; Medical sciences; NEP; neutral endopeptidase; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; radioligand; Science & Technology; thiorphan stability; tritiation; tritium labelled thiorphan; thiorphan stability; radioligand; NEP; RACECADOTRIL; enkephalinase; neutral endopeptidase; tritiation; tritium labelled thiorphan; Thiol; Radiolabelling; Enzyme; Enzyme inhibitor; Metalloendopeptidases; Tritium; Hydrogen Isotopes; Tritiation; Peptidases; α-Aminoacid; Hydrolases; Benzenic compound; Bromine Organic compounds; Neprilysin; Chemical synthesis
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1566

Tritium labelling of the enkephalinase inhibitor, thiorphan, is complicated by the presence of mercapto functional group. Reactions often used in aromatic tritiation, such as halogination and catalytic halogen/tritium displacement, are adversely affected by the presence of the divalent sulfur moeity. By protecting the SH group with t‐butyl group, the tritiation reaction proceeded smoothly without catalyst poisoning. The mercapto functionality was re‐generated with great ease and efficiency using 2‐nitrobenzenesulfenyl chloride and dithiothreitol (DTT). [3H]‐Thiorphan, thus, obtained had a radiochemical purity of >99% by AN‐HPLC and a specific activity of 18.42 Ci/mmol. [3H]‐Thiorphan showed good stability when stored at 4°C in an aqueous solution containing 10% methanol and 0.2% DTT in the dark. Copyright © 2008 John Wiley & Sons, Ltd. [3H]‐Thiorphan was synthesized in ten steps starting from methyl 3‐(dimethylamino)propionate. The key reaction involved t‐butyl protection of mercapto group which allowed efficient exchange of aromatic bromine with tritium. The labeled product had a specific activity 18.42 Ci/mmol. Thiorphan showed good stability when stored at 4°C in an aqueous solution containing 10% methanol and 0.2% DTT in the dark. Copyright © 2008 John Wiley & Sons, Ltd.