Smart Kelly, Zheng Ming-Qiang, Holden Daniel, Felchner Zachary, Zhang Li, Han Yanjiang, Ropchan Jim, Carson Richard E, Vasdev Neil, Huang Yiyun
Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada.
Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada.
Pharmaceuticals (Basel). 2023 Jan 28;16(2):194. doi: 10.3390/ph16020194.
Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [C]OCM-44 and [F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [C]OCM-44 volume of distribution () values in the brain increased with time; values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm across brain regions. The plasma free fraction was 0.6% for [F]OCM-50 and values (120-min) were 0.39-0.87 mL/cm in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [C]OCM-44 and [F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.
糖原合酶激酶3（GSK-3）是一系列神经退行性疾病和精神疾病潜在的治疗靶点。本研究的目的是在非人灵长类动物中评估两种主要的GSK-3正电子发射断层扫描（PET）放射性配体[C]OCM-44和[F]OCM-50，以评估它们临床转化的潜力。在成年恒河猴中使用动脉血采样，对这两种放射性示踪剂总共进行了9次PET扫描。提取脑区时间-活性曲线，并使用代谢物校正的动脉输入函数，用单组织和双组织房室模型进行拟合。在预先给予GSK-3抑制剂PF-04802367（PF-367，0.03-0.25mg/kg）后评估靶点选择性。两种放射性配体在整个灰质中均显示出良好的脑摄取和分布。[C]OCM-44在基线时血浆中的游离分数为3%，且代谢迅速。脑中[C]OCM-44的分布容积（）值随时间增加；拟合截断的60分钟扫描数据模型得到的 across脑区的值为1.4-2.9mL/cm。[F]OCM-50的血浆游离分数为0.6%，灰质区域的（120分钟）值为0.39-0.87mL/cm。在对阻断扫描期间血浆游离分数的增加进行校正后，区域的降低表明两种放射性配体在剂量为0.1mg/kg的PF-367作用下靶点占有率>80%，支持体内靶点选择性。[C]OCM-44和[F]OCM-50作为脑内GSK-3成像的放射性配体值得进一步评估，尽管放射性代谢物的积累可能会混淆图像分析。
