6-[F]Fluorodopamine

Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition and emotion. Parkinson’s disease (PD) is associated with a loss of dopamine-containing neurons in striatum of the brain (1, 2). Dopamine (DA) is synthesized within nerve cells (3). Chemically, L-tyrosine is converted to dihydroxyphenylalanine (L-DOPA) and then to dopamine in a two-step process. The first, rate limiting step is catalyzed by tyrosine 3-monoxygenase (tyrosine hydroxylase or TH). The second step is catalyzed by aromatic L-amino acid decarboxylase (L-DOPA decarboxylase, AAAD). In dopaminergic neurons, dopamine is not metabolized further, and is stored in vesicles in the presynaptic nerve terminals. Interstitial dopamine is re-captured by dopamine transporter, DAT. In noradrenergic neurons, dopamine is converted to norepinephrine (NE) by dopamine β-hydroxylase (DBH) and stored in vesicles in the neurons (4). Released NE in synaptic junctions is either inactivated by COMT in postsynaptic cells or transported by a NE transporter (NET) into the nerve terminals (uptake-1). Dopamine is also efficiently transported by NET. At extraneuronal locations, DAT is present in placenta and lung endothelial cells and NET is present in stomach and pancreas. There are also three non-neuronal transporters functioning in peripheral tissues such as the heart, liver, kidney, intestine, blood vessels, retina, and placenta. These uptakes by non-neuronal cells are termed uptake-2. After transported into sympathetic nerve ending by uptake-1, 6-[F]FDA is rapidly converted to 6-[F]fluoronorepinephrine (6-FNE) by DBH in neuronal vesicles (5). 6-[F]FDA is also metabolized via mitochondrial monoamine oxidase to yield [F]6-fluoro-3,4-dihydroxyphenylacetic acid (FDOPAC). In nonneuronal cells, 6-[F]FDA is converted by COMT sequentially to O-[F]methoxytyramine and [F]6-fluorochomovanillic acid (FHVA). FDOPAC taken up after release from sympathetic neurons by uptake-2 is converted to FHVA by COMT. Uptake of 6-[F]FDA into sympathetic nerve terminals, with conversion to and storage of 6-[F]FNE in vesicles, would lead to more intense positron emission tomography (PET) signals from sympathetically innervated tissues than noninnervated tissues.