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Abstract

Magnetic resonance imaging (MRI) has evolved into a powerful tool in modern biomedical research. Its signal specificity can be further improved using contrast agents and their application has largely contributed to the MRI development. We aim to develop new measurement techniques that would enable visualization of neuronal activity and better understanding of brain function by using responsive or 'smart' agents (SCA). These are biochemical markers that alter their MR signal upon a certain biochemical event due to changes in their microenvironment. Calcium ions or amino acid neurostransmitters are excellent markers tightly linked to brain activation, and are typically been the preferred target for a number of optical imaging methods. To accomplish our goals, we synthesize and study SCAs, complexes that respond to differing concentrations of endogenous Ca2+ or neurotransmitters by altering their magnetic properties. Over the past years we have reported a number of Gd3+ chelates linked to modified Ca2+ chelators that act as smart MRI contrast agents.[1] Some of the agents exhibited remarkable sensitivity towards Ca2+, dramatically altering their relaxometric properties. In a subsequent proof-of-principle study, we demonstrated the SCA response in a complex 3D cell culture model. Furthermore, we monitored the cellular signaling and Ca2+ transport through the plasma membrane upon administration of the SCA and calculated of the possible T1 values during the neuronal activity. The estimates of the actual T1 values suggest that MRI signal changes could be detectable by modern instrumentation and imaging protocols. We have also prepared a series of crown-ether containing SCA that are capable to sense amino acid neurotransmitters. Their relaxivity substantially reduces in presence of neurotransmitter molecule which is caused by the reduction in the hydration number of the studied complex. These are the first examples of the host-guest interaction between the lanthanide-based complexes and amino acid neurotransmitters.