New gadolinium-based MR contrast agents Gd-DO3A-EP (-phosphono-ethyl) and Gd-DO3A-EPE (-diethyl-phosphono-ethyl) were designed and synthesized to trace physiological changes of pH and calcium concentration in the extracellular space of brain. Phosphonate derivatives are known to have very high affinity towards calcium (MDP, methylene-diphosphonate) and can function as reporters of pH and calcium ions. Ethyl-phosphonate is appended covalently on the macrocycle without any amide linkage and binds reversibly as a function of pH/calcium concentration acting as reporter of cellular activity and neurotransmission. Here we demonstrate in-vitro MR relaxation changes induced by changes in pH revealing 50% changes in relaxivity r1.