Fluorine labeling

For compounds that contain a limited number of fluorine atoms, heteronuclear correlation spectroscopy experiments such as F H HETCOR and 2H-19F heteronuclear Overhauser enhancement spectroscopy (HOESY) can provide considerable assistance distinguishing structural isomers and diastereomers as well as for conformational analysis. HOESY experiments have been frequently used for conformational analysis of biomolecules containing fluorine labels.18... 

Brindle K, Williams S-P, Boulton M (1989) 19F NMR detection of a fluorine-labelled enzyme in vivo. FEBS Lett 255 121-124... 

Diirr UHN (2005) Solid-state F-NMR studies on fluorine-labeled model compounds and biomolecules. PhD thesis. Institute of Organic Chemistry. Universitat Karlsruhe (TH), Karlsruhe, p 163... 

Table 1. Different fluorine-labeled PET tracers with their functional targets...

J.C. Metcalfe, T.R. Hesketh, G.A. Smith, Free cytosolic Ca measurements with fluorine labelled indicators using F NMR, Cell Calcium 6 (1985) 183-195. 

G.A. Smith, R.T. Hesketh, J.C. Metcalfe, J. Feeney, P.G. Morris, Intracellular calcium measurements by F-19 Nmr of fluorine-labeled chelators, Proc. Natl. Acad. Sci. USA 80 (1983) 7178-7182. 

D. Procissi, F. Claus, J. Koziorowski, P. Burgman, C. Mate , S. Thakur, C. Ling, J.A. Koutcher, In vivo F MRS and F 2D-CSI investigation of a fluorine labeled 2-Nitroimidazole (TF-MISO). A potential functional reporter of hypoxia in solid tumors. Proc. Inti. Soc. Mag. Reson. Med. 2006, p. 1260. 

The use of fluorine labeled ligands or substrates allows one, via 19F NMR, to detect weak intermolecular interactions. One such technique (FAXS - Fluorine chemical shift Anisotropy and exchange for Screening) utilizes a fluorine-containing spy molecule to monitor changes in the transverse relaxation rate of the 19F resonance in the presence of a series of test compounds.43... 

Williams, S.-P., Fulton, A.M., Brindle, KM. (1993). Estimation of the intracellular free ADP concentration by 19F NMR studies of fluorine-labeled yeast phosphoglycerate kinase in vivo. Biochemistry 32,4895-4902. 

The structure of proteins can be examined using fluorine-19 NMR if an artificial amino acid with a fluorine label is incorporated into the structure. The advantages of incorporating fluorine in a protein compared to other magnetic nuclei is that it has a high sensitivity and abundance, and is fairly small, 1.35 A compared to 1.2 A for hydrogen. There is also... 

Rubidium [ F]fiuoride is used as a reagent for the [ F]fluorodenitration of nitroaromatic compounds containing activating groups (e.g., CN, COR, CO2R, OH. OMe, etc.). Rubidium [ F]fluoride gives better yields than other fluoride salts, such as potassium fluoride or cesium fluoride, which are extremely hygroscopic. This method constitutes a very convenient route to [ F]fluorine-labeled aromatics, which are often required in radiopharmaceutical studies. 

A study concerning the yields of fluorination by acid decomposition of piperidinotriazenes from several anilines with hydrogen fluoride (anhyd HF, coned aq HF, or HF, pyridine) in various solvents, such as tetrahydrofuran, benzene, dichloromethane, and acetic acid, was carried out in order to establish the best reaction conditions for the [ F]fluorine labeling of estrogens. Hence, 2 -fluorohexcstrol dimethyl ether (4) can be obtained from triazene 3 using 49% aqueous hydrogen fluoride. ... 

Fluoride sources other than hydrogen fluoride, such as tetrabutylammonium fluoride (TBAF) or cesium fluoride in the presence of acids (methanesulfonic acid, trifluoroacctic acid or cation-exchange resins), have been used for the aromatic fluorination of aryltriazenes (see Table Thus, no-carrier-added l F]fluorine-labeled pharmaceuticals, such as spiroperidol. spiperone-" (Table 4, entries 7 and 9). and haloperidol- (entry 8). are available in high radiochemical yield. 

Trifluoroethanol has become a much-used building-block [150] for a wide range of synthetic procedures (see also Chapter 6, Section II) (Figure 8.43b), and sigmatropic rearrangements have been exploited to move the fluorine labels to intemaT sites [151]. 

The fluoro-compounds show unexpected behaviour, for the barrier in 1,1-difluorocyclohexane is lower than that of cyclohexane which is in turn lower than that of 1,1-dimethylcyclohexane. The barrier in 1,1-dimethyl-4,4 difluorocyclohexane is lower than those of 1,1-dimethylcyclohexane which again in turn is lower than that of 1,1,4,4-tetramethylcyclohexane. The oddity is that in terms of steric size, a fluorine atom is expected to be intermediate between a hydrogen atom and a methyl group. It may be that these anomalies and others not so striking are due to fluorine atoms being involved in substantial attractive interactions. It is important that this point be elucidated in view of the widespread use of the fluorine labelling technique in measurement of barriers. 55)... 

The determination of the cryptoregiochemistry for the soluble castor A9 desaturase has been more difficult because the C-H bond cleavage is masked kineticaUy by other events in the catalytic cycle, which nullifies the use of an approach that relies on the measurement of an intermolecular KIE. Nevertheless, the results of experiments that use sulfur, oxygen, and fluorine-labeled substrates suggest that, in this case, the initial site of oxidation is at C-10 rather than C-9 (10, 16). 

Incorporation of fluorine into peptides and proteins is usually achieved through biosynthetic routes, chemical synthesis, or a combination of these two methods. Each method has its own advantages and shortcomings, but each requires a 19F-labeled amino acid. The most commonly used ones are commercially available analogues of aromatic amino acids, such as tryptophan, phenylalanine, tyrosine, and phenylglycine. Aliphatic 19F-labeled amino acids are not commonly available and usually have to be synthesized. The synthesis of most fluorinated amino acids is described in detail in the literature [1, 9,10], For structure analysis of peptides and proteins, it is important that (i) the fluorine label is rigidly attached to the peptide backbone, (ii) the label does not alter the structure or function of the peptide, (iii) the extent of fluorination is restricted to avoid multiple signals, and (iv)... 

Grage, S. L., Wang, J., Cross, T. A. and Ulrich, A. S. (2002) Structure analysis of fluorine-labelled tryptophan side-chains in gramicidin A by solid state 19F-NMR. Biophysical Journal, 83, 3336-3350. 

I believe that this book is extremely informative for researchers who want to take advantage of the use of fluorine in biomedical research such as rational drug design, theory and synthesis, the use of fluorine labels for chemical and structural biology, metabolism and biodistribution studies, protein engineering, clinical diagnosis, etc. This book will serve as an excellent reference book for graduate students as well as scientists at all levels in both academic and industrial laboratories. 

---