The usefulness of MALDI for small-molecule work has been limited by matrix chemical interference in the mass range of interest, tedious sample preparation, and various crystallization and sample deposition issues. We report instrument characterization and small-molecule quantification performance data from a high repetition rate laser MALDI ion source coupled to a triple quadrupole mass spectrometer. The high repetition rate laser improves sensitivity and precision and allows a proportional increase in sample throughput. Tandem mass spectrometry is used to discriminate the signal from the high chemical background caused by the MALDI matrix. Successful quantification requires use of an internal standard and a means of sample cleanup for typical in vitro sample compositions. This instrument combination and analysis technique is relatively insensitive to sample crystal quality and spot homogeneity. Quantitative performance results are characterized for 53 small-molecule pharmaceutical compounds and compared to those obtained by ESI-MS/MS. Further comparison between MALDI and ESI is examined, and the potential for high-throughput MALDI-MS/MS quantification is demonstrated.

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When phospholipids ionized by fast atom bombardment undergo collisionally induced dissociation (CID), they cleave at specific bonds between the functional groups contained on the lipid. These cleavages are common to all classes of phospholipids. By taking advantage of this fact, a general scheme has been developed that uses a triple-quadrupole mass spectrometer to rapidly characterize the phospholipid content and structures present in crude lipid extracts. This scheme is based on fast atom bombardment ionization of a crude lipid extract and on the combination of positive-ion neutral-loss and parent scans and negative-ion daughter scans. Neutral-loss and parent scans provide independent diagnostic mass spectra for each of many specific phospholipid classes, while daughter scans provide the emperical formulas and positions of the fatty acyl constituents on each phospholipid. An automated tandem mass spectrometry (MS/MS) instrument can perform an extensive phospholipid screening on a single sample. A useful mass profile of the phosphatidylethanolamine species present in a 1-pg sample of mixed phospholipids (equivalent to ten Escherichia coli cells) has been obtained. The spectra are reproducible and proportional to concentration over at least the five-logarithm range of cell concentrations studied. A rapid extraction procedure combined with the automated instrument control program produces profiles of the phospholipid classes, along with fatty acyl empirical formulas and position information, on selected phospholipid species, in a few minutes, from a single sample.

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