New tools for imaging: diagnostics based on therapeutics

 描述(由申请者提供)：诊断和监测疾病的敏感和具体的工具至关重要。在本申请的第一部分(K99)中，我描述了我目前的博士后项目，即开发多发性硬化症(MS)的PET示踪剂；多发性硬化症是一种影响年轻人的常见神经疾病。这种示踪剂与轴突电压门控K+通道结合，这些通道已被用于治疗，但从未用于成像。与迄今为止开发的髓鞘示踪剂不同，这种示踪剂在白质中的基线摄取率较低，在脱髓鞘时会增加，使其成为监测髓鞘形成变化的非常有前途的工具。这样的工具可以改善MS的监测和诊断方式，并为评估促进髓鞘再生的新疗法提供必要的终点。利用在这个项目中获得的原理和专业知识，我建议开发一种新的工具，用于使用不涉及放射性抗体(R00)的PET对单抗(MAbs)进行成像。这将通过在抗体中添加一种短肽来实现，该短肽旨在识别小分子示踪剂。由于小分子的药效学比抗体快得多，这就提供了使用F-18等寿命较短的同位素和低剂量辐射的可能性。在治疗性单抗时代的黎明，一种用于可视化和预测单抗治疗反应的通用工具具有改善患者护理和降低与这些治疗相关的成本的潜力。

 DESCRIPTION (provided by applicant): Sensitive and specific tools to diagnose and monitor diseases are crucial. In the first part of this application (K99), I describe my current postdoctorl project to develop a PET tracer for multiple sclerosis (MS); a common neurological condition that affects young adults. This tracer binds to axonal voltage gated K+ channels that have been exploited for therapy but never for imaging. Unlike the tracers for myelin developed to date, this tracer has low baseline uptake in white matter that increases upon demyelination, making it a very promising tool to monitor changes in myelination. Such a tool could improve how MS is monitored and diagnosed and provide the necessary endpoints to evaluate new therapies that promote remyelination. Using the principles and expertise acquired on this project, I propose to develop a new tool for imaging monoclonal antibodies (mAbs) using PET that does not involve radioactive antibodies (R00). This will be accomplished by adding to the antibody a short peptide that is designed to recognize a small molecule tracer. Because small molecules have much faster pharmacodynamics than antibodies this offers the possibility of using short-lived isotopes like F-18 and low doses of radiation. In the dawn of the therapeutic monoclonal antibody era a general tool to visualize and predict response to mAb therapies has the potential to improve patient care and decrease costs associated with these therapies.