Teva Branded Pharmaceutical Products R&D, Inc, Malvern, PA, 19355, USA.
Guide Pharmaceutical Consulting, LLC, Millstone, NJ, 08535, USA.
Eur J Nucl Med Mol Imaging. 2021 Apr;48(4):1103-1115. doi: 10.1007/s00259-020-05030-3. Epub 2020 Sep 29.
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 [F] fluspidine and [F] 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.
Using [F] 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 [F] 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.
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%).
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.
普里多吡啶是一种用于亨廷顿病（HD）的研究药物。普里多吡啶最初被认为是一种多巴胺稳定剂。然而，普里多吡啶在临床相关剂量下在临床前研究中表现出对西格玛-1 受体（S1R）的最高亲和力，并通过 S1R 增强神经保护作用。本研究使用 [F] 氟斯吡啶和 [F] 氟哌啶醇 PET，旨在评估健康志愿者（HV）中临床相关剂量下普里多吡啶与 S1R 和多巴胺 D2/D3 受体（D2/D3R）的体内靶标结合/受体占有率，并在少数 HD 患者中作为概念验证。
使用 [F] 氟斯吡啶 PET（300MBq，0-90min），11 名男性 HV（普里多吡啶 0.5 至 90mg；六个剂量组）和 3 名男性 HD 患者（普里多吡啶 90mg）进行了两次研究，一次是在单次给药前，一次是在 2 小时后。使用 [F] 氟哌啶醇 PET（200MBq，0-210min），4 名男性 HV 在给予普里多吡啶（90mg）后无和 2 小时进行了研究。通过 Lassen 图分析受体占有率。
HV 中 S1R 占有率作为普里多吡啶剂量（或血浆浓度）的函数，可以用三参数 Hill 方程描述，Hill 系数大于 1。在普里多吡啶剂量为 22.5 至 90mg 时，大脑各处均发现高程度的 S1R 占有率（87%至 91%）。普里多吡啶 1mg 时 S1R 占有率为 43%。相比之下，普里多吡啶 90mg 时，D2/D3R 占有率仅很小（约 3%）。
我们的 PET 研究结果表明，在临床相关的 90mg 单剂量下，普里多吡啶作为一种选择性 S1R 配体，表现出接近完全的 S1R 占有率，而 D2/D3R 的占有率可忽略不计。剂量 S1R 占有率关系表明普里多吡啶与 S1R 的协同结合。我们的研究结果对普里多吡啶的作用机制提供了重要的澄清，并支持在未来神经退行性疾病的临床试验中使用 45mg 每日两次的剂量来实现 S1R 的完全和选择性靶向。临床试验注册编号：NCT03019289 2017 年 1 月 12 日；EUDRA-CT-Nr. 2016-001757-41。
