Evaluation of ¹¹C-metoclopramide in rat: a moderate P-glycoprotein substrate with suitable baseline brain uptake

Objectives Inhibition and depletion of P-glycoprotein (P-gp) function at the blood-brain barrier (BBB) can be evidenced with PET using radiolabeled substrates of this efflux transporter. Due to extensive metabolism or very low baseline brain uptake, available radiotracers are not adapted to the study of P-gp induction at the BBB, which is proposed as an explanation for neuropharmacoresistance [1]. The antiemetic drug metoclopramide is a moderate substrate of Human and rodent P-gp. Preclinical studies and CNS effects observed in metoclopramide-treated patients suggest significant baseline brain permeation [2].

Methods ¹¹C-metoclopramide was radiolabeled from its corresponding O-desmethylated precursor. Arterial input function, metabolism and brain kinetics (37 MBq i.v, Siemens Inveon microPET scanner ; n=4 in each condition) were measured in Wistar rats. Influence of pharmacological dose metoclopramide (3 mg/kg) was tested by co-injection. P-gp inhibition was performed using tariquidar (8 mg/kg i.v, 5 min before tracer injection). Displacement was performed 30 min after tracer injection using 10 mg/kg metoclopramide in P-gp-inhibited rats.

Results Tracer dose ¹¹C-metoclopramide was extensively metabolized. Co-injection of a pharmacological dose of metoclopramide considerably improved the radiotracer stability (intact ¹¹C-metoclopramide = 65% at 30 min). Using this last approach, radioactivity was homogeneously distributed in the brain and rapidly reached equilibrium with estimated V_T of 0.97±0.12 mL.cm^-3. Tariquidar enhanced tracer brain uptake (V_T = 3.23±0.43 mL.cm^-3). Displacement had no influence on brain kinetics.

Conclusions ¹¹C-metoclopramide brain kinetics is effectively influenced by P-gp function at the rat BBB. Co-injection allows suitable baseline brain uptake and is not likely to inhibit P-gp [2]. Brain distribution is mainly non-specific. This clinically achievable protocol is promising for the study of P-gp modulation, including induction at the BBB.