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.

• Authors: Igor D Grachev, Philipp M Meyer, Georg A Becker, Marcus Bronzel, Doug Marsteller, Gina Pastino, Ole Voges, Laura Rabinovich, Helena Knebel, Franziska Zientek, Michael Rullmann, Bernhard Sattler, Marianne Patt, Thilo Gerhards, Maria Strauss, Andreas Kluge, Peter Brust, Juha-Matti Savola, Mark F Gordon, Michal Geva, Swen Hesse, Henryk Barthel, Michael R Hayden, Osama Sabri
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 48 Issue 4 Pg. 1103-1115 (04 2021) ISSN: 1619-7089 [Electronic] Germany
• PMID: 32995944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1'-benzyl-3-(2-fluoroethyl)-3H-spiro((2)benzofuran-1,4'-piperidine)
• Benzamides
• Benzofurans
• Piperidines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• fallypride
• pridopidine
• Dopamine

Topics

• Benzamides
• Benzofurans
• Brain (diagnostic imaging, metabolism)
• Dopamine
• Healthy Volunteers
• Humans
• Huntington Disease (diagnostic imaging)
• Male
• Piperidines
• Positron-Emission Tomography
• Receptors, Dopamine D2 (metabolism)
• Receptors, Dopamine D3 (metabolism)