High sigma-1 receptor (S1R) and very low dopamine 2/dopamine 3 receptor (D2/D3R) occupancy at clinically relevant doses of pridopidine in healthy volunteers (HV) and Huntington disease patients (HD): a F-18-Fluspidine and F-18-Fallypride PET study

PM Meyer; ID Grachev; GA Becker; M Bronzel; D Marsteller; O Voges; L Rabinovich; F Zientek; M Rullmann; B Sattler; M Patt; E Strauss; A Kluge; JM Savola; MF Gordon; M Geva; S Hesse; H Barthel; M Hayden; O Sabri

doi:10.1055/s-0040-1708168

Nuklearmedizin - NuclearMedicine, Inhaltsverzeichnis

Nuklearmedizin 2020; 59(02): 105
DOI: 10.1055/s-0040-1708168

Wissenschaftliche Vorträge

Kognitive Störungen

High sigma-1 receptor (S1R) and very low dopamine 2/dopamine 3 receptor (D2/D3R) occupancy at clinically relevant doses of pridopidine in healthy volunteers (HV) and Huntington disease patients (HD): a F-18-Fluspidine and F-18-Fallypride PET study

Autor*innen

PM Meyer

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
ID Grachev

²Teva Branded Pharmaceutical Products R&D, Inc., Frazer,, PA,, USA
GA Becker

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
M Bronzel

³ABX-CRO Advanced Pharmaceutical Services Forschungsgesellschaft mBH, Dresden,, Germany
D Marsteller

²Teva Branded Pharmaceutical Products R&D, Inc., Frazer,, PA,, USA
O Voges

³ABX-CRO Advanced Pharmaceutical Services Forschungsgesellschaft mBH, Dresden,, Germany
L Rabinovich

²Teva Branded Pharmaceutical Products R&D, Inc., Frazer,, PA,, USA
F Zientek

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
M Rullmann

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
B Sattler

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
M Patt

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
E Strauss

⁴AFL – Arzneimittelforschung Leipzig GmbH, Leipzig,, Germany
A Kluge

³ABX-CRO Advanced Pharmaceutical Services Forschungsgesellschaft mBH, Dresden,, Germany
JM Savola

²Teva Branded Pharmaceutical Products R&D, Inc., Frazer,, PA,, USA
MF Gordon

²Teva Branded Pharmaceutical Products R&D, Inc., Frazer,, PA,, USA
M Geva

⁵Prilenia Therapeutics Development Ltd., Herzliya,, Israel
S Hesse

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
H Barthel

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany
M Hayden

⁵Prilenia Therapeutics Development Ltd., Herzliya,, Israel
O Sabri

¹University of Leipzig, Department of Nuclear Medicine, Leipzig,, Germany

Abstract

Volltext

Ziel/Aim Pridopidine is an investigational drug that was designed as dopamine stabilizer to treat motor symptoms in HD. As shown precinically, Pridopidine has much higher affinity to S1Rs as compared to D2/D3 Rs. S1R activation mediates neuroprotection and mental enhancement. To clarify the mechanism of action of Pridopidine and observed clinical outcomes in prior clinical trials, we quantified, using S1R-specific (-)-F-18-Fluspidine and D2/D3 R-specific F-18-Fallypidrefe PET, the S1R occupancy (S1RO) and D2/D3R occupancy (D2/D3RO) by Pridopidine at previously used clinical doses in HV and HD.

Methodik/Methods Eleven male HV (27 ± 2 yrs; pridopidine 90 to 0.5 mg in 6 dose groups) and 3 male HD (43 ± 13 yrs, pridopidine 90 mg) were studied twice before and 2hrs following single oral doses of pridopidine using (-)-F-18-Fluspidine PET (300 MBq, 0–90 min p.i.). Distribution volume (V_T) was quantified using kinetic modeling (1TCM; metabolite correction). Four male HV (29 ± 5 yrs) were studied twice using F-18-Fallypidrefe PET (200 MBq, 0–210 min p.i.) before and 2hrs after a single oral dose of pridopidine (90 mg). Binding potential (BP_ND) was assessed (SRTM, cerebellum as ref. region). VOI-analyses were performed. For each subject/tracer, the receptor occupancy (RO) was calculated by Lassen plot analysis.

Ergebnisse/Results A typical sigmoid-shaped dose occupancy relation for S1R was established in HV for pridopidine doses ranging from 0.5 to 90 mg. In HV, there was high S1RO (87 ± 3 % to 91 ± 4 %) across all brain regions at doses ranging from 22.5 to 90 mg. S1RO was 43 % at 1 mg and 18 % at 0.5 mg pridopidine. In HD, very similar to HV, at 90 mg pridopidine, there was high S1RO (87 ± 7 %, n.s.). In contrast, in HV, there was only negligible D2/D3RO (3 ± 2 %) at 90 mg pridopidine.

Schlussfolgerungen/Conclusions Our PET findings indicate that after single oral dose of 90 mg (exposure correlates with 45 mg bi-daily at steady state), pridopidine shows full (~ 90 %) S1RO but only minimal (~ 3 %) D2/D3RO. These data provide significant clarification about the mechanism of action/clinical effects of pridopidine.