d'Orchymont Faustine, Tong Junchao, Vasdev Neil
Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto M5S 1A1, ON, Canada.
Department of Psychiatry, University of Toronto, Toronto M5S 1A1, ON, Canada.
ACS Med Chem Lett. 2025 Apr 2;16(5):844-850. doi: 10.1021/acsmedchemlett.5c00081. eCollection 2025 May 8.
The aim of this study is to synthesize and evaluate the GABA-benzodiazepine receptor agonist radiotracer ()-10-chloro-1-(3-(methoxy-C)pyrrolidine-1-carbonyl)-3-phenyl-6,7-dihydro-4-pyrido[2,1-]isoquinolin-4-one ([C]RO6899880) using and experiments to determine its suitability for human positron emission tomography (PET) neuroimaging studies. RO6899880 and its desmethyl precursor were synthesized over multiple steps in 3% and 2% yields, respectively. Reaction of the precursor with [C]CHI in DMF with NaOH at 23 °C for 5 min followed by HPLC purification and formulation produced [C]RO6899880 with a radiochemical yield of 4.1 ± 1.6% (nondecay corrected), radiochemical purity >95% and molar activities of 6.40 ± 0.63 GBq/μmol ( = 3). Preliminary autoradiography with [H]RO6899880 was carried out in brain tissues from rat, healthy human, patients with Alzheimer's disease and chronic traumatic encephalopathy, and aligned with the GABA antagonist radiotracer [H]flumazenil. PET imaging in rats revealed modest brain permeability, moderate clearance, and distribution across brain regions with higher uptake in cortical areas. However, polar radiometabolites were found in both plasma and brain homogenates. PET imaging of [C]RO6899880 in higher species including radiometabolism studies are needed prior to human translation.
本研究的目的是合成并评估γ-氨基丁酸-苯二氮䓬受体激动剂放射性示踪剂()-10-氯-1-(3-(甲氧基-C)吡咯烷-1-羰基)-3-苯基-6,7-二氢-4-吡啶并[2,1-]异喹啉-4-酮([C]RO6899880)，使用和实验来确定其是否适合用于人类正电子发射断层扫描(PET)神经成像研究。RO6899880及其去甲基前体通过多步合成，产率分别为3%和2%。前体与[C]CHI在DMF中于23℃与NaOH反应5分钟，然后通过HPLC纯化和制剂化得到[C]RO6899880，其放射化学产率为4.1±1.6%(未校正衰变)，放射化学纯度>95%，摩尔活度为6.40±0.63GBq/μmol(=3)。用[H]RO6899880在大鼠、健康人类、阿尔茨海默病患者和慢性创伤性脑病患者的脑组织中进行了初步放射自显影，并与γ-氨基丁酸拮抗剂放射性示踪剂[H]氟马西尼进行了比对。大鼠的PET成像显示其在脑内的通透性适中、清除率中等，且在脑区有分布，皮质区域摄取较高。然而，在血浆和脑匀浆中均发现了极性放射性代谢物。在进行人体转化之前，需要对包括放射性代谢研究在内的更高物种进行[C]RO6899880的PET成像。
