Multiple Brain Effects of Pridopidine in Huntington Disease Patients and Healthy Volunteers - A Simultaneous Sigma-1 Receptor PET/MRI Study

Introduction: Huntington disease (HD) is a devastating inherited neurodegenerative disorder. Pridopidine is currently under development as a drug to maintain functional capacity or to provide functional benefit in HD. Its pharmacological effect is mainly mediated via sigma-1 receptor (S1R) interaction. Our knowledge on how this interaction exerts different brain processes in vivo, however, is limited so far. It was, thus, the aim of this simultaneous PET/MRI study to investigate the pridopidine effect on neurotransmission, brain perfusion, metabolism, and functional connectivity.

Methods: This is a sub-study of a brain PET study which evaluated the S1R and dopamine-2 receptor occupancy by pridopidine in healthy volunteers (HVs) and HD patients. Here, the data of 3 HD patients (age 43±13yrs) and those of 7 HVs (age 29±3yrs) are presented. All subjects underwent simultaneous brain PET/multimodality MRI (up to 390min p.i., 3T Siemens Biograph mMR) under baseline conditions and after a single oral dose of the clinically tested dose of 90mg pridopidine. MRI included arterial spin labelling (ASL, pulsed sequence, VOI and SPM analysis, global normalisation, relative cerebral blood flow [rCBF]), resting-state fMRI (BOLD sequence, seed-based: basal ganglia, sensory-motor and default mode networks [DMN]), and proton MR spectroscopy (MRS, axial slice through striatum, 10 ROIs, each creatine [Cr]), choline [Cho], inositol [Ins], and glutamine/glutamate peaks, reference: N-acetylaspartate [NAA] peak). S1R occupancy was determined by (S)-(-)-[18F]Fluspidine PET and VOI analysis, 1-tissue compartment modelling (metabolite-corrected arterial input), and Lassen plot analysis.

Results: In HVs, 90mg pridopidine (i) occupied 91±4% of the S1Rs (n=4), (ii) decreased rCBF in temporal cortical (p=0.009) and cerebellar (p=0.007) areas, (iii) decreased Ins/NAA in white matter (p=0.037), and (iv) increased connectivity within the basal ganglia network (4/7 subjects) and DMN (6/7 subjects). In HD, the drug effect was not different with regard to S1R occupancy (n=3). While no drug effects on rCBF were observed in HD, pridopidine increased Cr/NAA (p=0.050) and Cho/NAA (p=0.018) in the putamina as well as functional connectivity within the default mode (3/3 patients) network.

Conclusions: Pridopidine in a clinically tested dose shows full S1R-occcupancy in HD patients and HVs which is associated with multiple effects on brain perfusion, metabolism, and functional connectivity. Especially the positive effect on the DMN network connectivity provides further motivation for the development of this drug in HD. These data, however, indicate that pharmacological PET/MRI is a useful tool to improve understanding of drug effects in the brain on a multi-modality level in a one-stop shop approach.

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