BACKGROUND: An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5. METHODS: We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, ΔBP(ND), could be detected above the noise in the measurement. RESULTS: Linear mixed modeling comparing ΔBP(ND) from test-retest to ΔBP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. ΔBP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies. CONCLUSIONS: NAC induced decrease in [(11)C] ABP688 ΔBP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission.
BACKGROUND: An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5. METHODS: We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, ΔBP(ND), could be detected above the noise in the measurement. RESULTS: Linear mixed modeling comparing ΔBP(ND) from test-retest to ΔBP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. ΔBP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies. CONCLUSIONS:NAC induced decrease in [(11)C] ABP688 ΔBP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission.
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Authors: Sophie E Holmes; Jean-Dominique Gallezot; Margaret T Davis; Nicole DellaGioia; David Matuskey; Nabeel Nabulsi; John H Krystal; Jonathan A Javitch; Christine DeLorenzo; Richard E Carson; Irina Esterlis Journal: J Cereb Blood Flow Metab Date: 2019-11-19 Impact factor: 6.200
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