Functional MRI for Brain Imaging: Design and synthesis of DOTA-based Gd contrast agents for tracking neurotransmitter

该项目的总体目标是开发用于神经成像应用的新型分子磁共振探针。这种传感器可用于通过非侵入性功能磁共振成像(FMRI)在活体大脑中选择性地进行神经递质成像(在本项目中为谷氨酸和γ-氨基丁酸(GABA))。这项技术的目的是对神经功能的机制获得新的见解，而且，它可能对大脑疾病的诊断和治疗至关重要。为了实现这一目标，在麻省总医院/哈佛医学院的Peter Caravan和麻省理工学院的Alan Jasanoff的合作下，我们将分子磁共振造影剂连接到适当的蛋白质结构域。基于Gd的造影剂提供所需的MR信号，而相应的生物分子选择性地结合特定的神经递质。因此，这些特性在一种生物共轭化合物中的组合形成了新的MRI传感器家族的基础。利用模块化合成策略，可以以极大的多样性产生制备这种生物结合物所需的合适的MRI造影剂。所得到的传感器的特性将使用磁共振测量来表征，以确定适合功能磁共振应用的神经递质敏感探针。

The overall goal of this project is to develop novel molecular magnetic resonance probes for neuroimaging applications. Such sensors can be employed in selective neurotransmitter imaging approaches in the living brain (in this project: glutamate and gamma-aminobutyric acid (GABA)) by using non-invasive functional magnetic resonance imaging (fMRI). The aim of this technique is to obtain new insights into the mechanisms of neural functions and, moreover, it could be crucial for the diagnosis and therapy of brain disorders. To meet this goal, in a collaboration between Peter Caravan (Massachusetts General Hospital/Harvard Medical School) and Alan Jasanoff (Massachusetts Institute of Technology), we will conjugate molecular MRI contrast agents to appropriate protein domains. The gadolinium based contrast agent provides the requested MR signal, while the corresponding biomolecule selectively binds specific neurotransmitters. Hence, the combination of these properties within one bioconjugate forms the basis for a new family of MRI sensors. Appropriate MRI contrast agents that are required for the preparation of such bioconjugates can be generated in great diversity employing the modular synthetic strategies. The properties of the resulting sensors will be characterized using magnetic resonance measurements to identify neurotransmitter sensitive probes suitable for fMRI applications.