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

本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。通过使用非侵入性功能磁共振成像（fMRI），这种传感器可以用于活体大脑中的选择性神经递质成像方法（在本项目中：谷氨酸和γ-氨基丁酸（GABA））。这项技术的目的是获得对神经功能机制的新见解，此外，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Peter Caravan（马萨诸塞州总医院/哈佛医学院）和Alan Jasanoff（马萨诸塞州理工学院）的合作下，我们将分子MRI造影剂与适当的蛋白质结构域结合。钆基造影剂提供所需的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，在一个生物缀合物中这些特性的组合形成了MRI传感器的新家族的基础。制备这种生物缀合物所需的适当MRI造影剂可以采用模块化合成策略以极大的多样性产生。所得传感器的特性将使用磁共振测量来表征，以识别适合于功能磁共振成像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.