ABSTRACT
Drug transporters mediate the uptake and elimination of drugs in various organs; therefore, having knowledge of how a transporter functions in the body would play a key role in ensuring drug efficacy in in vivo systems. In this context, we designed and synthesized [(11)C]dehydropravastatin, a novel PET probe that would be potentially useful for evaluation of the functions of the OATP1B1 and MRP2 transporters, based on the use of palladium(0)-mediated rapid C-[(11)C]methylation (viz., the rapid cross-coupling between [(11)C]methyl iodide and a boron intermediate).
Subject(s)
ATP-Binding Cassette Transporters/analysis , Liver/chemistry , Organic Anion Transporters/analysis , Positron-Emission Tomography , Pravastatin/analogs & derivatives , Radiopharmaceuticals/chemical synthesis , ATP-Binding Cassette Transporters/metabolism , Animals , Liver/metabolism , Liver-Specific Organic Anion Transporter 1 , Male , Organic Anion Transporters/metabolism , Pravastatin/chemical synthesis , Pravastatin/chemistry , Radiopharmaceuticals/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.
