| Neurotransmitters are chemical messengers responsible for passing signals from one nerve cell to another. The neurotransmitter life cycle is comprised of: (I) release, (II) uptake and (III) metabolism. This thesis describes the design, development and application of new optical reporters for molecular imaging of neurotransmitter metabolism, uptake and release in living cells. The chemical design of the reporters relied on substrate plasticity of the enzymes and transporters involved in the life cycle of neurotransmitter dopamine. The monitoring of neurotransmitter metabolism by monoamine oxidases (MAO A and B) was achieved by developing an irreversible redox switch based on a facile oxidation cyclization reporting mechanism.;Neurotransmitter uptake in adrenal chromaffin cells and acute brain slices has been visualized with fluorescent false neurotransmitters (FFNs) designed as fluorescent substrates for the synaptic vesicle monoamine transporter (VMAT). The probe FFN511 accumulates in dopamine terminals in the striatum as well as secretory vesicles of chromaffin cells. FFNs act as exogenous monoamines and provide optical tracers to neurotransmitters without disturbing their normal function.;FFNs provide the first means to directly visualize neurotransmitter release. FFNs were used to examine populations of individual dopamine terminals, revealing heterogeneity in synaptic activity in the brain that has not been previously reported.;Altogether, as dopamine homeostasis is essential for learning and motivation, while abnormal dopamine transmission underlies neurological and psychiatric disorders including Parkinson's disease and schizophrenia, the ability to visualize the pre synaptic processes will contribute broadly to neuroscience, neuropharmacology and disease diagnostics. |
