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.

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 (V_T) 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 (C_avg2-4h; 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)