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Amino neurotransmitters(NTs),such as amino acids and monoamines,play vital roles in nerve cell communication and regulate a variety of biological processes.Abnormal concentrations of these NTs in brain are associated with various central nervous system disorders such as anxiety,depression,schizophrenia,Parkinsons disease,and Alzheimers disease.Visualization of the distribution of NTs in tissue will be essential in understanding their roles in various neurophysiological processes and pathological mechanisms.Mass spectrometry imaging(MSI),as a powerful tool for in situ analysis of biomolecules in tissue,has shown great potential for this application.However,trace level analysis of NTs by MSI has proven challenging because of their low-ionization efficiency and ion suppression effects.Chemical derivatization is an efficient strategy for the detection of amino metabolites and has been applied to matrix-assisted laser desorption/ionization(MALDI)MSI in recent studies1-3.The derivative products of amino NTs with increased mass are more easily ionized and detected,while still suffering from the matrix ion interference in low mass region.In this study,we combined on-tissue chemical derivatization and an ambient ionization technique coupled with an ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry(FTICR MS)to achieve excellent sensitivity,high mass accuracy,and structural specificity for imaging of endogenous amino NTs directly in rat brain tissues.4-hydroxy-3-methoxycinnamaldehyde(CA)was used as the derivatization reagent,the carbonyl of which formed a stable Schiff base with the amine moiety.The electrospray deposition4 process of CA solution onto tissue slides was sufficient for good analyte derivatization and further ambient MSI analysis without additional incubation or matrix application,simplifying sample preparation and minimizing metabolite delocalization.As a result,monoamine NTs like dopamine and amino acid NTs like γ-aminobutyric acid,glycine,taurine,aspartate,and glutamic acid could be identified and spatially visualized in rat brain without matrix interference,exhibiting superior sensitivity and imaging performance in comparison to MALDI MS.