title: Different brain kinetics of two sigma 1 receptor ligands, [3H](+)-pentazocine and [11C]SA4503, by P-glycoprotein modulation.
abstract: We compared the brain kinetics of radiolabeled (+)-pentazocine and SA4503, which have a high and selective affinity for sigma(1) receptors. Brain uptake of [(11)C]SA4503 was high after intravenous injection followed by a gradual decrease in mice, whereas that of [(3)H](+)-pentazocine rapidly decreased. The brain uptake of the two radioligands was dose-dependently reduced, but the reduction of [(3)H](+)-pentazocine was found at higher doses. Percentages of the saturable binding of [(3)H](+)-pentazocine was much lower than that of [(11)C]SA4503. The brain uptake of [(3)H](+)-pentazocine was greatly blocked by SA4503 at a dose of 2 micromol/kg, while that of [(11)C]SA4503 was blocked by (+)-pentazocine at a dose of 20 micromol/kg and over. When mice were treated with cyclosporin A, a P-glycoprotein modulator, the uptake of [(3)H](+)-pentazocine was enhanced, but that of [(11)C]SA4503 was not. Under control and P-glycoprotein-modulated conditions, the brain uptake of both radioligands was reduced by haloperidol, another representative sigma receptor ligand, to a different extent. We concluded that the P-glycoprotein modulation resulted in the different brain kinetics of the two radioligands. The radiolabeled SA4503 is suitable as an in vivo probe, but radiolabeled (+)-pentazocine is not.
authors.affiliation: Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan. kawamura@pet.tmig.or.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsuno
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism; D051379:Mice; D010423:Pentazocine / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011869:Radioligand Assay / Q000379:methods*; D017480:Receptors, sigma / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D010423:Pentazocine; D010879:Piperazines; D017480:Receptors, sigma; D014316:Tritium; D000097605:Sigma-1 Receptor; C101789:SA 4503