Development of PET imaging probes for ROCK2

ROCK2 PET 成像探针的开发

• 批准号: 10359030
• 负责人: Zhengxin Cai
• 金额: $ 82.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359030
• 关键词: APP-PS1; Affect; Affinity; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Anatomy; Autopsy; Binding; Biological Assay; Biological Markers; Brain; Characteristics; Chemicals; Clinical Research; Clinical Trials; Cognition; Cyclic AMP-Dependent Protein Kinases; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Early Intervention; Economic Burden; Emotional; Family; Future; Genetic; Heart Diseases; Hippocampus (Brain); Human; Hydrogen Bonding; Image; Image Analysis; In Vitro; J20 mouse; Kinetics; Label; Lead; Libraries; Ligands; Literature; Malignant Neoplasms; Mediating; Metabolism; Methods; Modeling; Molecular Weight; Monitor; Mus; Neurodegenerative Disorders; Pathologic; Pathway interactions; Patients; Penetration; Persons; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Preparation; Process; Property; Protein Kinase; Proteins; ROCK1 gene; Radiolabeled; Rodent; Rodent Model; Senile Plaques; Signal Pathway; Societies; Specificity; Structure; Synapses; Testing; Time; Toxic effect; Tracer; Transgenic Organisms; Translating; United States; Up-Regulation; Validation; Western Blotting; asymptomatic Alzheimer' s disease; base; blood-brain barrier penetration; brain tissue; cheminformatics; clinical investigation; cognitive function; density; design; dosimetry; early detection biomarkers; effective intervention; familial Alzheimer disease; frontal lobe; human study; imaging modality; imaging probe; imaging study; improved; in vivo; inhibitor; longitudinal positron emission tomography; neuroimaging; new therapeutic target; nonhuman primate; novel; overexpression; pharmacokinetic model; pre-clinical; prevent; prodromal Alzheimer' s disease; public health relevance; radiotracer; response; rho; socioeconomics; tau aggregation; translation to humans; treatment strategy; white matter

ABSTRACT The objective of this project is to develop, validate, and translate novel positron emission tomography (PET) imaging probes for rho-associated coiled-coil containing protein kinase 2 (ROCK2). Consistent with prior postmortem studies, significant synaptic loss was found using SV2A PET in the hippocampus and frontal cortex of patients with MCI and early AD, indicating progressive synaptic loss along the disease path. The synapse loss in MCI/AD patients is expected to be mediated through activation of rho/ROCK2 signaling pathway. Elevated ROCK2 has been observed in postmortem brain tissues of asymptomatic AD and MCI patients and in transgenic rodent models of familial AD. These data demonstrate the potential of detecting preclinical and prodromal AD through ROCK2 PET imaging, which may lead to identification of new therapeutic targets with a defined early intervention time window to delay or prevent the synapse loss and onset of dementia. Therefore, we propose to develop and translate ROCK2 PET imaging probes for future clinical investigations. Successful completion of this project will yield a ROCK2 PET imaging probe ready to be tested in humans as a sensitive and quantitative in vivo biomarker for preclinical and prodromal AD, which will allow early interventions to slow or halt disease progression.

摘要 这个项目的目标是开发、验证和翻译新的正电子发射断层扫描（PET） 含有蛋白激酶2（ROCK 2）的rho相关卷曲螺旋的成像探针。与先前一致 死后研究，使用SV 2A PET在海马和额叶中发现了显著的突触丢失， MCI和早期AD患者的皮质，表明沿着疾病路径沿着进行性突触丢失。 MCI/AD患者中的突触丢失预期通过rho/ROCK 2信号传导的激活来介导 通路在无症状AD和MCI的死后脑组织中观察到升高的ROCK 2 患者和家族性AD的转基因啮齿动物模型中。这些数据表明， 通过ROCK 2 PET成像，可以识别临床前和前驱AD， 具有确定的早期干预时间窗的治疗靶点，以延迟或防止突触丧失， 痴呆症的发病因此，我们建议开发和翻译ROCK 2 PET成像探头，以供将来使用。 临床研究。该项目的成功完成将产生一个ROCK 2 PET成像探头， 作为临床前和前驱AD的敏感且定量的体内生物标志物在人体中进行测试， 这将允许早期干预来减缓或阻止疾病进展。