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Effect of dopamine D2 receptor antagonists on [18F]-FEOBV binding

Schildt, A., de Vries, E. F. J., Willemsen, A. T. M., Giacobbo, B. L., Moraga-Amaro, R., Sijbesma, J. W. A., van Waarde, A., Sossi, V., Dierckx, R. A. J. O. & Doorduin, J., 3-Feb-2020, In : Molecular pharmaceutics.

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The interaction of dopaminergic and cholinergic neurotransmission in, e.g. Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride or vehicle, 90-min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma, and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p>0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p=0.022, Cohen's d=2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was non-significantly increased in the striatum after haloperidol (adjusted p=0.4, Cohen's d=1.77) and raclopride (adjusted p=0.052, Cohen's d=1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment non-significantly increasedKii in the striatum 1.3-fold compared to control rats (adjusted p=0.1, Cohen's d=1.1) while it reduced Ki in the cerebellum by 28% (adjusted p=0.0004, Cohen's d=2.2) compared to control rats. Pretreatment with haloperidol led to a non-significant reduction in Ki in the striatum (10%, adjusted p=1, Cohen's d=0.44) and a 40% to 50% lower Ki than controls in all other brain regions (adjusted p<0.0005, Cohen's d=3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a non-selective D2 / σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

Original languageEnglish
JournalMolecular pharmaceutics
Publication statusE-pub ahead of print - 3-Feb-2020

ID: 117120998