Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator

Wyss, Matthias T.; Ametamey, Simon M.; Treyer, Valérie; Bettio, Andrea; Blagoev, Milen; Kessler, Lea J.; Burger, Cyrill; Weber, Bruno; Schmidt, Mark E.; Gasparini, F.; Buck, Alfred

doi:10.1016/j.neuroimage.2007.01.005

Cited by 36 publications

(38 citation statements)

References 19 publications

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“…Recent autoradiographic studies with PET ligand show high concentrations of mGluR5 in the striatum, cortex and hippocampus (Wyss et al 2007). However, in 6-OHDA lesioned rats, MPEP binding was increased in comparison to controls.…”

Section: Discussionmentioning

confidence: 94%

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Leonibus

Managò

Giordani

et al. 2008

Neuropsychopharmacol

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Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudateputamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.

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Section: Discussionmentioning

confidence: 94%

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Leonibus

Managò

Giordani

et al. 2008

Neuropsychopharmacol

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“…The b-scintillator (Swisstrace, Zurich, Switzerland) has been described in detail earlier (Weber et al, 2003;Wyss et al, 2007). In short, it consists of a scintillation tip (Bicron, BF12, Newbury, OH, USA) with a length of 1 mm and a diameter of 0.25 mm attached to a high numerical aperture glass fiber.…”

Section: B-scintillatormentioning

confidence: 99%

Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-¹¹C-Acetate

Wyss

Weber

Treyer

et al. 2008

J Cereb Blood Flow Metab

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The purpose of this study was to investigate astrocytic oxidative metabolism using 1-11 C-acetate. 1-11 C-acetate kinetics were evaluated in the rat somatosensory cortex using a b-scintillator during different manipulations (test-retest, infraorbital nerve stimulation, and administration of acetazolamide or dichloroacetate). In humans a visual activation paradigm was used and kinetics were measured with positron emission tomography. Data were analyzed using a one-tissue compartment model. The following features supported the hypothesis that washout of radiolabel (k 2 ) is because of 11 C-CO 2 and therefore related to oxygen consumption (CMRO 2 ): (1) the onset of 11 C washout was delayed; (2) k 2 was not affected by acetazolamide-induced blood flow increase; (3) k 2 demonstrated a significant increase during stimulation in rats (from 0.014 ± 0.007 to 0.027 ± 0.006 per minute) and humans (from 0.016±0.010 to 0.026±0.006 per minute); and (4) dichloroacetate led to a substantial decrease of k 2 . In the test-retest experiments K 1 and k 2 were very stable. In summary, 1-11 C-acetate seems a promising tracer to investigate astrocytic oxidative metabolism in vivo. If the washout rate indeed represents the production of 11 C-CO 2 , then its increase during stimulation would point to a substantially higher astrocytic oxidative metabolism during brain activation. However, the quantitative relationship between k 2 and CMRO 2 needs to be determined in future experiments.

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“…The clearest examples of work which can be compared derive from studies on pharmacodynamic markers, investigating whether a compound interacts appropriately with its molecular target at its target organ, i.e., a receptor in the brain. For example, a PET ligand for the mGlu 5 receptor has been developed, allowing a direct comparison of the level of receptor occupancy and distribution of mGlu 5 agonists or antagonists in animals and humans in vivo (Ametamey et al 2006Wyss et al 2007). The development of surrogate efficacy biomarkers has been more challenging, although the effects of the mGlu 2 agonist LY354740 in fear-potentiated startle in both animals and healthy volunteers have been described and can serve as an example for such an approach (Bueno et al 2005;Helton et al 1998;Johnson et al 2003;Tizzano et al 2002;Walker et al 2002).…”

Section: Metabotropic Glutamate Receptors In Translationmentioning

confidence: 99%

“…Recent developments in imaging technology, specifically increased resolution, allow imaging in rodents and non-human primates alongside human studies and can aid in comparing distributions across species. In a series of studies testing the selective mGlu 5 PET ligand 11 C-ABP688 in rats, humans and mice, Ametamey et al were able to demonstrate very similar patterns of ligand binding in these species (Ametamey et al 2006Wyss et al 2007). These studies showed high binding in the hippocampus, striatum, and cortex, in accordance with distribution patterns seen using immunohistochemistry and in situ hybridization for the mGlu 5 receptor in both human (Daggett et al 1995) and rat brain (Romano et al 1995).…”

Section: Translational Research With Mglur Binding: Development Of a mentioning

confidence: 99%

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

Nordquist

Steckler²,

Wettstein

et al. 2008

Psychopharmacology

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Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

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Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator

Cited by 36 publications

References 19 publications

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-¹¹C-Acetate

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

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Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator

Cited by 36 publications

References 19 publications

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-11C-Acetate

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

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Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-¹¹C-Acetate