PET imaging agents directed at the rate limiting enzymes in the synthesis of the neurotransmitter dopamine and serotonin will be developed and evaluated as tracers in the assessment, in vivo, o neurotransmitter turnover rate. The targeted enzymes are tyrosine hydroxylase (TH) and tryptophan hydroxylase (TrpH) which are the rate limiting enzymes in the biosynthesis of dopamine and serotonin respectively. alpha-Fluoromethyl-p- tyrosine (FMPT) and alpha-fIuoromethyl-L-tryptophan (FMTrp) are TH an TrpH substrates, respectively. Both compounds are transformed by their respective hydroxylating enzyme into products which bind irreversibly the enzyme in the next step in the synthesis of their respective neurotransmitter. The dual enzyme activation of these compounds will result in high neuronal selectivity The use 11C-labelled FMPT and FMTrp as PET tracers may therefore simplify quantitation of dopamine an serotonin neuronal activity since the amount of the accumulated trapped radioactivity would be dependent on the enzyme activity as regulated by neuronal activity. Time course, biodistribution and metabolism of 14C or 3H Iabelled FMPT and FMTrp will be assessed in rodents. Preliminary validation using PET will be done using rhesus monkeys to verify the time course of brain uptake, specific and non-specific localization an clearance. These tracers will then be further evaluated in rats, if warranted, by autoradiography using 14C or 3H Iabelled compounds. Since both dopamine and serotonin are involved in neuropsychiatric disorders, the non-invasive assessment of neuronal turnover rate using this PET method may provide useful data to better understand the role of these chemical transmitters to health and disease. Potential applications of the PET technique developed in this project include early diagnosis of neuropsychiatric diseases, development and monitoring of therapies for neurodegenerative diseases such Parkinson's disease and psychiatric disorders such as schizophrenia, depression, affective disorders, and aggressive, impulsive and violent behaviors. Observations made in this research may give insight into the etiology of these disorders which may lead to better approaches to their prevention and therapy.
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