title: Pharmacological evaluation of (S)-8-[123I]iodobretazenil: a radioligand for in vivo studies of central benzodiazepine receptors.
abstract: In vitro studies on cortical membranes indicated (S)-8-[(123)I]iodobretazenil bound saturably to a single population of binding sites (B(max) = 2.33 pmol/mg protein) with a dissociation constant K(d) = 1.9 nM. (R)-8-[(123)I]Iodobretazenil displayed only non-specific binding. In vivo biodistribution of (S)-8-[(123)I]iodobretazenil in rats indicated high accumulation in regions of high BZR density. Radioactivity was blocked by preadministration with iodobretazenil and flumazenil, while non-BZR drugs had no effect on the uptake of activity in any brain region. (S)-8-[(123)I]Iodobretazenil uptake was saturable in a dose dependent manner (ID(50) = 0.13 mg/kg) in all brain regions. With the (R)-enantiomer no specific uptake was observed. Metabolite studies at 1-3 h p.i. indicated that greater than 95% of activity extracted from brain tissue corresponded to unchanged radiotracer while that in plasma was over 70%. (S)-8-[(123)I]Iodobretazenil potently and selectively labels BZR in vivo and deserves further investigation as a possible SPECT radiotracer.
authors.affiliation: Radiopharmaceuticals Division R&D, Australian Nuclear Science & Technology Organisation Menai NSW 2234, Sydney, Australia. akx@antso.gov.au
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
authors.forename: Karine
authors.initials: K
authors.lastname: Mardon
authors.forename: Filomena
authors.initials: F
authors.lastname: Mattner
authors.forename: Christian
authors.initials: C
authors.lastname: Loc'h
authors.forename: Meredith E
authors.initials: ME
authors.lastname: McPhee
authors.forename: Branko
authors.initials: B
authors.lastname: Dikic
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: Damon D
authors.initials: DD
authors.lastname: Ridley
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D046508:Culture Techniques; D005260:Female; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D011869:Radioligand Assay / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: C478097:8-iodobretazenil; D001570:Benzodiazepinones; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A