Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Abstract

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.

Methods: Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot.

Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).

Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Keywords: Dopamine D2/D3 receptor occupancy; Huntington disease; PET; Pridopidine; Sigma-1 receptor occupancy; [18F]fluspidine.

Conflict of interest statement

Dr. Grachev was an employee of Teva Pharmaceuticals at the time of the study and is currently an employee of Guide Pharmaceutical Consulting. Drs. Gordon, Rabinovich, and Knebel are working for Teva Pharmaceuticals. Drs. Savola, Marsteller, and Pastino were employed by Teva Pharmaceuticals at the time of the study. Drs. Kluge, Bronzel, and Voges are staff members of ABX-CRO Advanced Pharmaceutical Services. Drs. Geva and Hayden who are now employed by Prilenia Therapeutics Development were former staff members of Teva Pharmaceuticals at the time of the study. In September 2018, Teva Pharmaceutical sold and transferred its rights pertaining to pridopidine to Prilenia Therapeutics. The remaining authors declare no competing interests.

Figures

Fig. 1

[18F] fluspidine baseline and post-drug PET of sigma-1 receptor (S1R) availability in healthy volunteers (HVs) and patients with Huntington disease (HD) and non-linear relationship between pridopidine dose (or plasma concentration) and S1R occupancy. [18F] fluspidine PET of S1R availability at baseline and post-drug in HVs and patients with HD. Almost complete S1R engagement/occupancy (VT) by pridopidine exemplified in one healthy volunteer (a) and one HD patient (c) is demonstrated within the whole brain at post-drug PET (90 mg pridopidine) as compared with baseline PET. For visualization purpose, parametric PET/MR images are shown. There is a sigmoidal curve relationship (b) between the pridopidine dose (left) or plasma concentration (Cavg2-4h; right, both on logarithmic scale) and S1R occupancy in HVs treated by a single dose of pridopidine ranging from 0.5 to 90 mg. The continuous line curve reflects fitting with a three-parameter model (Hill coefficient > 1) which was preferred, whereas the dotted line curve presents a two-parameter type model (Hill coefficient = 1)

Fig. 2

One-tissue compartment model fits of 90 min [18F] fluspidine PET data at baseline and post-drug in healthy volunteers (HVs) and patients with Huntington disease (HD). One-tissue compartment model fits of 90 min [18F] fluspidine PET data at baseline (a, c; PET1) and acquired 2 h after oral administration of 90 mg pridopidine (b, d; PET2) are exemplified for the cerebellum, frontal cortex, striatum, and corpus callosum in one representative HV (a, b) and one patient with HD (c, d)

Fig. 3

[18F] fallypride baseline and post-drug PET of dopamine D2/D3 receptor (D2/D3R) availability in healthy volunteers. Parametric PET/MR images of D2/D3R are demonstrated. There is no D2/D3R occupancy of pridopidine paradigmatically demonstrated in one healthy volunteer as assessed by [18F] fallypride PET at baseline and 2 h following single dose of 90 mg pridopidine

Fig. 4

Simplified reference tissue model fits of 210 min [18F] fallypride PET data at baseline and post-drug in healthy volunteers (HVs). Simplified reference tissue model fits of 210 min [18F] fallypride PET data at baseline (a; PET1) and acquired 2 h after oral administration of 90 mg pridopidine (b; PET2) are exemplified for the striatum, thalamus, and midbrain using the cerebellum as reference region in one representative healthy volunteer (HV)