Development of PET imaging probes for ROCK2

摘要 本项目的目标是开发、验证和翻译新型正电子发射断层扫描(PET)。 含蛋白激酶2(ROCK2)的Rho相关螺旋线圈的成像探针。与之前的一致 死后研究发现，使用SV2APET在海马区和额部发现显著的突触丢失 MCI患者和早期AD患者的大脑皮质，表明疾病过程中进行性突触丢失。这个 MCI/AD患者突触丢失可能是通过激活Rho/ROCK2信号介导的 路径。在无症状AD和MCI的死后脑组织中观察到ROCK2的升高 患者和家族性阿尔茨海默病转基因啮齿动物模型。这些数据证明了检测的潜力 临床前和前驱AD通过ROCK2 PET显像，可能导致识别新的 具有明确的早期干预时间窗口以延迟或防止突触丢失的治疗靶点和 痴呆症的发作。因此，我们建议今后开发和翻译ROCK2 PET成像探针 临床调查。该项目的成功完成将产生一个ROCK2 PET成像探头 作为临床前和先兆AD的灵敏和定量的体内生物标志物在人类身上进行测试， 这将使早期干预能够减缓或阻止疾病的进展。

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.