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

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.