title: Imaging in Central Nervous System Drug Discovery.
abstract: The discovery and development of central nervous system (CNS) drugs is an extremely challenging process requiring large resources, timelines, and associated costs. The high risk of failure leads to high levels of risk. Over the past couple of decades PET imaging has become a central component of the CNS drug-development process, enabling decision-making in phase I studies, where early discharge of risk provides increased confidence to progress a candidate to more costly later phase testing at the right dose level or alternatively to kill a compound through failure to meet key criteria. The so called "3 pillars" of drug survival, namely; tissue exposure, target engagement, and pharmacologic activity, are particularly well suited for evaluation by PET imaging. This review introduces the process of CNS drug development before considering how PET imaging of the "3 pillars" has advanced to provide valuable tools for decision-making on the critical path of CNS drug development. Finally, we review the advances in PET science of biomarker development and analysis that enable sophisticated drug-development studies in man.
authors.affiliation: Imanova Ltd, London, United Kingdom; Division of Brain Sciences, Imperial College London, London, United Kingdom; Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom. Electronic address: roger.gunn@imanova.co.uk.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: Imanova Ltd, London, United Kingdom; Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002491:Central Nervous System Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D002491:Central Nervous System Agents