With the aim of evaluating the potential of SIMS to provide molecular information from small molecules within biological systems, here we investigate the effect of different biological compounds as they act as matrices. The results highlight the fact that the chemical environment of a molecule can have a significant effect on its limit of detection. This has implications for the imaging of drugs and xenobiotics in tissue sections and other biological matrices. A 1: 1 mixture of the organic acid 2,4,6-trihydroxyacetophenone and the dipeptide valine-valine demonstrates that almost complete suppression of the [M + H](+) ion of one compound can be caused by the presence of a compound of higher proton affinity. The significance of this is highlighted when two similar drug molecules, atropine (a neutral molecule) and ipratropium bromide (a quaternary nitrogen containing salt) are mixed with brain homogenate. The atropine [M + H](+) ion shows significant suppression whilst the [M - Br](+) of ipratopium bromide is detected at an intensity that can be rationalised by its decreased surface concentration. By investigating the effect of two abundant tissue lipids, cholesterol and dipalmitoylphosphatidyl choline (DPPC), on the atropine [M + H](+) signal detected in mixtures with these lipids we see that the DPPC has a strong suppressing effect, which may be attributed to gas phase proton transfer. (c) 2006 Elsevier B.V. All rights reserved.