Fluorinated dopamines

This technique has been applied to the synthesis of fluorinated dopamine and other compounds of biological significance Fluoroheterocycles such as fluoro-lmidazoles [35, 36] and fluoropyrazoles [37] can also be prepared by the photo Balz-Schiemann technique (equation 9) Photoohemically induced in situ fluoro dediazoniation can also be applied to arenediazonium fluorides in hydrogen fluo ride-pyridine media Thus, o-fluoroanisole is obtained in 73% yield at 20 °C after 18 h [35]... 

Other F-labeled tracers, for example different fluorinated dopamine derivatives, enable, e.g., very differentiated diagnosis of Parkinson s disease [86]. Fluorine-18-derivatized diagnostics have also been used to trace the metabolic pathway of drugs through the body in clinical tests. The radiation dose to which the test person is subjected is in the same range as, e. g., that used for a stomach X-ray examination. Examples of F-labeled radiopharmaceuticals and their target sites and applications are illustrated in Scheme 4.39. 

J. Mukherjee, Z.Y. Yang, M.K. Das, T. Brown, Fluorinated benzamide neuroleptics-lll. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[ F]fluoropropyl)-2,3-dime-thoxybenzamide as an improved dopamine D-2 receptor tracer, Nucl. Med. Biol. 22 (1995) 283-296. 

C. Halldin, T. Hogberg, L. Farde, Fluorine-18-labeled NCQ 115, a selective dopamine D-2 receptor ligand. Preparation and positron emission tomography, Nucl. Med. Biol. 21 (1994) 627-631. 

Fluorinated dihydroxyphenylalanine p F]DOPA is a precursor for the neurotransmitter dopamine and is commonly used in the imaging of Parkinson s disease. In oncological imaging [ F]DOPA has been assessed for imaging of brain tumors, advanced neuroendocrine tumors and medullary thyroid cancer [215],... 

Aromatic amino acids are biogenetic precursors of neuroamines (dopamine, serotonin, histamine, etc.). On the other hand, phenylalanine (Phe) is frequently present in peptide sequences, while tyrosine is an important site of phosphorylation of proteins. Aromatic amino acids and neuroamines fluorinated on the aromatic ring have been the focus of many investigations. Indeed, after incorporation in polypeptides and proteins, they can be used as probes in NMR and in PET. 

In vivo regional brain biodistribution studies of fluorine-18 derivatives in mice indicated that in vivo selectivity for the dopamine reuptake site critically depends on the carbon chain length between the piperazine ring and the solitary aromatic ring. It has been concluded that the fluorine-18 analogues464 do not offer any advantage over another currently available [18F]GBR 12909 radiotracer466 for study of the dopamine reuptake system. 

Dihydroxyphenylalanine (DOPA) (99) is produced by tyrosine hydroxylase-catalyzed hydroxylation of Tyr. Recent interest in the use of [18F]-6-F-DOPA (100) as a PET scanning agent for regional dopaminergic brain function is based on its conversion, in the brain, to [,8F]-6-F-dopamine (101)161. The fact that fluorine in the 6-position of DOPA, dopamine and other catecholamines retards methylation by catechol-O-methyl transferase presumably increases the biological half-life of the tracer. In contrast, fluorine in the 5-position increases the rate of methylation162. 

The photochemical Balz-Schiemann reaction has been used for the preparation of interesting fluoroarenc pharmaceutical agents, such as ring-fluorinated tyraminc and dopamine derivatives (Table 9. entries 1-3), and 2-, 5-, and 6-fluoronorepinephrine precursors (entries 4 and 5), from the corresponding nitroarenes. 

Another type of fluorinated amino acid analogs are the -fluoromethylene derivatives of the acids [3]. For example, fluoromethylene dopa is metabolized to the corresponding dopamine derivative, which is a powerful inhibitor of monoamine oxidase and thus of interest for treatment of Parkinson s disease (Scheme 4.37). 

The substitution of hydrogen by F-fluorine has also been used for the production of 5-[ F]fluoro-DOPA (Firnau et al. 1973) and 6-[ F]fluoro-L-DOPA (3,4-di-hydroxy-6-[ F] fluoro-L-phenylalanine 6-[ F]FDOPA) (Garnett et al. 1983a, b Firnau et al. 1980, 1984 Adam et al. 1986 Coenen et al. 1988) (cf O Fig. 42.4). 6-[ F]FDOPA is transported across the blood-brain barrier, where it is decarboxylated to produce 6-[ F]fluoro-dopamine. 

Before specific ligands for dopamine transporters were developed, [ F]6-L-fluorodopa was used to assess presynaptic dopaminergic function. [ F]6-L-fluorodopa, is a fluorinated analog of natural body constituent, L-dopa (L-3,4-dihydroxyphenylalanine) [15]. [ F]6-L-fluorodopa is metabolized to 3-0-methyl-6-fluoro-L-dopa (3-OMFD), which enters the brain with nonspecific binding mechanism and complicates kinetic modehng of dopamine synthesis. 

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