Synthesis and evaluation of a new vesamicol analog o-[11C]methyl-trans-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter.
Synthesis and evaluation of a new vesamicol analog o-[11C]methyl-trans-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter.
复制标题
作为囊泡乙酰胆碱转运蛋白 PET 配体的新型 vesamicol 类似物 o-[11C]methyl-trans-decalinvesamicol 的合成和评估。
DOI：
10.1007/s12149-015-1039-6
复制
发表时间：
2015
影响因子：
2.6
通讯作者：
Kinuya S. and Shiba K.
中科院分区：
文献类型：
--
作者：
Kitamura Y.;Kozaka T.;Miwa D.;Uno I.;Azim M. A.-u.;Ogawa K.;Taki J.;Kinuya S. and Shiba K.
我们关注囊泡乙酰胆碱转运蛋白（VAChT）作为阿尔茨海默病早期诊断的靶点，因为胆碱能神经系统的功能障碍与阿尔茨海默病的症状密切相关，如识别、记忆和学习问题。由于其对sigma受体（σ-1和σ-2）的亲和力较低，邻甲基反式十烷维胺醇（OMDV）对囊状乙酰胆碱转运体（VAChT）具有较高的亲和力和选择性。[11C]制备了OMDV，并通过体内评价研究了其作为一种新的PET配体用于VAChT成像的潜力。方法以[11C]甲基碘化物为原料，经钯促进交联反应制备[11C]OMDV，放化产率60 ~ 75%，放化纯度大于98%，EOB后30min比活性为5 ~ 10 TBq/mmol。分别于注射后2、10、30、60 min进行[11C]OMDV在大鼠血液、脑区及主要脏器的体内生物分布研究。通过体内阻断研究和PET-CT成像研究，检测[11C]OMDV对VAChT的结合选择性。结果体内研究表明[11C]OMDV可通过血脑屏障（BBB）在大鼠脑内蓄积。同时给药维萨米可显著抑制[11C]OMDV的脑区域积累。相比而言，(+)-戊唑嗪（一种选择性的σ-1受体配体）和(+)-3-（3-羟基苯基）- n -丙基哌啶[(+)-3- ppp]（一种σ-1和σ-2受体配体）对[11C]OMDV的脑积累没有显著影响。PET-CT成像显示，联合给药维萨米可抑制脑内[11C]OMDV的积累。结论[11C]OMDV在体内大鼠脑内选择性与VAChT高亲和力结合，[11C]OMDV可能在未来作为VAChT特异配体用于PET成像。
IntroductionWe focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer’s diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2),o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [11C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.Method[11C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, with a radiochemical yield of 60–75 %, a radiochemical purity of greater than 98 %, and a specific activity of 5–10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [11C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET–CT imaging study were performed to check the binding selectivity of [11C]OMDV for VAChT.ResultsIn vivo studies demonstrated [11C]OMDV passage through the blood–brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [11C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [11C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET–CT imaging revealed inhibition of [11C]OMDV accumulation in the brain by co-administration of vesamicol.Conclusion[11C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [11C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.