Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain

Substance P (SP) and neurokinin-1 receptors (NK-1R) are localized within central and peripheral sensory pain pathways. The roles of SP and NK-1R in pain processing, the anatomical distribution of NK-1R and efficacy observed in preclinical pain studies involving pain and sensory sensitization models, suggested that NK-1R antagonists (NK-1RAs) would relieve pain in patient populations. Despite positive data available in preclinical tests for a role of NK-1RAs in pain, clinical studies across several pain conditions have been negative. In this review, we discuss how functional imaging-derived information on activity in pain-processing brain regions could have predicted that NK-1RAs would have a low probability of success in this therapeutic domain.

► Reevaluate the failed NK-1RA story in the light of potential contributions functional imaging may contribute to go–no go decisions in drug development. ► phMRI and fMRI of an available NK1RA (fosaprepitant) has highlighted unique information that functional imaging can provide on CNS drug candidates including target activation and effects on putative analgesic circuitry. ► phMRI and fMRI have potential use in clinical drug development to evaluate drug dosing and networks in the brain affected by centrally acting drugs in early phase clinical trials. ► For drugs that have multiple sites of action or when it is difficult to make a target specific PET tracer, fMRI may offer insights into how drugs affect CNS circuitry in health and disease.