基于PET脑纹状体D2/3受体显像技术评价抗帕金森病DR激动药罗匹尼罗的DR占有治疗窗及其机制研究

Parkinson's disease is a nervous system degenerative disease in middle-aged and old people. Ropinirole, a non-ergoline dopamine agonist, has been selected as one of the preferred drug treatment by the guide. Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores were used to assess clinical therapeutic effect, which is easily affected by the subjective factors of patients and doctors. Therefore, it is badly necessary to find a more objective therapeutic effect index. For treatment effect is proportional to the dopamine receptor (DR) occupancy, the best way to solve this problem is to study the therapeutic window, using PET cerebral imaging technology. Currently, foreign research mainly focus on DR antagonists, which are used for the treatment of neuropsychiatry. These studies certified that DR occupancy may be a subjective way to evaluate clinical therapeutic effect. However, there is no study about DR agonist to date, and even no study about DR occupancy in China. Our previous research demonstrates the feasibility of PET brain imaging technology in studying DR occupancy and association between the concentration and occupancy after ropinirole was administered. In consequence, using PET imaging technology, the association between DR occupancy and the concentration of ropinirole in monkey brain will be studied, and a PK/PD model will be built to privide a new therapeutic regimen, which will be much more safety and effective. In further, a possible DR occupancy therapeutic window in clinical and its mechanism will be found. And in all, a new platform to study DR occupancy of DR agonist will be investigated to Parkinson’s disease base on our study.

帕金森病是一种中老年常见的神经系统退行性疾病，非麦角类罗匹尼罗为代表的多巴胺受体（DR）激动剂为治疗首选药物。现行临床疗效指标如UPDRS评分等易受主观影响，临床需一种更为客观有效的疗效指标。而利用PET脑纹状体D2/3受体显像技术开展的DR占有率可使解决该问题成为可能。国外研究主要集中在DR抑制药，但由于技术原因DR激动药研究未见报道，而在我国DR占有率研究仍为空白。本课题组前期大鼠研究论证了该技术在罗匹尼罗DR占有率测定的可行性以及其与药物浓度的相关性。本研究旨在应用以18F-Fallypride为显像剂的PET脑显像技术探索猴体内罗匹尼罗的血药浓度与纹状体DR占有的相关性，建立PK/PD模型为临床提供罗匹尼罗安全有效的给药方案，并进一步探讨临床可能的治疗窗及其机制；并以此为基础建立运用显像技术开展DR占有率研究的技术平台。

帕金森病是一种中老年常见的神经系统退行性疾病，非麦角类罗匹尼罗为代表的多巴胺受体（DR）激动剂为治疗首选药物。现行临床疗效指标如UPDRS评分等易受主观影响，临床需一种更为客观有效的疗效指标。.首先，本研究建立了食蟹猴体内18F-Fallypride的扫描方法，建立UPLC-MS/MS测定食蟹猴血浆中罗匹尼罗浓度的方法。.其次，建立石蟹猴静脉注射MPTP建立了稳定的帕金森病动物模型，并开展模型评价，建立了PET显像技术评价帕金森模型成立的方法，结果与帕金森模型评分和运动计数具有高度一致性，适合帕金森模型的评价，可以作为模型成功的评价指标之一。.基于稳定的PD猴模型，我们进行了PD猴服用罗匹尼罗后有效性和安全性的评价。本研究开展了以18F-Fallypride为显像剂的PET显像与受体激动剂罗匹尼罗药效的相关性研究，结果显示BP值得变化率与行为学评分变化率之间有着很好的相关性（y = 1.0394x - 4.1574；R² = 0.8567）。因此推断，以18F-Fallypride为显像剂的PET显像可以作为客观全面的药效评价指标，从而描述激动剂治疗帕金森病的药效。在安全性评价研究中，开展了以18F-Fallypride为显像剂的PET显像与受体激动剂罗匹尼罗安全性的相关性研究，由于试验设计中给药剂量由高到低，使得BP值存在累积，进而无法得到BP值与安全性的相关性。.最后，对食蟹猴血浆中罗匹尼罗药动学进行研究，结果表明，在0.2~1.5 mg/kg范围内在体内呈线性药代动力学特征。进而对药动学与药效、安全性的相关性进行分析，初步推测出当Cmax达到1.21ng/mL，AUC0-t达到2.34 h•ng•mL-1时开始起效。当Cmax大于2.68 ng/mL，AUC0-t大于3.77 h•ng•mL-1时容易发生不良反应。基于药动学与我们新建立的药效指标PET值建立PK-PD模型，通过PK-PD模型的预测功能，以期为临床上实现从血药浓度数据对罗匹尼罗治疗帕金森疾病安全性及有效性进行推测提供了可能性，为临床上使用血药浓度罗匹尼罗安全有效治疗窗提供了坚实的基础。