Imaging the GABA-Benzodiazepine Receptor Subtype Containing the α5-Subunit In Vivo with [¹¹C]Ro15 4513 Positron Emission Tomography

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.

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

“…Partial disruption of GABAergic neurons in the cortex of mice causes seizures, anxiety, and impaired social behavior, consistent with GABA signaling defects contributing to the etiology of autism-spectrum disorders (50). Unlike GABRB3, GABRA5 and GABRG3 proteins do not primarily localize in cerebral cortex (51)(52)(53), consistent with our expression data (Supplementary Figure 1). Deletion of both Gabra5 and Gabrg3 does not cause an apparent phenotype in mice (54,55), however, Gabrb3-deficient mice exhibit phenotypes such as seizures, sleep abnormalities, and stereotyped behaviors consistent with characteristics of AS, RTT, and autism (55).…”

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…Careful selection of the target to be imaged in combination et al 1997 [36] Glutamate receptor: mGluR1 et al 2013 [37] Glutamate receptor: mGluR5 et al 2007 [38] Glutamate receptor: mGluR5 et al 2008 [39] Glutamate receptor: mGluR5 et al 2012 [40] Glutamate receptor: mGluR5 et al 2013 [41] Glutamate NMDA receptor: PCP site [ 11 C]ketamine Kumlien et al 1999 [42] Glutamate NMDA receptor: PCP site [ 11 C]CNS-5161 Hammers et al 2004 [43] Glutamate NMDA receptor: PCP site [ 18 F]fl uoromemantine Ametamey et al 2002 [44] Glutamate NMDA receptor: PCP site [ 18 F]GE-179 McGinnity et al 2014 [45] Glutamate NMDA receptor: glycine-site et al 2007 [46] Histamine receptor: H1 et al 1991 [47] (To be continued) [53] Opioid receptor: et al 1990 [54] Opioid receptor: et al 1997 [55] Opioid receptor: et al 2010 [56] Opioid receptor: unselective et al 1990 [54] Opioid A schematic view of this complex situation, identifying important molecules involved in the three classes of diseases noted above, is shown in Fig. 2.…”

“…2002 [53] Opioid receptor: μ [ 11 C]carfentanil Frost et al 1990 [54] Opioid receptor: δ [ 11 C]methylnaltrindol Madar et al 1997 [55] Opioid receptor: κ [ 11 C]GR103545 Tomasi et al 2010 [56] Opioid receptor: unselective [ 11 C]diprenorphine Frost et al 1990 [54] Opioid receptor: unselective…”

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

“…Aside from its obvious utility for comparative anatomy of the mGlu 5 receptor distribution in vivo, having an mGlu 5 receptor ligand such as 11 C-ABP688 also presents the possibility to conduct blocking and competition studies in vivo similarly to work that has been conducted on other receptors, i.e., NMDA (Ametamey et al 1999), benzodiazepine (Bottlaender et al 1994;Lingford-Hughes et al 2002), and dopamine (Kassiou et al 2002;Nikolaus et al 2005) receptors. By circumventing the need to radiolabel each novel compound, competition and blocking studies can considerably speed imaging studies with new compounds.…”