A Potential of Positron Emission Tomography in the Drug Development of Non-sedative Antihistamines

Histamine H1 receptor antagonists, or antihistamines, are very effective for treatment of various allergic disorders such as seasonal rhinitis and urticaria. Sometimes antihistamines induce sedative CNS side effects that might result in dangerous traffic accidents. That is why a lack of sedation is important for development of new antihistamines. It is clear that all antihistamines have a potential to produce subjective (sleepiness, fatigue etc.) and objective sedation (impaired performance), dependent on the histaminergic mechanisms involved in the control of arousal. We have proposed the usefulness of H1 receptor occupancy measurement with Positron Emission Tomography (PET) using ¹¹C-doxepin as a tracer. The PET measurement is currently included as one of the three major factors defined by the international Consensus Group on New Generation Antihistamines (CONGA) for evaluation of antihistamines: 1) incidence of subjective sleepiness, 2) objective and psychomotor functions, and 3) PET measurement of H1 receptor occupancy. Merit of PET measurement is that we can directly calculate the receptor occupancy for each separate drug while the former two should be discussed based on the difference between placebo and active placebo. PET will be used more actively in the development of various new drugs in future.