Developing mass spectrometry for the quantitative analysis of neuropeptides.

INTRODUCTION: Neuropeptides are signaling molecules originating in the neuroendocrine system that can act as neurotransmitters and hormones in many biochemical processes. Their exact function is difficult to characterize, however, due to dependence on concentration, post-translational modifications, and the presence of other comodulating neuropeptides. Mass spectrometry enables sensitive, accurate, and global peptidomic analyses that can profile neuropeptide expression changes to understand their roles in many biological problems, such as neurodegenerative disorders and metabolic function. AREAS COVERED: We provide a brief overview of the fundamentals of neuropeptidomic research, limitations of existing methods, and recent progress in the field. This review is focused on developments in mass spectrometry and encompasses labeling strategies, post-translational modification analysis, mass spectrometry imaging, and integrated multi-omic workflows, with discussion emphasizing quantitative advancements. EXPERT OPINION: Neuropeptidomics is critical for future clinical research with impacts in biomarker discovery, receptor identification, and drug design. While advancements are being made to improve sensitivity and accuracy, there is still room for improvement. Better quantitative strategies are required for clinical analyses, and these methods also need to be amenable to mass spectrometry imaging, post-translational modification analysis, and multi-omics to facilitate understanding and future treatment of many diseases.