Journal Article Possible role of organic cation transporters in the distribution of [11C]sulpiride, a dopamine D2 receptor antagonist

Takano, Harumasa  ,  Ito, Sumito  ,  Zhang, Xuan  ,  Ito, Hiroshi  ,  Ming-Rong, Zhang  ,  Suzuki, Hiroshi  ,  Maeda, Kazuya  ,  Kusuhara, Hiroyuki  ,  Suhara, Tetsuya  ,  Sugiyama, Yuichi

106 ( 9 )  , pp.2558 - 2565 , 2017-05
We synthesized [11C]sulpiride as a positron emission tomography (PET) 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 (ca 222 MBq) or with therapeutic dose of sulpiride (500 mg, po) 3 hours prior to the injection in a crossover fashion. Whole body PET imaging demonstrated that [11C]sulpiride accumulated exceedingly in the bladder, followed by liver, gall bladder and kidney respectively; at 30 minutes 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 2.6μM), hOCT2 (Km 68μM), hMATE1 (Km 40μM) and hMATE2-K (Km 60μM). 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 useful radiologand to investigate the organic cation transporters in humans.

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