Tissue distribution of new chemical entities is a critical component of pre-clinical drug development. Autoradiography has been the only practical technique for examining drug distribution in animal whole-body to date. Compared to autoradiography, imaging mass spectrometry does not require radiolabeled compound, and has the advantage of distinguishing the parent molecule from its metabolites.

Two examples will be given to illustrate the utility of this emerging technique in drug discovery. In the first example, compound X was active in vitro, but showed no in vivo efficacy for a CNS target. LC-MS determination of whole brain homogenate suggested that drug exposure was sufficiently high. However, imaging mass spectrometry showed that >90 % of the compound X was localized in the ventricle area and did not reach the cortex where the drug target was located, explaining the lack of efficacy. In the second example, the distribution of drug-related material following an oral dosing of the antihistamine terfenadine was examined by imaging mass spectrometry. The molecular specificity of this technique allowed pre-systemic metabolism to be directly visualized for the first time.