PET measurement system as a biomarker of central nervous system pharmacological effect of drugs.

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PET is useful for evaluating pharmacological effect of drugs although only a few clinical trials have been conducted in Japan due to poor environment both in technologies and regulations. We have established the so-called in-house GMP-based quality control according to the guidelines issued by the Japan Radioisotope Association (Version 2001) in the Institute of Biomedical Research and Innovation. An imaging CRO specializing in PET was established locally to support clinical trials using PET. An in-house license for the PET research nurse has also been established. Using these systems, a clinical study was conducted regarding PET measurement of the central nervous system pharmacological effect of a drug. Some antihistamines have a sedative effect as they enter the brain and block the histamine H1 receptor, which is difficult to evaluate in behavioral tests due to large variation but can be measured as H1 receptor occupancy using PET with C-11 labeled doxepin. Olopatadine is a slightly sedative antihistamine, but the sedative effect wears off after repeated medication. In the present study, H1 receptor binding potential (BP) was measured with PET on 17 subjects with perennial nasal allergy at baseline, at the initial dose of olopatadine, and at another dose after repeated administration of olopatadine for four weeks. The BP of the frontal cortex under the initial single dose was slightly lower than the baseline, but it showed a marked decrease following 4-week medication, which suggests down regulation of H1 receptor possibly due to increased endogenous histamine level and may be related to the wearing off phenomenon. The results indicate that it is possible and plausible to evaluate the central nervous system effect of a drug and its repeated administration on the receptor using PET, which may be useful for drug development.