MRI in CNS Drug Development

There are three ways in which magnetic resonance imaging is typically used in drug development: to validate the role of drugs and neuropharmacological systems in terms of their effects on the brain, the development of brain markers to evaluate drugs—these can be associated with particular disorders or symptoms—and the evaluation of compounds with neuroimaging markers. MRI is effectively multimodal. Markers of brain function are sensitive to drug modulation and include perfusion and blood flow, functional imaging with tasks, brain connectivity, tracking of activity with rapidly changing blood levels from drug administration, and spectroscopy for brain metabolite levels. Fast pharmacokinetics can be tracked, and drugs with slower pharmacokinetics can be assessed for context-dependent effects and quantitative effects on blood flow and brain metabolite levels. These methods can be applied to healthy volunteers, combined with models of dysfunction, or in patients to translate evidence in experimental animals, validate theory, and provide early indicators of potential efficacy. Significant challenges exist with MRI methodology such as the limited evaluation of reliability, the modeling of confounds, stratification of individuals to understand response and nonresponse or base definitions on functional neurobiological deficits requiring treatment, and bridging the gap between the modulation of brain systems and clinical outcome. Numerous examples exist to demonstrate the success and future potential of MRI methodologies in the drug development process, which, if correctly applied, can provide a principled basis for some treatment options over others, leading to clear go/no-go decision early in the development and accelerating the delivery of novel therapeutics for those in need.