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

PET可用于评价药物的药理作用，但由于日本的技术和法规环境较差，目前仅进行了几项临床试验。我们已经根据日本放射性同位素协会(2001年版)在生物医学研究和创新研究所发布的指南建立了所谓的基于GMP的内部质量控制。在当地成立了一个专门从事PET的成像CRO，以支持使用PET的临床试验。PET研究护士的内部许可证也已经建立。使用这些系统，进行了一项关于PET测量药物的中枢神经系统药理效应的临床研究。一些抗组胺药物在进入大脑时具有镇静作用，并阻断组胺H1受体，由于变化很大，很难在行为测试中进行评估，但可以使用带有C-11标记的多塞平的PET来测量H1受体的占有率。奥洛他定是一种轻微的镇静抗组胺药物，但在反复服药后镇静作用消失。本文对17例常年性鼻变态反应患者用正电子发射计算机断层扫描(PET)测定了基线、初始剂量奥洛他定和重复用药4周后不同剂量的H1受体结合电位。单次给药后额叶皮质血压略低于基础值，用药4周后血压明显下降，提示H1受体功能下调可能与内源性组胺水平升高有关，可能与疲劳现象有关。结果表明，用正电子发射计算机断层扫描技术评价药物的中枢神经系统效应及其对受体的重复给药是可能的，这可能有助于药物的开发。

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.