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

Bioorg Med Chem. 2013 Dec 15;21(24):7584-90. doi: 10.1016/j.bmc.2013.10.041. Epub 2013 Nov 1.

Abstract

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.

Keywords: Hepatobiliary transport; Metformin; Multi-drug and toxin extrusion transporter 1 (MATE1); Positron emission tomography (PET); Pyrimethamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Carbon Isotopes
  • Liver / metabolism*
  • Male
  • Metformin / chemical synthesis
  • Metformin / chemistry
  • Metformin / pharmacokinetics*
  • Mice
  • Organic Cation Transport Proteins / metabolism*
  • Positron-Emission Tomography*
  • Tissue Distribution

Substances

  • Carbon Isotopes
  • MATE1 protein, mouse
  • Organic Cation Transport Proteins
  • Metformin