Occupancy of the central benzodiazepine receptors during benzodiazepine treatment determined by PET

Pauli, Stefan; Farde, Lars; Halldin, Christer; Sedvall, Göran

doi:10.1016/0924-977x(91)90498-j

Cited by 11 publications

(5 citation statements)

References 7 publications

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“…Benzodiazepine agonists have previously been believed to exert their effects when occupying only a relatively small number of receptors in humans. This is based on [ 11 C]flumazenil PET and [ 123 I]iomazenil SPET studies showing sedation or sleep is associated with clonazepam (0.03 mg/kg) at 15% to 23% occupancy, with diazepam (30 mg) at 24%, with alprazolam (2 mg) at 16%, and with midazolam (50 mcg/kg) at 17% to 35% or (6 mg/h) at 20% to 30% ( Shinotoh et al , 1989 ; Pauli et al , 1991 ; Videbaek et al , 1993 ; Malizia et al , 1996 ; Fujita et al , 1999 ). Zolpidem is the only licensed benzodiazepine subtype-selective drug with appropriate pharmacokinetics we were able to give to humans though, as it is an agonist, this limited the dose we were able to give safely.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Myers

Rosso

Watson

et al. 2012

J Cereb Blood Flow Metab

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This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

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Section: Discussionmentioning

confidence: 99%

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Myers

Rosso

Watson

et al. 2012

J Cereb Blood Flow Metab

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“…that occupied only 15–24% of benzodiazepine sites (Shinotoh et al, 1989) whereas, doses of diazepam (30 mg p.o.) and alprazolam (0.5 mg every 6 h) that caused sedation were associated with respective occupancies of 24% and 16% (Fujita et al, 1999; Pauli et al., 1991). In addition, a 20 mg dose of the α1-subtype-preferring hypnotic compound zolpidem produced 26–29% occupancy (at a plasma drug concentration of ∼100 ng/mL), suggesting that a typical clinically efficacious dose of zolpidem (10 mg) would correspond to around 15% occupancy (Abadie et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Preclinical and clinical pharmacology of TPA023B, a GABA_A receptor α2/α3 subtype-selective partial agonist

et al. 2010

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In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

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“…Moreover, this occupancy is probably due to TPA023 rather than any metabolite(s) because the major metabolites (the isobutanol and NH-triazole) have very poor brain penetration (Atack, 2009). The extent of occupancy of benzodiazepine binding sites seen at either 0.032 (60 -70%) or 0.32 mg/kg (ϳ100%) TPA023 was much higher than that achieved in humans by using clinically relevant doses of lorazepam (6%) (LingfordHughes et al, 2005) or hypnotic doses of midazolam (Յ35%) (Malizia et al, 1996), diazepam (24%) (Pauli et al, 1991), clonazepam (15-24%) (Shinotoh et al, 1989), or zolpidem (21%) (Abadie et al, 1996). These data are consistent with .…”

Section: Downloaded Frommentioning

confidence: 99%

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes

Ator¹,

Atack

Hargreaves³

et al. 2009

J Pharmacol Exp Ther

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Abuse-liability-related effects of subtype-selective GABA A modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo [4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at ␣ 1 -, ␣ 2 -, ␣ 3 -, and ␣ 5 -containing GABA A receptors, whereas 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (TPA023) has weaker partial agonist efficacy at ␣ 2 and ␣ 3 and none at ␣ 1 and ␣ 5 subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032-0.1 mg/kg) and TPA023 (0.0032-0.32 mg/ kg) was compared with lorazepam (0.01-0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [ 11 C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the ␣ 1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced ␣ 2/3 subtype efficacy.When they were introduced in the early 1960s, the benzodiazepines, typified by diazepam, represented a major advance in the treatment of generalized anxiety disorder relative to older treatments (Lader, 1993). They had a rapid onset of anxiolytic efficacy, were generally well tolerated, and relatively safe in overdose. Nevertheless, beginning in the late 1970s, concerns over the abuse potential and dependence liability of benzodiazepines resulted in more restrictive legislation (i.e., legal scheduling under the Controlled Substances Act in the United States in 1975 and by the World Health Organization in 1982) as well as a general reluctance of physicians to prescribe benzodiazepines (Williams and McBride, 1998). Benzodiazepines are abused by people who have a history of drug abuse, those on long-term benzodiazepines may independently escalate their dosage, patients can be overly reluctant to comply with physician recommendations to reduce benzodiazepine use, and there is considerable evidence of adverse ...

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Occupancy of the central benzodiazepine receptors during benzodiazepine treatment determined by PET

Cited by 11 publications

References 7 publications

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Preclinical and clinical pharmacology of TPA023B, a GABA_A receptor α2/α3 subtype-selective partial agonist

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes

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Occupancy of the central benzodiazepine receptors during benzodiazepine treatment determined by PET

Cited by 11 publications

References 7 publications

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

Contact Info

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Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Preclinical and clinical pharmacology of TPA023B, a GABA_A receptor α2/α3 subtype-selective partial agonist

Reducing Abuse Liability of GABA_A/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α₁ and α_2/3 Subtypes