Functional Magnetic Resonance Imaging (fMRI) based on Blood-Oxygen-Level-Dependent (BOLD) contrast is currently the mainstay of neuroimaging, whose ever growing applications provide a wealth of information regarding the human brain. The chief advantage of BOLD-fMRI is its non-invasive nature and excellent coverage, but it is limited by poor temporal and spatial resolution, and its surrogate nature. In fact, BOLD imaging, as well as other fMRI methods, are insufficient for a detailed study of the neural networks that underly human or animal cognition. We propose to develop a new approach. The aim is to study exogenous MR contrast agents that are ‘responsive’ biochemical functional markers, capable of detecting neuronal activity in real time and translating it into changes of MR contrast. Our objective is to develop glutamate responsive contrast agents to image changes in different parts of the brain upon neural activation. We also aim to improve the sensitivity of these bio-responsive agents by introducing additional modality for Positron Emission Tomography (PET) in the molecules. Initially, novel selective classes of specific, efficacious and optimized Glutamate receptors antagonists along with contrast enhancing macrocyclic lanthanide-chelates, will be developed. The initiatives in chemistry include both tailored organic synthesis and complexation of non-toxic metallo-pharmaceuticals, whose ligand design is dictated by the desired structure-activity relationship. Glutamate receptor sensitive specific extracellular responsive contrast agents will be considered. Every agent will be characterized by different chemical methods and finally evaluated by means of in vitro MR/PET measurements in simulated physiological conditions.