C-Labeling of Acyclic Retinoid Peretinoin by Rapid C-[C]methylation to Disclose Novel Brain Permeability and Central Nervous System Activities Hidden in Antitumor Agent

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the C-labeled ester produced [C]peretinoin in 13 ± 8% RCY (n = 3). After pharmaceutical formulation, the resulting [C]benzyl ester and [C]peretinoin had high radiochemical purity (>99% each) and molar activities of 144 and 118 ± 49 GBq μmol at total synthesis times of 31 min and 40 ± 3 min, respectively. Rat brain PET imaging for the [C]ester revealed a unique time-radioactivity curve, suggesting the participation of the acid [C]peretinoin for the brain permeability. However, the curve of the [C]peretinoin rose steadily after a shorter time lag to reach 1.4 standardized uptake value (SUV) at 60 min. These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of > 3.0 at 90 min). With the opportunity to identify high brain uptake of [C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages.