Department of Translational Imaging Biomarkers, Merck & Co., Kenilworth, New Jersey.
Department of Translational Imaging Biomarkers, Merck & Co., Kenilworth, New Jersey.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2022 Jun;7(6):598-606. doi: 10.1016/j.bpsc.2020.09.014. Epub 2020 Sep 29.
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 C-glutamate+glutamine (Glx) H3:H4 labeling ratio, in nonhuman primates using localized H-magnetic resonance spectroscopy combined with C-glucose infusions.
We began with numerical simulations in an established model of brain glutamate metabolism, showing that the C-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 H-magnetic resonance spectroscopy method (point-resolved spectroscopy sequence/echo time = 20 ms), obviating the need for specialized hardware and pulse sequences typically used with C-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.
The C-Glx H3:H4 ratios in the monkeys showed that BNC375 increases neuronal metabolism in nonhuman primates in vivo, detectable on an individual basis.
This study demonstrates that the ratio of C-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.
开发针对中枢神经系统疾病相关认知缺陷的治疗方法目前是一项重大医学需求。尽管非常需要此类治疗方法，但药物开发过程中的一个重大挑战是缺乏强大的生物标志物来评估靶标调节并指导临床决策。我们使用局部 H 磁共振波谱学结合 C-葡萄糖输注，在非人类灵长类动物中开发了一种新的、可转化的神经元谷氨酸代谢生物标志物，即 C-谷氨酸+谷氨酰胺（Glx）H3:H4 标记比。
我们首先在一个已建立的大脑谷氨酸代谢模型中进行了数值模拟，结果表明 C-Glx H3:H4 比应该是三羧酸循环活性的敏感生物标志物，三羧酸循环活性是整体神经元代谢的关键指标。我们表明，该生物标志物可以使用标准的 H 磁共振波谱学方法（点分辨波谱序列/回波时间=20ms）可靠地测量，从而避免了使用通常与 C 磁共振波谱学一起使用的特殊硬件和脉冲序列的需要，从而提高了整体临床可转化性。最后，我们在 8 只雄性恒河猴给药前和给药后使用了这种生物标志物，给药的化合物是 BNC375，它是一种α7 烟碱型乙酰胆碱受体的正变构调节剂，可增强谷氨酸信号在体外，并在临床前物种中引起认知促进作用。
猴子的 C-Glx H3:H4 比值表明，BNC375 在非人类灵长类动物体内增加了神经元代谢，可在个体基础上检测到。
这项研究表明，C-Glx H3:H4 标记的比率是一种生物标志物，它可以提供一种客观的方法来检测影响谷氨酸能神经传递的化合物，并可能改善治疗药物开发的决策。
