Improved Synthesis of the Thiophenol Precursor N-(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand

Junfeng Wang; Timothy M Shoup; Anna-Liisa Brownell; Zhaoda Zhang

doi:10.1016/j.tet.2019.06.010

Improved Synthesis of the Thiophenol Precursor N-(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand

Tetrahedron. 2019 Jul 19;75(29):3917-3922. doi: 10.1016/j.tet.2019.06.010. Epub 2019 Jun 6.

Authors

Junfeng Wang^{1

2}, Timothy M Shoup², Anna-Liisa Brownell², Zhaoda Zhang¹

Affiliations

¹ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Suite 2301 Charlestown, MA 02129.
² Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 125 Nashua Street, Suite 660, Boston, MA 02114.

Abstract

Recently [¹¹C]mG4P012 (previously [¹¹C]KALB012 and presently named as [¹¹C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and L-dopa-induced dyskinesia. [¹¹C]mG4P012 was shown to be a promising PET radioligand for mGluR4 in the monkey brain and for further development in human subjects. However, the previously reported multi-step synthesis of the thiophenol precursor suffered from low yields and difficult workup procedures. To support the translational research of [¹¹C]mG4P012 and the other potential applications, we have developed a new route for synthesis of the thiophenol precursor and optimized the reaction conditions. The synthesis of N-(4-chloro-3-mercaptophenyl)picolinamide from 1-chloro-4-nitrobenzene has been greatly improved from 8% to 52% total yield with easy handling and in gram scales.

Keywords: N-(3-mercaptophenyl)picolinamide derivatives; mGluR4 PAM; mGluR4 PET ligand; the thiol protection.

Abstract

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