Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [¹¹C]domperidone and [¹¹C]metoclopramide. In P-gp-overexpressing cells, the IC₅₀ of tariquidar, a potent P-gp inhibitor, was drastically different using [¹¹C]domperidone (221 nM [198–248 nM]) or [¹¹C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [¹¹C]domperidone compared with [¹¹C]metoclopramide (p < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUC_brain) of [¹¹C]metoclopramide was 2.4-fold higher compared with [¹¹C]domperidone (p < 0.001), consistent with a 1.8-fold higher BBB penetration (AUC_brain/AUC_plasma). The maximal increase in the brain exposure (2.9-fold, p < 0.0001) and BBB penetration (2.9-fold, p < 0.0001) of [¹¹C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [¹¹C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB.

The development of efficient and broadly applicable silylation methodologies remains a central goal in synthetic organic and organosilicon chemistry. Traditionally, silylation reactions employ chlorosilanes or hydrosilanes, often necessitating the use of moisture-sensitive and corrosive reagents. Herein, we report a high-yielding, operationally simple, rapid, and economical silylation platform based on trifluoromethyltrimethylsilane (TMSCF₃) and catalytic potassium hydroxide (KOH). This reaction system enables access to a broad array of substrates─including terminal alkynes and alcohols─exhibiting high functional group tolerance and facilitating the efficient silylation of pharmaceutically relevant molecules.