The Application of in silico Methods for Prediction of Blood-Brain Barrier Permeability of Small Molecule PET Tracers

Designing positron emission tomography (PET) tracers for targets in the central nervous system (CNS) is challenging. Besides showing high affinity and high selectivity for their intended target, these tracers have to be able to cross the blood-brain barrier (BBB). Since only a small fraction of small molecules is estimated to be able to cross the BBB, tools that can predict permeability at an early stage during the development are of great importance. One such tool is in silico models for predicting BBB-permeability. Thus far, such models have been built based on CNS drugs, with one exception. Herein, we sought to discuss and analyze if in silico predictions that have been built based on CNS drugs can be applied for CNS PET tracers as well, or if dedicated models are needed for the latter. Depending on what is taken into account in the prediction, i.e., passive diffusion or also active influx/efflux, there may be a need for a model build on CNS PET tracers. Following a brief introduction, an overview of a few selected in silico BBB-permeability predictions is provided along with a short historical background to the topic. In addition, a combination of previously reported CNS PET tracer datasets were assessed in a couple of selected models and guidelines for predicting BBB-permeability. The selected models were either predicting only passive diffusion or also the influence of ADME (absorption, distribution, metabolism and excretion) parameters. To conclude, we discuss the potential need of a prediction model dedicated for CNS PET tracers and present the key issues in respect to setting up a such a model.