Toyohara Jun, Sakata Muneyuki, Hatano Kentaro, Yanai Shuichi, Endo Shogo, Ishibashi Kenji, Wagatsuma Kei, Ishii Kenji, Ishiwata Kiichi
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Ann Nucl Med. 2016 Oct;30(8):534-43. doi: 10.1007/s12149-016-1094-7. Epub 2016 Jun 21.
We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.
In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [(11)C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [(11)C]CB184, was evaluated. Acute toxicity of [(11)C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [(11)C]CB184 was also evaluated after the decay-out of (11)C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [(11)C]CB184 in a normal human volunteer was performed.
A suitable preparation method for [(11)C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [(11)C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [(11)C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [(11)C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [(11)C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [(11)C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [(11)C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [(11)C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.
[(11)C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.
我们使用N,N-二正丙基-2-[2-(4-[(11)C]甲氧基苯基)-6,8-二氯咪唑并[1,2-a]吡啶-3-基]乙酰胺([(11)C]CB184)在人脑进行了临床前和首例人体正电子发射断层扫描(PET)研究，以成像18 kDa转位蛋白(TSPO)，该蛋白在神经炎症状态下的活化小胶质细胞中过表达。
对CB184的体外选择性进行了表征。根据小鼠分布数据计算[(11)C]CB184在人体中的辐射吸收剂量。评估了盐酸CB184在大鼠中以5.81 mg/kg体重的剂量（比[(11)C]CB184的临床等效剂量高10000倍以上）的急性毒性。在(11)C衰变后，还评估了[(11)C]CB184注射400倍剂量以给予假定剂量740 MBq [(11)C]CB184的急性毒性。用反向突变试验（Ames试验）研究了CB184的致突变性。用旷场试验研究了CB184注射对小鼠的药理作用。在一名正常人类志愿者中进行了[(11)C]CB184对TSPO的首次PET成像。
建立了[(11)C]CB184注射的合适制备方法。CB184在28种标准受体结合谱中显示出低活性。[(11)C]CB184在人体中的辐射吸收剂量对于临床使用足够低，并且未发现CB184或[(11)C]CB184注射的急性毒性。未观察到CB184有致突变性或对运动活性或焦虑状态的明显影响。在一名正常人类志愿者中给予[(11)C]CB184后，我们安全地进行了PET脑成像。90分钟的动态扫描显示放射性在脑中快速初始摄取，随后迅速清除。[(11)C]CB184在灰质中均匀分布。[(11)C]CB184的总分布容积在丘脑中最高，其次是小脑皮质和其他部位。尽管区域差异较小，但观察到的[(11)C]CB184结合模式与正常人类脑中TSPO的分布一致。在人体外周，[(11)C]CB184被代谢：60分钟后血浆中30%的放射性被检测为未变化形式。
[(11)C]CB184适用于人脑TSPO成像，并提供可接受的辐射剂量。在PET成像所需剂量下注意到了药理安全性。
