Possible Role of Organic Cation Transporters in the Distribution of [11C]Sulpiride, a Dopamine D2 Receptor Antagonist.

We synthesized [11C]sulpiride as a positron emission tomography probe for investigating the drug distribution in the human body. [11C]Sulpiride was injected to healthy male subjects in either tracer dose of [11C]sulpiride (approximately 222 MBq) or with therapeutic dose of sulpiride (500 mg, peroral) 3 h before the injection in a crossover fashion. Whole-body positron emission tomography imaging demonstrated that [11C]sulpiride accumulated exceedingly in the bladder, followed by liver, gall bladder, and kidney, respectively, at 30 min after the injection, whereas scarcely in the brain. Oral dose of sulpiride decreased the hepatic accumulation of the radioactivity by 60%. From in vitro experiments, we found that sulpiride is a substrate of hOCT1 (Km 2.6 μM), hOCT2 (Km 68 μM), hMATE1 (Km 40 μM), and hMATE2-K (Km 60 μM). Moreover, the uptake of sulpiride by human hepatocytes was diminished by tetraethylammonium, and saturable with Km of 18 μM. Oct1/2 double knockout mice and wild-type mice received Mate1 inhibitors (pyrimethamine/cimetidine) manifested reduced renal clearance of sulpiride, accompanied with its accumulation in the plasma. In conclusion, we found that sulpiride is a substrate of OCT1, OCT2, MATE1, and MATE2-K, and this suggests that [11C]sulpiride would be a useful radioligand to investigate the organic cation transporters in humans.