Approaches for the discovery of novel positron emission tomography radiotracers for brain imaging

Purpose Positron emission tomography (PET) is a widely used imaging technique with many biomedical and drug development applications. The implementation of this technology requires the availability of selective radiotracers with suitable physicochemical characteristics relevant for each target, disease process/pathology, or physiological application. The purpose of the present review was to outline a typical high-level flow scheme for the discovery of PET radiotracers and discuss a variety of methods employed in the field to prosecute the flow scheme steps. In addition, techniques will be described which may be employed to overcome obstacles encountered during the execution of a radiotracer discovery flow scheme when specific challenges are encountered. Methods Based on our experience and a survey of the available literature we critically reviewed the manner in which laboratories execute each radiotracer discovery flow scheme step according to the ex vivo, in vitro, and in vivo resources available. Results We found that PET radiotracer identification requires that certain steps or scientific hurdles are met. The strategy or technology applied to answer these scientific challenges varies across laboratories as a function of access to resources. These resources may be accessed through collaboration with other scientists and laboratories. There has been an attempt by a number of research groups to define the optimal physiochemical property space for brain-penetrant PET radiotracers and to use these criteria to reduce the number of molecules further evaluated in vitro or in vivo. While these represent useful guidelines, they should not be taken as rules as none of them have demonstrated 100% accuracy in predicting success and failure of potential PET radiotracers. The advent and application of new technologies, such as protein target overexpression and viral vector administration, along with improvements in LC–MS/MS sensitivity, are expanding the ability of laboratories to initiate radiotracer discovery efforts for targets challenged by low rodent protein target expression or differences in protein sequences between rodent and human. Conclusions The techniques and approaches available for the discovery of novel small molecule CNS PET radiotracers continue to evolve. As new research technologies and scientific input from a variety of disciplines are applied to the discovery effort, novel solutions are generated and expand the field of radiotracer discovery.