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

Abstract

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.

Keywords: Biomarker; Glutamate; Imaging; MRS; Nicotinic acetylcholine receptor; Positive allosteric modulator.