Abstract
PurposeDopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD.MethodsWe longitudinally characterized in vivo [18F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [3H] fallypride autoradiography at 12 months of age.ResultsWe implemented an improved synthesis method for [18F] fallypride to yield high molar activity (MA, 298–360 GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [18F] fallypride was > 100 GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [3H] fallypride autoradiography.ConclusionsWe observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [18F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.
Highlights
Huntington’s disease (HD) is a devastating hereditary autosomal progressive neurodegenerative disorder
In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to Wild type (WT) littermates
These results are in line with clinical findings in HD patients, suggesting [18F] fallypride Positron emission tomography (PET) imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies
Summary
Huntington’s disease (HD) is a devastating hereditary autosomal progressive neurodegenerative disorder. Dopamine (DA) receptors are subdivided into D1-like and D2-like receptor families, and reduced density and activity of these receptors has been reported in the striatum of early-manifest HD patients (Niccolini et al 2014). In another study about 40% reduction in binding of [11C]SCH23390 and [11C] raclopride to D1R and D2R, respectively, has been reported in HD patients (Ginovart et al 1997). Reduction in radioligand binding was significantly associated with the duration of symptoms, suggesting these receptors could be reliable quantitative targets to monitor disease progression (Niccolini et al 2014; Ginovart et al 1997)
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