Neuronal uptake and metabolism of 2- and 6-fluorodopamine: False neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues

The neuronal uptake and metabolism of 2-fluorodopamine (2F-dopamine), 6-fluorodopamine (6F-dopamine) and tritium-labeled dopamine were compared in heart, submaxillary gland and spleen of rats to assess the utility of ¹⁸F-labeled 2F- or 6F-dopamine for positron emission tomographic imaging of sympathetically innervated tissues. Tritiated dopamine with and without 2F- or 6F-dopamine, or tritiated 2F-dopamine alone, were injected i.v. into rats that were or were not pretreated with desipramine to block catecholamine neuronal uptake or with reserpine to block vascular translocation of catecholamines. Tissue and plasma samples were obtained at intervals up to 1 hr after injections. At 1 hr after injection of tritiated dopamine, tritium-labeled norepinephrine, dopamine, dihydroxyphenylacetic acid and dihydroxyphenylglucol accounted for less than 2% of the tritium in plasma but up to 92% of that in tissues; tritiated norepinephrine accounted for 70% or more of the tritium in tissues. In contrast, at 1 hr after injection of tritiated 2F-dopamine, tritiated 2F-norepinephrine accounted for 30 to 46% of the tritium in tissues. Desipramine and reserpine, pretreatment blocked the tissue accumulation of tritiated and fluorinated dopamine as well as their dihydroxy-metabolites, indicating that accumulation of exogenous norepinephrine and dopamine analogs was within sympathetic storage vesicles. Relative to the doses of dopamine precursors, less 2F- and 6F-norepinephrine accumulated in tissues than tritiated norepinephrine, due largely to inefficient β-hydroxylation of fluorinated dopamine. Fluorination of dopamine at the carbon-2 position on the aromatic ring impaired β-hydroxylation to the norepinephrine derivative more than did fluorination at the carbon-6 position; thus, the tissue accumulation of 6F-norepinephrine was more than 2-fold greater that that of 2F-norepinephrine. Both 2F- and 6F-dopamine are taken up readily into storage vesicles of sympathetic neurons, but both are poorer substrates than tritiated dopamine for labeling storage pools of norepinephrine. Of the two fluorinated catechols, 6F-dopamine appears to be better suited than 2F-dopamine for positron emission tomographic imaging of sympathetically innervated tissues.