Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (±)-5-OH-VAT is potent (K_i = 4.64 ± 0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ₁ and σ₂ receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while (−)-5-OH-VAT originally serves as the radiolabeling precursor of (−)-[¹⁸F]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate (−)-5-OH-[¹⁸F]VAT as a radiotracer for VAChT, we performed in vitro binding assay to determine the potency of the minus enantiomer (−)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (−)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (−)-5-OH-[¹⁸F]VAT was explored using three strategies. (−)-5-OH-[¹⁸F]VAT was achieved with a good yield (24 ± 6%) and high molar activity (∼37 GBq/µmol, at the end of synthesis) using a microwave assisted two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (−)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (−)-5-OH-[¹⁸F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [¹⁸F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain.

水泡乙酰胆碱转运蛋白（VAChT）是一种可靠的生物标记物，用于评估与患者认知障碍相关的脑内胆碱能神经元的丢失。5- Hydrotetralin化合物（±）-5-OH-VAT是有效的（ķ_我 = 4.64±0.32 nM）的和选择性的中VAChT（> 1800倍和398倍为σ ₁和σ ₂，分别受体）具有良好的亲水性（LogD = 1.78），而（-）-5-OH-VAT最初是（-）-[ ¹⁸ F] VAT的放射性标记前体，这是有希望的VAChT放射性示踪剂，logD值为2.56。为了评估（-）-5-OH- [ ¹⁸ F] VAT作为VAChT的放射性示踪剂，我们执行了体外结合测定法来测定负对映异构体（-）-5-OH-VAT和正对映异构体（+）-5-OH-VAT的效力，表明（-）-5-OH-VAT是更有效的VAChT对映体。使用三种策略探索了（-）-5-OH- [ ¹⁸ F] VAT的放射性合成。（-）-5-OH- [ ¹⁸ F] VAT使用微波辅助的两步法获得了良好的收率（24±6％）和高的摩尔活性（〜37 GBq / µ mol，在合成结束时）一锅程序始于di-MOM保护的含硝基前体（-）- 6。非人类灵长类动物（NHP）大脑中的MicroPET研究表明，（-）-5-OH- [与[ ¹⁸ F] VAT相比， ¹⁸ F] VAT容易穿透血脑屏障，并且特别是在富含VAChT的纹状体中积累，并且纹状体的清除动力学得到改善。尽管如此，较低的靶标与非靶标之比可能会限制其在体内测量大脑中VAChT水平的用途。