title: Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats.
abstract: The enantiomers of [N-methyl-11C]PK 11195, a radioligand for PET studies of PK (peripheral benzodiazepine) binding sites, have been prepared from the newly synthesized N-desmethyl-enantiomers by 11C-methylation with N.C.A. [11C]iodomethane. The brain uptake and retention of each enantiomer was compared with that of the racemic radioligand after i.v. administration into normal rats and into rats with focal cortical lesions. No significant differences in the uptakes of the enantiomers were observed in regions devoid of PK binding sites. However, the R-enantiomer was retained to a significantly greater extent than the S-enantiomer in olfactory bulbs-tubercles, which contain some PK binding sites, and also in 9-day-old focal cortical lesions, which are greatly enriched in PK binding sites associated with macrophage infiltration. The observed differences are consistent with the approximately 2-fold greater affinity of the R-enantiomer for PK binding sites reported in vitro and imply that the use of this enantiomer would have advantages over the use of the racemate currently used for PET studies.
authors.affiliation: MRC Cyclotron Unit, Hammersmith Hospital, London, England.
authors.forename: F
authors.initials: F
authors.lastname: Shah
authors.forename: S P
authors.initials: SP
authors.lastname: Hume
authors.forename: V W
authors.initials: VW
authors.lastname: Pike
authors.forename: S
authors.initials: S
authors.lastname: Ashworth
authors.forename: J
authors.initials: J
authors.lastname: McDermott
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002250:Carbon Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D007546:Isoquinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037850:PK 11195