The intent of this research is to develop new imaging agents that localize selectively in norepinephrine (NE) and dopamine (DA) neurons of the brain. The target loci for these new radiotracers are the neurotransmitter storage vesicles within the neurons rather than postsynaptic receptors. Labeled with gamma- or positron-emitting radionuclides, these agents will enable quantitative assessment of neuronal involvement and/or damage in depression, Parkinsonism and schizophrenia. Two false neurotransmitters, H-3 metaraminol (MR) and I-125-m-iodobenzylguanidine (MIBG), are selective markers for peripheral sympathetic nerves. Since these tracers do not appreciably penetrate the blood-brain-barrir, lipophilic protracer forms will be synthesized which enter the brain and undergo decarboxylation or hydrolysis to the parent tracers. Labile acyl, benzoly, and alkoxycarbonyl derivatives of MIBG will be evaluated for their ability to undergo acid or enzyme catalyzed hydrolysis within the brain. F-18-6-Fluoro-3-(3-hydroxyphenyl)-2-methylserine (HPMS) will serve as the aromatic amino acid precursor of F-18-6-fluoro-Mr, a radiotracer which should selectively accumulate in NE neurons. Similarly, F-18-6-fluoro-alpha-methyl-m-tyrosine (MMT) will seve as the carboxy protracer form of F-18-6-fluoro-alpha-methyl-m-tyramine (MMTA) which should selectively localize in DA neurons. Co-administration of the peripheral aromatic amino acid decarboxylase inhibitor carbidopa should enhance the brain extraction of HPMS and MMT. Unlike F-18-fluorodopamine, F-18-MR and F-18-MMTA are not substrates for COMT or MAO and thus should be more amenable to tacer kinetic modeling. Indices of neuronal selectivity for MR, MMTA and MIBG will be calculated from their accumulation patterns in 7 brain regions. The metabolic fate of the protracers will be determined by extraction of brain homogenates and radio-HPLC analysis of the radioactive product(s). The distribution of radioactivity in the rat brain will be determined by quantitative autoradiography in normals and in animals with unilateral lesions of the substantia nigra. Promising protracers will be labeled with F-18 or I-123; time-activity curves and regional brain ditribution will be determined in monkeys using positron emission tomography and single photon tomography. Pharmacologic interventions (desipramine, reserpine) in both rats and monkeys will be employed to corroborate the involvement of neuronal uptake and storage pathways.
