11C-labeling of 20(S)-protopanaxadiol, an aglycon of ginsenoside, based on the use of Pd(0)-mediated rapid C-[11C]methylation of boronic precursors.

Abstract

Ginsenosides, the pharmacologically active components of Panax ginseng, are widely used in herbal medicine and reportedly exert diverse biological effects, including anticancer, anti-inflammatory, and neuroprotective activities. However, their pharmacological mechanisms remain poorly understood, owing to the lack of chemical probes suitable for in vivo analyses. Herein, we report the development of a ¹¹C radiolabeling of 20(S)-protopanaxadiol (PPD), a major aglycone-type active ginsenoside metabolite, for positron emission tomography (PET) imaging. For the ¹¹C labeling of PPD, we focused on the terminal vinyl methyl group of the dammarane-type triterpene backbone, a common structural element found in ginsenosides. A boronic precursor applicable for rapid ¹¹C-methylation was efficiently synthesized via steps focusing on the controlled cross-metathesis of an internal olefin. The subsequent Pd(0)-mediated rapid ¹¹C-methylation was conducted in N,N-dimethylformamide (DMF)/H₂O using [Pd₂(dba)₃], P(o-tolyl)₃, and sodium ascorbate, which functioned as a base and a radical scavenger. After formulation, the resulting [¹¹C]PPD was obtained in a decay-corrected radiochemical yield of 15 ± 2 % (n = 3), with a total radioactivity of 1.0 ± 0.3 GBq (n = 3) and molar activity of 124 ± 7 GBq/μmol (n = 3). Radiochemical purity was ≥99 %, and the total synthesis time was 29 min. Using [¹¹C]PPD, PET imaging of the brains of healthy rats and abdomens of healthy mice demonstrated low brain uptake and pronouncedly clear hepatobiliary excretion of radiolabeled species. These findings may provide a foundation for the general labeling of ginsenoside structures with ¹¹C radioisotopes, thereby enabling systematic in vivo pharmacokinetic analyses of PPD derivatives to advance ginsenoside-based drug development.