Regional Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788 Binding Reflect Selectivity for α1 versus α2 and α3 Subunit-Containing GABAA Receptors

Atack, John; Smith, Alison J.; Emms, Frances; McKernan, Ruth M.

doi:10.1016/s0893-133x(98)00052-9

Cited by 72 publications

(46 citation statements)

References 25 publications

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“…Among parents and controls, age had no relation to binding. DISCUSSION We found that patients with SSADH deficiency have reduced benzodiazepine receptor binding measured with 11 C-FMZ-PET. Parents, clinically unaffected, showed no binding reduction.…”

Section: Figure 2 [11c]-flumazenil Pet Scans In An Affected Subject (mentioning

confidence: 61%

“…There were statistically significant differences in 11 C FMZ binding among patients, parents, and controls in all ROIs except midbrain; in the globus pallidus, a trend toward significance was found (table 2 and figure 2). Since no significant left-right difference in cortical BP ND were found, left and right ROIs were averaged.…”

Section: Resultsmentioning

confidence: 89%

“…Other PET studies have shown that 11 C-FMZ-PET can detect alterations in GABA receptor binding. Prolonged vigabatrin treatment is associated with decreased binding in children with epilepsy.…”

mentioning

confidence: 99%

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Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Pearl¹,

Gibson²,

Quezado³

et al. 2009

Neurology

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Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gammahydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utiliz- Succinic semialdehyde dehydrogenase (SSADH) deficiency, also called 4-hydroxybutyric aciduria (McKusick 279180) and aldehyde dehydrogenase 5a1 (Aldh5a1), is an autosomal recessive disorder. About 350 patients are known, with about 85% under 18, making this the most prevalent pediatric neurotransmitter disorder. 1 In the absence of SSADH, transamination of GABA to succinic semialdehyde is followed by its conversion to 4-hydroxybutryic acid (gamma-hydroxybutyric acid, or GHB), leading to CNS GABA and ␥-hydroxy butyrate (GHB) accumulation.2 Major clinical manifestations include developmental delay, hypotonia, ataxia, and seizures. Hyperkinetic behavior, aggression, self-injurious behaviors, and hallucinations have also been described; EEG abnormalities include generalized and focal epileptiform discharges, photosensitivity, and background slowing.

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Section: Figure 2 [11c]-flumazenil Pet Scans In An Affected Subject (mentioning

confidence: 61%

Section: Resultsmentioning

confidence: 89%

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Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Pearl¹,

Gibson²,

Quezado³

et al. 2009

Neurology

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“…The in vivo receptor binding of compounds A, B and diazepam was measured according to previously published methods [15]. In brief, animals were dosed orally, typically as suspensions in 0.5% aqueous Methocel (A4C) (The Dow Chemical Company, Midland, USA), with the compound of interest.…”

Section: In Vivo Binding Studiesmentioning

confidence: 99%

“…with [ 3 H]Ro 15-1788 (diluted to 10 mCi/ml in isotonic saline and administered as 5 ml/g to mice and 1 ml/g to rats). The 3 min interval between administration of [ 3 H]Ro 15-1788 and killing the animal was chosen since it has previously been shown that this results in maximum in vivo binding [15]. The animals were culled by stunning and decapitation and trunk blood was collected into heparinised tubes.…”

Section: In Vivo Binding Studiesmentioning

confidence: 99%

Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands

Pike

Cook

Watt

et al. 2007

Biopharm & Drug Disp

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The in vivo occupancy of brain benzodiazepine binding sites by compounds A and B was measured using a [(3)H]Ro 15-1788 binding assay and related to plasma and brain drug concentrations. The plasma concentration associated with 50% occupancy was higher for compound A than compound B (73 and 3.7 nM, respectively), however, there was little difference in the brain concentrations required (73 and 63 nM). Both compounds showed a non-linear relationship between plasma and brain concentrations such that above brain concentrations of approximately 100 nM increasing plasma concentrations did not result in a concomitant increase in brain concentrations. This is consistent with brain concentrations being dependent on a saturable compartment which was postulated to be the benzodiazepine binding site-containing GABA(A) receptors. This hypothesis was tested in alpha1H101R mice, in which the alpha1 subunit of the GABA(A) receptor is rendered insensitive to benzodiazepine binding resulting in an approximate 50% reduction in the total benzodiazepine-containing GABA(A) receptor population. It was shown that the Occ(50) brain concentrations in the alpha1H101R animals was lower (17 nM) than in wild type mice (63 nM), as was the plateau concentration in the brain (105 and 195 nM, respectively). These data suggest measured concentrations of compounds A and B in brain tissue are dependent on receptor expression with a minimal contribution from unbound and non-specifically bound compound.

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Synthesis of [ ¹⁸ F]Flumazenil ([ ¹⁸ F]FZ)

Schirrmacher

Kostikov

Massaweh

et al. 2012

Radiochemical Syntheses

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Regional Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788 Binding Reflect Selectivity for α1 versus α2 and α3 Subunit-Containing GABAA Receptors

Abstract: The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788

Cited by 72 publications

References 25 publications

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands

Synthesis of [ ¹⁸ F]Flumazenil ([ ¹⁸ F]FZ)

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Regional Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788 Binding Reflect Selectivity for α1 versus α2 and α3 Subunit-Containing GABAA Receptors

Abstract: The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788

Cited by 72 publications

References 25 publications

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands

Synthesis of [ 18 F]Flumazenil ([ 18 F]FZ)

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Synthesis of [ ¹⁸ F]Flumazenil ([ ¹⁸ F]FZ)