The impact of dopamine D2-like agonist/antagonist on [18F]VAT PET measurement of VAChT in the brain of nonhuman primates.,European Journal of Pharmaceutical Sciences

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The impact of dopamine D2-like agonist/antagonist on [18F]VAT PET measurement of VAChT in the brain of nonhuman primates.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-15 , DOI: 10.1016/j.ejps.2019.105152
Hui Liu ₁ , Zonghua Luo ₁ , Jiwei Gu ₁ , Yi Su ₁ , Hubert Flores ₂ , Stanley M Parsons ₃ , Yun Zhou ₁ , Joel S Perlmutter ₄ , Zhude Tu ₁

Affiliation

Vesicular acetylcholine transporter (VAChT) is a promising target for a PET measure of cholinergic deficits which contribute to cognitive impairments. Dopamine D2-like agonists and antagonists are frequently used in the elderly and could alter cholinergic function and VAChT level. Therefore, pretreatment with dopamine D2-like drugs may interfere with PET measures using [18F]VAT, a specific VAChT radioligand. Herein, we investigated the impact of dopaminergic D2-like antagonist/agonist on VAChT level in the brain of macaques using [18F]VAT PET. PET imaging studies were carried out on macaques at baseline or pretreatment conditions. For pretreatment, animals were injected using a VAChT inhibitor (-)-vesamicol, a D2-like antagonist (-)-eticlopride, and a D2-like agonist (-)-quinpirole, separately. (-)-Vesamicol was injected at escalating doses of 0.025, 0.05, 0.125, 0.25 and 0.35 mg/kg; (-)-eticlopride was injected at escalating doses of 0.01, 0.10 and 0.30 mg/kg; (-)-quinpirole was injected at escalating doses of 0.20, 0.30, and 0.50 mg/kg. PET data showed [18F]VAT uptake declined in a dose-dependent manner by (-)-vesamicol pretreatment, demonstrating [18F]VAT uptake is sensitive to reflect the availability of VAChT binding sites. Furthermore, (-)-eticlopride increased [18F]VAT striatal uptake in a dose-dependent manner, while (-)-quinpirole decreased its uptake, suggesting striatal VAChT levels can be regulated by D2-like drug administration. Our findings confirmed [18F]VAT offers a reliable tool to in vivo assess the availability of VAChT binding sites. More importantly, PET with [18F]VAT successfully quantified the impact of dopaminergic D2-like drugs on striatal VAChT level, suggesting [18F]VAT has great potential for investigating the interaction between dopaminergic and cholinergic systems in vivo.

中文翻译：

多巴胺 D2 样激动剂/拮抗剂对非人灵长类动物大脑中 VAChT 的 [18F]VAT PET 测量的影响。

囊泡乙酰胆碱转运蛋白 (VAChT) 是 PET 测量胆碱能缺陷（导致认知障碍）的一个有前途的目标。多巴胺 D2 样激动剂和拮抗剂经常用于老年人，可能会改变胆碱能功能和 VAChT 水平。因此，使用多巴胺 D2 类药物进行预处理可能会干扰使用 [18F]VAT（一种特定的 VAChT 放射性配体）进行的 PET 测量。在此，我们使用 [18F]VAT PET 研究了多巴胺能 D2 样拮抗剂/激动剂对猕猴大脑中 VAChT 水平的影响。在基线或预处理条件下对猕猴进行 PET 成像研究。对于预处理，分别使用VAChT抑制剂(-)-维沙考、D2样拮抗剂(-)-艾氯必利和D2样激动剂(-)-喹吡罗给动物注射。 (-)-Vesamicol 以 0.025、0.05、0.125、0.25 和 0.35 mg/kg 的递增剂量注射； (-)-艾氯必利以0.01、0.10和0.30 mg/kg的递增剂量注射； (-)-喹吡罗以 0.20、0.30 和 0.50 mg/kg 的递增剂量注射。 PET 数据显示，(-)-维沙考预处理后，[ 18 F] VAT 摄取量以剂量依赖性方式下降，表明 [ 18 F] VAT 摄取量对反映 VAChT 结合位点的可用性很敏感。此外，(-)-艾氯必利以剂量依赖性方式增加[18F]VAT纹状体摄取，而(-)-喹吡罗降低其摄取，表明纹状体VAChT水平可以通过D2样药物给药来调节。我们的研究结果证实，[18F]VAT 提供了一种可靠的工具来体内评估 VAChT 结合位点的可用性。更重要的是，PET与[18F]VAT成功量化了多巴胺能D2类药物对纹状体VAChT水平的影响，表明[18F]VAT在研究体内多巴胺能和胆碱能系统之间的相互作用方面具有巨大潜力。

更新日期：2019-11-15

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