The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo.
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), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]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 [(11)C]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, [(11)C]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.
RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: ewan_hume@riken.jp.
W Ewan
WE
Hume
Tomotaka
T
Shingaki
Tadayuki
T
Takashima
Yoshinobu
Y
Hashizume
Takashi
T
Okauchi
Yumiko
Y
Katayama
Emi
E
Hayashinaka
Yasuhiro
Y
Wada
Hiroyuki
H
Kusuhara
Yuichi
Y
Sugiyama
Yasuyoshi
Y
Watanabe
D000818:Animals; D001692:Biological Transport; D002247:Carbon Isotopes; D008099:Liver / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
D002247:Carbon Isotopes; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D008687:Metformin
Hepatobiliary transport; Metformin; Multi-drug and toxin extrusion transporter 1 (MATE1); Positron emission tomography (PET); Pyrimethamine