High Sigma-1 Receptor (S1r) But Minimal Dopamine-2 / Dopamine-3 Receptor (D2/D3r) Occupancy At Clinically Relevant Doses Of Pridopidine In Health Volunteers And Huntington Disease Patients Investigated By Using (S)-(-)-[F-18]Fluspidine And [F-18]Fallypride Pet

338 Objectives: Pridopidine is an investigational drug originally postulated to act as dopamine stabilizer to treat motor symptoms in Huntington disease (HD) patients. However, preclinical data shows that pridopidine has much higher affinity to S1Rs than to D2/D3Rs. S1R activation mediates neuroprotective properties in numerous models of neurodegenerative diseases, and enhances neuronal plasticity. To determine the target engagement of pridopidine at clinically relevant doses , we used S1R-specific (S)-(-)-[18F]Fluspidine and D2/D3R-specific [18F]Fallypride PET imaging to quantify the S1R occupancy (S1RO) and D2/D3R occupancy (D2/D3RO) by pridopidine at previously used clinical doses in healthy volunteers (HV) and HD patients. Methods: Eleven male HVs (27 ± 2 yrs; pridopidine 0.5 mg to 90 mg in 6 dose groups) and 3 male HD patients (43 ± 13 yrs, pridopidine 90 mg) were imaged. Each subject was evaluated twice: without pridopidine and 2 hours following a single oral dose of pridopidine, using (S)-(-)-[18F]Fluspidine PET (300 MBq, 0-90 min p.i., Siemens PET/MRI). Distribution volumes (VT) were obtained using kinetic modeling (1TCM; metabolite correction). In addition, four male HVs (29 ± 5 years) were studied twice using [18F]Fallypride PET (200 MBq, 0-210 min p.i.), without and 2 hours following a single oral dose of pridopidine (90 mg). Binding potentials (BPND) were obtained using a simplified reference tissue model (cerebellum as reference region). VOI analyses were performed. For each subject/tracer, the receptor occupancy (RO) was calculated by Lassen plot analysis. Results: A sigmoid-shaped dose/response relation (Hill equation) was established for pridopidine concerning the S1R occupancy in HVs at pridopidine doses ranging from 0.5 to 90 mg. In the HVs, there was a high degree of S1R occupancy (87 ± 3% to 91 ± 4%) across all brain regions at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy below 50% was demonstrated after reducing the pridopidine dose to 1 mg (43%). The lowest dose of 0.5 mg pridopidine evaluated in this study still achieved a RO of 18%. In HD patients, very similar to the HVs, a high degree of S1R occupancy (87 ± 7%) was observed with a pridopidine dose of 90 mg. In contrast to the high S1R occupancy, D2/D3R occupancy was negligible (3 ± 2%) with pridopidine 90 mg evaluated in HVs. Conclusions: Our PET findings indicate that, after a single dose of 90 mg (exposure correlates with the clinical dose of 45 mg bi-daily (bid) at steady state), pridopidine acts as a selective S1R ligand showing near complete S1R occupancy (~90%) but only minimal (~3%) D2/D3R occupancy. These data provide significant clarification about pridopidine’s mechanism of action and support further use of the 45 mg bid dose to achieve full and selective targeting of the S1R in future clinical Trials.