Effect of Dopamine D2 Receptor Antagonists on [18F]-FEOBV Binding

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D-2 receptor antagonists were used to assess changes in [F-18]-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 (K-i) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [F-18]-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 [F-18]-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 [F-18]-FEOBV, normalized for injected dose and body weight, was nonsignificantly 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 [F-18]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased K-i in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced K-i in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in K-i in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower K-i than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in K-i induced by the selective D-2 receptor antagonist raclopride can in part be quantified using [F-18]-FEOBV PET imaging. Haloperidol, a nonselective D-2/sigma- receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [F-18]-FEOBV binding to sigma receptors. Hence, further studies evaluating the binding of [F-18]-FEOBV to sigma receptors using selective a receptor ligands are necessary.