Collision cross sections obtained with ion mobility mass spectrometry as new descriptor to predict blood-brain barrier permeation by drugs

Evaluating the ability of a drug to permeate the blood-brain barrier is not a trivial task due to the structural complexity of the central nervous system. Nevertheless, it is of immense importance to identify related properties of the drugs either to be able to produce a desired effect in the brain or to avoid unwanted side effects there. In the past, multiple methods have been used for that purpose. However, these are sometimes methodologically problematic and do not claim universal validity. Therefore, additional new methods for judging blood-brain barrier penetration by drugs are advantageous. Accordingly, within the scope of this study, we tried to introduce a new structure-derived parameter to predict the blood-brain barrier permeation of small molecules based on ion mobility mass spectrometry experiments – the collision cross section, as an illustration of the branching and the molecular volume of a molecule. In detail, we used ion mobility quadrupole time-of-flight mass spectrometric data of 46 pharmacologically active small-molecules as well as literature-derived permeability and lipophilicity data to set up our model. For the first time we were able to show a strong correlation between the brain penetration of pharmacologically active ingredients and their mass spectrometric collision cross sections.