(-)-o-[11 C]methyl-trans-decalinvesamicol ((-)-[11 C]OMDV) as a PET ligand for the vesicular acetylcholine transporter.,SYNAPSE

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(-)-o-[11 C]methyl-trans-decalinvesamicol ((-)-[11 C]OMDV) as a PET ligand for the vesicular acetylcholine transporter.
SYNAPSE ( IF 1.6 ) Pub Date : 2020-06-05 , DOI: 10.1002/syn.22176
Daisuke Miwa ₁ , Yoji Kitamura ₁ , Takashi Kozaka ₁ , Taiki Shigeno ₁ , Kazuma Ogawa ₂ , Junichi Taki ₂ , Seigo Kinuya ₂ , Kazuhiro Shiba ₁

Affiliation

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 and o‐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.

中文翻译：

(-)-o-[11 C]methyl-trans-decalinvesamicol ((-)-[11 C]OMDV) 作为囊泡乙酰胆碱转运蛋白的 PET 配体。

为了开发一种 PET 成像剂来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-十氢萘醌([ ¹¹ C] OMDV)不仅因为它们对囊泡乙酰胆碱转运蛋白 (VAChT) 的结合亲和力和选择性存在差异，而且它们的体内活性也存在差异。[ ¹¹ C]OMDV 在体外和体内都对 VAChT 具有高结合亲和力。外消旋OMDV和ö -trimethylstannyl-反-decalinvesamicol（OTDV），这是前体的合成[ ¹¹C]OMDV，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)比(+)-OMDV(57.5 nM)高8倍。在生物分布研究中，两种对映异构体（(-)-[ ¹¹ C]OMDV 和 (+)-[ ¹¹ C]OMDV）的血脑屏障渗透性在术后 2 分钟时同样高（约 1.0%ID/g） -注射。然而，(+)-[ ¹¹ C]OMDV 从大脑中的清除速度比 (-)-[ ¹¹ C]OMDV 快。在体内阻断研究中，积累（ - ） - [ ¹¹ C] OMDV在皮层显着通过vesamicol合用降低（对照的约30％），和脑吸收（ - ） - [¹¹ C]OMDV 未因 (+)-喷他佐辛或 (+)-3-(3-羟基苯基)-N-丙基哌啶 ((+)-3-PPP) 的共同给药而显着改变。PET-CT 成像显示，通过共同给药维沙考可抑制大鼠脑对 (-)-[ ¹¹ C] OMDV 的摄取。总之，(-)-[ ¹¹ C]OMDV 是 OMDV 的对映异构体，在体内大鼠脑中以高亲和力选择性结合 VAChT。(-)-[ ¹¹ C]OMDV 可用作研究大脑突触前胆碱能神经元的潜在 PET 配体。

更新日期：2020-06-05

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