一种新型正电子发射断层显像（PET）示踪剂F-脱氧硫胺素：合成、代谢动力学及脑硫胺素代谢状态评估

A novel PET tracer F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status.

作者信息

Wang Changpeng, Zhang Siwei, Zou Yuefei, Ma Hongzhao, Jiang Donglang, Sheng Lei, Sang Shaoming, Jin Lirong, Guan Yihui, Gui Yuan, Xu Zhihong, Zhong Chunjiu

机构信息

Department of Neurology, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai, 200032, China.

Jiangsu Huayi Technology Co., Ltd., Jiangsu, 215519, China.

出版信息

EJNMMI Res. 2020 Oct 20;10(1):126. doi: 10.1186/s13550-020-00710-5.

DOI:10.1186/s13550-020-00710-5

PMID:33079296

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7575681/

Abstract

BACKGROUND

Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer's disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed.

METHODS

A novel PET tracer of F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated.

RESULTS

The F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015).

CONCLUSION

The F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

摘要

背景

一些神经心理疾病与硫胺素代谢异常有关，包括科萨科夫 - 韦尼克综合征和阿尔茨海默病。然而，脑硫胺素代谢状态的体内检测仍然无法实现，需要进一步开发。

方法

通过两步路线使用自动化模块合成了一种新型的F - 脱氧硫胺素PET示踪剂。通过高效液相色谱（HPLC）评估了主要质量控制参数，如比活度和放射化学纯度。通过放射性校准器测定放射化学浓度。通过微型正电子发射断层扫描/计算机断层扫描（PET/CT）研究了小鼠和狨猴脑中F - 脱氧硫胺素的代谢动力学和水平。分别使用HPLC和γ计数器测定了F - 脱氧硫胺素在小鼠体内的稳定性、肾排泄率和生物分布。此外，还研究了注射后60分钟内脑内F - 脱氧硫胺素的滞留量（以曲线下面积（AUC）表示）与血硫胺素水平之间的相关性。

结果

F - 脱氧硫胺素在体外和体内均稳定。F - 脱氧硫胺素在小鼠体内的摄取和清除速度很快。1分钟内在肝脏中达到最大标准摄取值（SUVmax）为4.61±0.53，在肾脏中半分钟内达到18.67±7.04。注射60分钟后，肝脏和肾脏中的SUV分别降至0.72±0.05和0.77±0.35。注射后，肾脏、肝脏和胰腺表现出较高的F - 脱氧硫胺素蓄积水平，而脑、肌肉、脂肪和性腺显示出较低的蓄积浓度，这与先前关于小鼠硫胺素分布的报道一致。注射后90分钟内，硫胺素缺乏（TD）的C57BL/6小鼠脑中F - 脱氧硫胺素水平比对照小鼠高1.9倍，TD的ICR小鼠脑中该水平比对照小鼠高3.1倍。狨猴脑内示踪剂在60分钟内的AUC为29.33±5.15，与血硫胺二磷酸水平呈负相关（r = - 0.985，p = 0.015）。