RT Journal Article
SR Electronic
T1 Comparison of Lorazepam [7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2<em>H</em>-1,4-benzodiazepin-2-one] Occupancy of Rat Brain γ-Aminobutyric Acid<sub>A</sub> Receptors Measured Using in Vivo [<sup>3</sup>H]Flumazenil (8-Fluoro 5,6-dihydro-5-methyl-6-oxo-4<em>H</em>-imidazo[1,5-<em>a</em>][1,4]benzodiazepine-3-carboxylic Acid Ethyl Ester) Binding and [<sup>11</sup>C]Flumazenil Micro-Positron Emission Tomography
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1030
OP 1037
DO 10.1124/jpet.106.114884
VO 320
IS 3
A1 John R. Atack
A1 Paul Scott-Stevens
A1 John S. Beech
A1 Tim D. Fryer
A1 Jessica L. Hughes
A1 Marcel C. Cleij
A1 Jean-Claude Baron
A1 John C. Clark
A1 Richard J. Hargreaves
A1 Franklin I. Aigbirhio
YR 2007
UL http://jpet.aspetjournals.org/content/320/3/1030.abstract
AB The occupancy by lorazepam of the benzodiazepine binding site of rat brain GABAA receptors was compared when measured using either in vivo binding of [3H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester) in terminal studies or [11C]flumazenil binding in anesthetized animals assessed using a small animal positron emission tomography (PET) scanner (micro-PET). In addition, as a bridging study, lorazepam occupancy was measured using [3H]flumazenil in vivo binding in rats anesthetized and dosed under micro-PET conditions. Plasma lorazepam concentrations were also determined, and for each occupancy method, the concentration required to produce 50% occupancy (EC50) was calculated because this parameter is independent of the route of lorazepam administration. For the in vivo binding assay, lorazepam was dosed orally (0.1–10 mg/kg), whereas for the micro-PET study, lorazepam was given via the i.v. route as a low dose (0.75 mg/kg bolus) and then a high dose (0.5 mg/kg bolus then 0.2 mg/ml infusion). The lorazepam plasma EC50 in the [11C]flumazenil micro-PET study was 96 ng/ml [95% confidence intervals (CIs) = 74–124 ng/ml], which was very similar to the [3H]flumazenil micro-PET simulation study (94 ng/ml; 95% CI = 63–139 ng/ml), which in turn was comparable with the [3H]flumazenil in vivo binding study (134 ng/ml; 95% CI = 119–151 ng/ml). These data clearly show that despite the differences in dosing (i.v. in anesthetized versus orally in conscious rats) and detection (in vivo dynamic PET images versus ex vivo measurements in filtered and washed brain homogenates), [11C]flumazenil micro-PET produces results similar to [3H]flumazenil in vivo binding. The American Society for Pharmacology and Experimental Therapeutics