The synthesis and biodistribution of [¹¹C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo

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• 作者：W. Ewan Hume ; Tomotaka Shingaki ; Tadayuki Takashima ; Yoshinobu Hashizume ; Takashi Okauchi ; Yumiko Katayama ; Emi Hayashinaka ; Yasuhiro Wada ; Hiroyuki Kusuhara ; Yuichi Sugiyama ; Yasuyoshi Watanabe
• 关键词：Positron emission tomography (PET) ; Metformin ; Multi-drug and toxin extrusion transporter 1 (MATE1) ; Hepatobiliary transport ; Pyrimethamine
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 December, 2013
• 年：2013
• 卷：21
• 期：24
• 页码：7584-7590
• 全文大小：761 K

文摘

In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), ¹¹C-labelled metformin was synthesized and then evaluated as a PET probe. [¹¹C]Metformin ([¹¹C]4) was synthesized in three steps, from [¹¹C]methyl iodide. Evaluation by small animal PET of [¹¹C]4 showed that there was increased concentrations of [¹¹C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [¹¹C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [¹¹C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations.