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

Hui Liu, Zonghua Luo, Jiwei Gu, Yi Su, Hubert Flores, Stanley M Parsons, Yun Zhou, Joel S Perlmutter, Zhude Tu

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 2020 Feb 15

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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. Copyright © 2019 Elsevier B.V. All rights reserved.

Citation

Hui Liu, Zonghua Luo, Jiwei Gu, Yi Su, Hubert Flores, Stanley M Parsons, Yun Zhou, Joel S Perlmutter, Zhude Tu. 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 : official journal of the European Federation for Pharmaceutical Sciences. 2020 Feb 15;143:105152