A Novel Biomarker of Neuronal Glutamate Metabolism in Nonhuman Primates Using Localized 1H-Magnetic Resonance Spectroscopy: Development and Effects of BNC375, an α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator
| Autor: | Graeme F. Mason, Gerard Sanacora, Ying Chen, Douglas L. Rothman, Liza Gantert, Kenneth D. Anderson, Stephen F. Previs, Corin O. Miller, Justina M. Thomas, Jason M. Uslaner |
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| Rok vydání: | 2022 |
| Předmět: |
Allosteric modulator
Chemistry Cognitive Neuroscience 05 social sciences Central nervous system Glutamate receptor Neurotransmission 050105 experimental psychology Glutamine 03 medical and health sciences Nicotinic acetylcholine receptor Glutamatergic 0302 clinical medicine medicine.anatomical_structure medicine Biomarker (medicine) 0501 psychology and cognitive sciences Radiology Nuclear Medicine and imaging Neurology (clinical) Neuroscience 030217 neurology & neurosurgery Biological Psychiatry |
| Zdroj: | Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 7:598-606 |
| ISSN: | 2451-9022 |
| DOI: | 10.1016/j.bpsc.2020.09.014 |
| Popis: | Background The development of treatments for cognitive deficits associated with central nervous system disorders is currently a significant medical need. Despite the great need for such therapeutics, a significant challenge in the drug development process is the paucity of robust biomarkers to assess target modulation and guide clinical decisions. We developed a novel, translatable biomarker of neuronal glutamate metabolism, the 13C-glutamate+glutamine (Glx) H3:H4 labeling ratio, in nonhuman primates using localized 1H-magnetic resonance spectroscopy combined with 13C-glucose infusions. Methods We began with numerical simulations in an established model of brain glutamate metabolism, showing that the 13C-Glx H3:H4 ratio should be a sensitive biomarker of neuronal tricarboxylic acid cycle activity, a key measure of overall neuronal metabolism. We showed that this biomarker can be measured reliably using a standard 1H-magnetic resonance spectroscopy method (point-resolved spectroscopy sequence/echo time = 20 ms), obviating the need for specialized hardware and pulse sequences typically used with 13C-magnetic resonance spectroscopy, thus improving overall clinical translatability. Finally, we used this biomarker in 8 male rhesus macaques before and after administration of the compound BNC375, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor that enhances glutamate signaling ex vivo and elicits procognitive effects in preclinical species. Results The 13C-Glx H3:H4 ratios in the monkeys showed that BNC375 increases neuronal metabolism in nonhuman primates in vivo, detectable on an individual basis. Conclusions This study demonstrates that the ratio of 13C-Glx H3:H4 labeling is a biomarker that may provide an objective readout of compounds affecting glutamatergic neurotransmission and could improve decision making for the development of therapeutic agents. |
| Databáze: | OpenAIRE |
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