(－)‐o‐[11C]methyl‐trans‐decalinvesamicol ((－)‐[11C]OMDV) as a PET ligand for the vesicular acetylcholine transporter
(－)‐o‐[11C]methyl‐trans‐decalinvesamicol ((－)‐[11C]OMDV) as a PET ligand for the vesicular acetylcholine transporter
复制标题
(-)-o-[11C]甲基-反式-十氢萘维沙考 ((-)-[11C]OMDV) 作为囊泡乙酰胆碱转运蛋白的 PET 配体
DOI：
10.1002/syn.22176
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发表时间：
2020
期刊：
影响因子：
2.3
通讯作者：
Shiba Kazuhiro
中科院分区：
文献类型：
--
作者：
Miwa Daisuke;Kitamura Yoji;Kozaka Takashi;Shigeno Taiki;Ogawa Kazuma;Taki Junichi;Kinuya Seigo;Shiba Kazuhiro
为了开发PET成像剂以可视化由阿尔茨海默病引起的脑胆碱能神经元和突触变化，分离并研究了（−）-和（+）-o-[11 C]甲基-反式-十氢萘脂酶氯霉素（[11 C] OMDV）不仅在它们对囊泡乙酰胆碱转运蛋白（VAChT）的结合亲和力和选择性方面的差异，而且在它们的体内活性方面的差异。[11 C] OMDV在体外和体内均对VAChT具有高结合亲和力。外消旋OMDV和[11 C] OMDV合成前体--三甲基甲锡烷基-反式-十氢萘威霉素（OTDV）通过HPLC分离为（-）-光学异构体（（-）-OMDV和（-）-OTDV）和（+）-光学异构体（（+）-OMDV和（+）-OTDV）。在体外结合试验中，（-）-OMDV（7.2 nM）对VAChT的结合亲和力（Ki）是（+）-OMDV（57.5 nM）的8倍。在生物分布研究中，两种对映体（（−）-[11 C] OMDV和（+）-[11 C] OMDV）在注射后2 min的血脑屏障渗透性相似（约1.0%ID/g）。然而，（+）-[11 C] OMDV从大脑中清除的速度快于（-）-[11 C] OMDV。在体内阻断研究中，与vesamicol联合给药可显著降低（−）-[11 C] OMDV在皮质中的蓄积（约为对照的30%），与（+）-喷他佐辛或（+）-3-（3-羟基苯基）-N-丙基哌啶（（+）-3-PPP）联合给药未显著改变（−）-[11 C] OMDV的脑摄取。PET-CT成像显示，联合给予vesamicol可抑制大鼠脑摄取（−）-[11 C] OMDV。综上所述，OMDV的对映体（−）-[11 C] OMDV在大鼠脑内以高亲和力选择性结合VAChT。（-）-[11 C] OMDV可作为研究脑内突触前胆碱能神经元的潜在PET配体。
To develop a PET imaging agent to visualize brain cholinergic neurons and synaptic changes caused by Alzheimer's disease, (−)‐ and (+)‐o‐[11C]methyl‐trans‐decalinvesamicol ([11C]OMDV) were isolated and investigated for differences in not only their binding affinity and selectivity to vesicular acetylcholine transporter (VAChT), but also their in vivo activities. [11C]OMDV has a high binding affinity for VAChT both in vitro and in vivo. Racemic OMDV ando‐trimethylstannyl‐trans‐decalinvesamicol (OTDV), which are precursors for synthesis of [11C]OMDV, were separated into (−)‐optical isomers ((−)‐OMDV and (−)‐OTDV) and (+)‐optical isomers ((+)‐OMDV and (+)‐OTDV) by HPLC. In the in vitro binding assay, (−)‐OMDV(7.2 nM) showed eight times higher binding affinity (Ki) to VAChT than that of (+)‐OMDV(57.5 nM). In the biodistribution study, the blood–brain barrier permeability of both enantiomers ((−)‐[11C]OMDV and (+)‐[11C]OMDV) was similarly high (about 1.0%ID/g) at 2 min post‐injection. However, (+)‐[11C]OMDV clearance from the brain was faster than (−)‐[11C]OMDV. In the in vivo blocking study, accumulation of (−)‐[11C]OMDV in the cortex was markedly decreased (approximately 30% of control) by coadministration of vesamicol, and brain uptake of (−)‐[11C]OMDV was not significantly altered by coadministration of (+)‐pentazocine or (+)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine ((+)‐3‐PPP). PET‐CT imaging revealed inhibition of the rat brain uptake of (−)‐[11C]OMDV by coadministration of vesamicol. In conclusion, (−)‐[11C]OMDV, which is an enantiomer of OMDV, selectively binds to VAChT with high affinity in the rat brain in vivo. (−)‐[11C]OMDV may be utilized as a potential PET ligand for studying presynaptic cholinergic neurons in the brain.