Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography

Anne Lingford-Hughes, Susan P Hume, Adrian Feeney, Ella Hirani, Safiye Osman, Vincent J Cunningham, Victor W Pike, David J Brooks, David J Nutt

Research output: Contribution to journalArticle

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Abstract

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the alpha1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the alpha5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the alpha1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the alpha5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.
Original languageEnglish
Pages (from-to)878-89
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume22
Issue number7
DOIs
Publication statusPublished - 2002

Fingerprint

GABA-A Receptors
Positron-Emission Tomography
Flumazenil
L 655,708
Flunitrazepam
Occipital Lobe
Brain
Cerebellum
gamma-Aminobutyric Acid
Ro 15-4513
Hippocampus
Pharmaceutical Preparations

Keywords

  • Animals
  • Azides
  • Benzodiazepines
  • Binding, Competitive
  • Carbon Radioisotopes
  • Cerebellum
  • Cerebral Cortex
  • Flumazenil
  • Hippocampus
  • Humans
  • Kinetics
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A
  • Tissue Distribution
  • Tomography, Emission-Computed

Cite this

Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. / Lingford-Hughes, Anne; Hume, Susan P; Feeney, Adrian; Hirani, Ella; Osman, Safiye; Cunningham, Vincent J; Pike, Victor W; Brooks, David J; Nutt, David J.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 22, No. 7, 2002, p. 878-89.

Research output: Contribution to journalArticle

Lingford-Hughes, Anne ; Hume, Susan P ; Feeney, Adrian ; Hirani, Ella ; Osman, Safiye ; Cunningham, Vincent J ; Pike, Victor W ; Brooks, David J ; Nutt, David J. / Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. In: Journal of Cerebral Blood Flow and Metabolism. 2002 ; Vol. 22, No. 7. pp. 878-89.
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T1 - Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography

AU - Lingford-Hughes, Anne

AU - Hume, Susan P

AU - Feeney, Adrian

AU - Hirani, Ella

AU - Osman, Safiye

AU - Cunningham, Vincent J

AU - Pike, Victor W

AU - Brooks, David J

AU - Nutt, David J

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N2 - There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the alpha1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the alpha5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the alpha1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the alpha5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

AB - There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the alpha1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the alpha5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the alpha1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the alpha5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

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KW - Azides

KW - Benzodiazepines

KW - Binding, Competitive

KW - Carbon Radioisotopes

KW - Cerebellum

KW - Cerebral Cortex

KW - Flumazenil

KW - Hippocampus

KW - Humans

KW - Kinetics

KW - Male

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, GABA-A

KW - Tissue Distribution

KW - Tomography, Emission-Computed

U2 - 10.1097/00004647-200207000-00013

DO - 10.1097/00004647-200207000-00013

M3 - Article

VL - 22

SP - 878

EP - 889

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 7

ER -