Huntington's disease (HD) is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. Patients display progressive motor, cognitive, and psychiatric impairment. Symptoms usually start at midlife. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain (Menalled, 2005).
It has been established in a HD mouse model that inhibition of PDE10 improves cognition and thus PDE10 might be a good therapeutic target (Giralt et al., 2013). A pilot study of [18F]-MNI-659 PET already showed a markedly reduced binding in HD compared to healthy volunteers (Jennings et al., 2013). Furthermore, the mechanism underlying HD-related suppression of inhibition has been shown to include tonic activity of metabotropic glutamate receptor subtype 5 (mGluR5) as a pathophysiological hallmark (Dvorzhak, Semtner, Faber, & Grantyn, 2013) and inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment (Scheifer et al., 2004).
With the objective to elucidate the role of phosphodiesterase and glutamatergic pathways using small animal PET imaging, this study aims to use [18F]-MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazo-lin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a PET radiotracer with high affinity for PDE 10 and [11C]-ABP-688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective mGluR5 antagonist, as tracers in a knock-in model of Huntington's disease.