Methionine, fluorinated

The main radiopharmaceuticals labelled with fluorine-18, routinely prepared ([2-i F] fluorodeoxyglucose [ F]FDG [26-28], [i F]fluoro-L-DOPA [29], [i F]altanserin [30, 31], [ F]setoperone [32]) are presented with their uses in Table 2. For comparison, the most common tracers labelled with carbon-11 (methionine [33], palmitic acid [34], flumazenil (RO 15.1788) [35], PK 11195 [36], raclopride [37], deprenyl [38], Way-100635 [39], McN-5652Z [40], CGP 12177 [41]) are shown in Table 3. By far, [ F]FDG is the most widely studied, particularly in oncology for the diagnosis of tumours, detection of sub-clinical diseases, assessment of therapy responses, and detection of recurrence. F-Steroids [42], F-proteins or peptides, or F-labelled tissue specific agents have also been synthesized for the detection and monitoring of various malignancies [43]. 

So far only a few dozen organofluorine compounds have been isolated from living organisms, for example fluoroacetic acid, 4-fluorothreonine and rw-fluoro-oleic acid [244-246], The reason that nature has not invested in fluorine chemistry could be a combination of low availability of water-dissolved fluoride in the environment due to its tendency to form insoluble fluoride salts, and the low reactivity of water-solvated fluoride ion. However, in 2002, O Hagan and collaborators [247] published the discovery of a biochemical fluorination reaction in a bacterial protein extract from Streptomyces cattleya converting S-adenosyl-L-methionine (SAM) to 5 -fluoro-5 deoxyadenosine (5 -FDA). The same protein extract contained also the necessary enzymatic activity to convert 5 -FDA into fluoroacetic acid. In 2004, the same authors published the crystal structure of the enzyme and demonstrated a nucleophilic mechanism of fluorination [248,249]. 

Finally, recent developments on research into the first C-F bond forming enzyme are summarized. The fluorinase enzyme isolated from Streptomyces cat-tleya catalyzes the formation of 5 -fluoro-5 -deoxyadenosine from S-adenosyl-L-methionine and fluoride. The substrate specificity and subsequent transformation of the fluorinated nucleoside to fluoroacetic acid and to fluoro threonine are discussed. 

For the first time, an enzyme able to create a carbon-fluorine bond has been isolated from Streptomyces cattleya. This enzyme has been characterized and then named fluorinase. In the presence of fluoride ions, this enzyme catalyzes the conversion of 5-adenosyl methionine into 5 -fluoro-5 desoxyadenosine (Figure 4.3). ... 

S -Mono-, di-, and trifluoro derivatives of methionine and 5-fluoroalkyl derivatives of cysteine are accessible through fluorination. Thus, fluorination of methionine sulfoxide with xenon fluoride, or more easily using DAST, provided 5-monofluor-omethionine. Photochemical trifluoromethylation of homocysteine leads to 5-trifluoromethionine. These S -fluoroalkyl compounds are also available through fluoroalkylation of homocysteine. Thus, the addition of difluorocarbene (formed from Freon 11 (CHF2CI)) affords S -difluoromethionine. ... 

Many bacterial enzymes and proteins, which are modified by the introduction of F-Phe or F-Tryp, have been obtained. Mammalian proteins containing F-Pro or other fluorinated amino acids have also been obtained, either in a direct manner in vivo) or, more efficiently, by the expression of the gene in a bacteria. Thus, trifluoro-methionine has been incorporated by E. coli in the lysozyme of a bacteriophage. Because this enzyme contains three methionines, it has been used to study the interactions of this protein with its ligands by F NMR. ... 

A popular reaction with XeF2 is the fluorination of methyl or methylene a to a sulfur atom in thioethers. Methionine or its protected derivatives 43316 and other thioamino acids316 have been thus fluorinated. This reaction was also used as a tool to introduce the fluorine atom into various nucleosides (equation 186)317. 

Kaschten B, Stevenaert A, Sadzot B, Deprez M, Degueldre C, Del Fiore G, Luxen A, Reznik M (1998) Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine. J Nucl Med 39 778-785. 

This chapter focuses on how fluorinated methionine analogues interact with biological systems. Specifically the compounds L-monofluoromethionine (l-(S)-(monofluoromethyl) homocysteine MFM), L-difluoromethionine (L-(S)-(difluoromethyl)homocysteine DFM), and L-trifluoromethionine (L-(S )-(trifluoromethyl(homocysteine) TFM) will be the subject of this article (Figure 17.1). A discussion of their syntheses and chemical and conformational properties will be presented. This will be followed by a discussion of their incorporation into peptides and proteins and the properties of the resulting fluorinated biomolecules. The 19F NMR spectroscopic characteristics of these biomolecules will be covered along with how these resonances have revealed information on the properties of the difluoro- and trifluoromethyl moiety (and on the proteins as well ). Further elaboration of these amino acids with metalloenzymes completes the survey. 

One of the goals for the study of methionine biochemistry utilizing these fluorinated methionines was to control, in a stepwise fashion, the electron density and the... 

Although DFM and TFM are important contributions to the range of spectroscopic probes available for application to biochemical studies, other properties of these fluorinated amino acid analogues can also be of use. For example, the subtle change in size of the thiomethyl group and the alteration in the electronic properties of the sulfur atom in these methionine analogues could be useful properties to explore biological systems. In order to obtain... 

In conclusion, the application of DFM and TFM to bioorganic chemistry has led to new information on how fluorinated compounds interact with enzymes, has provided novel 19F NMR biophysical probes for use in biochemistry, and has led to subtle structurally and electronically modified analogues of methionine with which to probe enzymes. The addition of several fluorine atoms to a simple structure such as methionine has certainly led to an interesting series of adventures in bioorganic chemistry. 

Janzen, J. F., Wang, P. M. C. and Lemire, A. E. (1983) Fluorination of methionine and methio-nylglycinc derivatives with xenon difluoride. J. Fluorine Chem., 22, 557-559. 

The full paper on the synthesis of 14 -fluoro-steroids by perchloryl fluoride fluorination of A -17-acetates has now appeared. It has been shown that 16a-bromoacetoxyprogesterone alkylates cysteine, histidine, methionine, lysine, and /5-mercaptoethanol under physiological conditions. 

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