Longitudinal characterization of mGluR5 using $^{11}C$-ABP688 PET imaging in the Q175 mouse model of Huntington's disease

The metabotropic glutamate receptor type 5 (mGluR5) represents a potential therapeutic target for the treatment of Huntingtons disease (HD). Using 11C-ABP688, a non-competitive and highly selective antagonist for mGluR5, we aimed to longitudinally characterize in vivo changes of mGluR5 by means of PET imaging in the Q175 mouse model of HD. Methods: 11C-ABP688 PET imaging, followed by an X-ray computed tomography (CT) scan, was performed in heterozygous Q175 mice (n = 18) and wild-type (WT) littermates (n = 18) at three different time points (namely 6, 9, and 13 months of age). 11C-ABP688 binding potential (BPND) was calculated for each time point in striatum and cortex using the cerebellum as reference region. In addition, voxel-based statistical parametric mapping (SPM) analysis was performed on BPND images. Post-mortem validation of mGluR5 levels and neuronal density was performed at 6 months of age. Results: 11C-ABP688 BPND of heterozygous Q175 animals was significantly reduced at all time points in the striatum (6 months: -13.1%, P < 0.001, 9 months: -13.5%, P < 0.001, and 13 months: -14.2%, P < 0.001) and in the cortex (6 months: -9.8%, P < 0.01, 9 months: -10.2%, P < 0.01, and 13 months: -10.6%, P < 0.01) when compared to WT littermates. Longitudinal changes of 11C-ABP688 BPND were also found in heterozygous mice showing a reduction at 13 months compared to 6 months (-10.4%, P < 0.05). SPM analysis confirmed reduced BPND in heterozygous compared to WT as well as the time-related decline of 11C-ABP688 binding in the striatum of heterozygous Q175 mice. Post-mortem analysis confirmed mGluR5 decrease in both striatum (-36.6%; P < 0.01) and cortex (-16.6%; P < 0.05) of heterozygous Q175 mice, while no difference in neuronal density was found. Conclusion: In vivo imaging of mGluR5 using 11C-ABP688 PET/CT revealed a marked reduction of ligand binding in the striatum and cortex of heterozygous mice compared to WT animals as well as a temporal decline in heterozygous Q175 mice. This study suggests 11C-ABP688 PET imaging as potential biomarker to monitor the disease progression and therapeutic strategies in HD.

Jaar van publicatie:2018

Trefwoorden:A1 Journal article

BOF-keylabel:ja

BOF-publication weight:10

CSS-citation score:1

Auteurs:International

Authors from:Higher Education

Toegankelijkheid:Open