Positron Emission Tomography (PET) Neuroimaging of the <i>Pink1-/-</i> Rat Parkinson Disease Model with the Norepinephrine Transporter (NET) Ligand [¹⁸F]NS12137

Abstract

Evidence suggests that the neurotransmitter norepinephrine may play an important role in Parkinson disease (PD). The norepinephrine transporter (NET) regulates noradrenergic signaling and can serve as an index of noradrenergic innervation in neuroimaging studies. The Pink1-/- rat model, which exhibits many signs similar to PD, notably in the nonmotor domain, exhibits abnormal noradrenergic markers. Here, we sought to (1) implement reference region pharmacokinetic modeling of positron emission tomography (PET) imaging with the novel NET ligand [18F]NS12137, (2) validate the resulting indices of NET concentration, and (3) characterize NET in the Pink1-/- model. Long–Evans Pink1-/- male rats were imaged by PET with [18F]NS12137 at 9 and 11 months and compared with wild-type (WT) controls. An additional group of WT rats of both sexes were imaged with [18F]NS12137 PET after pretreatment with the specific and selective NET ligand nisoxetine. Binding in locus coeruleus (LC), thalamus (Thal), and prelimbic area (PrL), regions rich in NET, was analyzed by a two-tissue compartment reversible binding model using a cerebellar reference region. [18F]NS12137 binding exhibited moderate test–retest reproducibility in LC, Thal, and PrL. Nisoxetine blockade yielded substantial reductions of [18F]NS12137 binding in LC. Compared with WT controls, Pink1-/- rats exhibited reduced binding in Thal and PrL. Pharmacokinetic analysis of [18F]NS12137 PET provides a reproducible and specific measure of NET binding and indicates reduced NET in PD-related brain regions in Pink1-/- rats. Noninvasive in vivo [18F]NS12137 PET imaging is therefore a promising method for the study of potential therapies in the Pink1-/- rat.