Matrix assisted laser desorption/ionization (MALDI) is the leading high spatial resolution (≤ 10 µm) imaging mass spectrometry (IMS) technology owing to its broad molecular coverage and ability to specifically target selected molecular classes based on different sample preparation approaches. A little over a decade ago, 1,5-Diaminonaphtalene (DAN) was proposed as a low volatility dual polarity matrix for high spatial resolution lipid IMS and has remained the commonly used matrix for such analysis. Recent reports have described alternatives such as norharman (expensive) and anthranilic acid derivatives (volatile). Here we propose the use of aminated cinnamic acid analogues (ACAA) that produce both small crystal size and provide high vacuum stability as affordable, high spatial resolution MALDI IMS matrices.<br/>ACAA compounds have shown great potential to be the primary MALDI matrix for tissue IMS of lipids at high spatial resolution. The proposed analogues have been found to be vacuum stable for more than 48h at pressure as low as 5x10<sup>-7</sup> mbar along with producing sub micrometer scale crystals when sprayed with mixture of polar aprotic solvents on tissue. UV-vis analysis of the ACAA compounds showed that these derivatives have higher extinction coefficient than regular MALDI matrices generating smaller spot size on tissue during imaging experiments. While DAN is known to produce dimethyl phosphatidylethanolamine (DMPE) like fragment in negative ion mode the new ACAA compounds significantly reduce the formation of these fragments. A final advantage for these ACAA compounds is there relatively low toxicity compared to DAN. The new ACAA compounds have enabled 5 um spatial resolution IMS of both human kidneys and human eyes as part of the Human BioMolecular Atlas Program in both positive and negative ion mode allowing the visualization of hundreds of lipids at cellular resolution.

Aminated cinnamic acid analogues as dual polarity matrices for high spatial resolution MALDI imaging mass spectrometry of lipids

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