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NEUROPHARMACOLOGY

Comparison of Lorazepam [7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one] Occupancy of Rat Brain -Aminobutyric Acid_A Receptors Measured Using in Vivo [³H]Flumazenil (8-Fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic Acid Ethyl Ester) Binding and [¹¹C]Flumazenil Micro-Positron Emission Tomography

Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom (J.R.A., P.S.-S.); Departments of Anesthesia (J.S.B.), Clinical Neurosciences (J.L.H.) and Wolfson Brain Imaging Centre (T.D.F., M.C.C., J.-C.B., J.C.C., F.I.A.), Addenbrookes Hospital, Cambridge, United Kingdom; and Imaging Research and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania (R.J.H.)

The occupancy by lorazepam of the benzodiazepine binding site of rat brain GABA_A 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.

Address correspondence to: Dr. John R. Atack, Neuroscience, Johnson & Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, La Jolla, CA 92121. E-mail: JAtack{at}prdus.jnj.com