Development of PET imaging probes for ROCK2

ROCK2 PET 成像探针的开发

• 批准号: 10096302
• 负责人: Zhengxin Cai
• 金额: $ 83.65万
• 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/10096302
• 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; Cognitive; 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; Patients; Penetration; 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; density; design; dosimetry; early detection biomarkers; familial Alzheimer disease; frontal lobe; human study; imaging modality; imaging probe; imaging study; improved; in vivo; inhibitor/antagonist; 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 Proteins; 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.

抽象的 该项目的目标是开发、验证和转化新型正电子发射断层扫描 (PET) 含有蛋白激酶 2 (ROCK2) 的 rho 相关卷曲螺旋成像探针。与之前一致 尸检研究发现，使用 SV2A PET 在海马体和额叶中发现显着的突触损失 MCI 和早期 AD 患者的皮质，表明沿疾病路径进行性突触丧失。这 MCI/AD 患者的突触丢失预计是通过激活 rho/ROCK2 信号传导介导的 途径。在无症状 AD 和 MCI 死后脑组织中观察到 ROCK2 升高 患者和家族性 AD 的转基因啮齿动物模型。这些数据证明了检测的潜力 通过 ROCK2 PET 成像来识别临床前和前驱 AD，这可能导致识别新的 具有明确的早期干预时间窗口的治疗目标，以延迟或防止突触损失和 痴呆症发作。因此，我们建议为未来开发和转化ROCK2 PET成像探针 临床研究。该项目的成功完成将产生一个 ROCK2 PET 成像探头，准备好 作为临床前和前驱 AD 的敏感和定量体内生物标志物在人体中进行测试， 这将使早期干预能够减缓或阻止疾病进展。