Tritium HIE with electron‐poor tertiary benzenesulfonamide moiety; application in late‐stage labeling of T0901317 (original) (raw)

Journal of Labelled Compounds and Radiopharmaceuticals, 2021

Abstract

The multi-functional radioligand [3 H]T0901317 ([3 H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X and retinoic acid-related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [3 H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo-intermediate potentially preclude its widespread use in biochemical, pharmacological and pathological studies in research lab settings. We exploit recent reports on hydrogen-isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho-directing group that facilitates C-H activation in the presence of homogenous iridium(I) catalysts. Herein, we report a time- and cost-efficient method for the tritium late-stage labeling of compound 1 - a remarkably electron-poor substrate owing to the tertiary trifluoroethylsulfonamide moiety. Under a straightforward HIE condition using a commercially available Kerr-type NHC Ir(I) complex, [(cod)Ir (NHC)Cl], the reaction with 1 afforded a specific activity of 10.8 Ci/mmol. Additionally, alternative HIE conditions using the heterogeneous catalyst of Ir-black provided sufficient 0.72 D-enrichment of 1, but unexpectedly failed while repeating with tritium gas.

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