Fluorine radiopharmaceuticals labeled

Electrophilic fluorination is the process by which fluorine is delivered to an electron-donating reactant, such as an alkene, aromatic ring or carbanion, by a formal positive-fluorine reagent to form a carbon-fluorine covalent bond. These reactions are fast and have proven extremely valuable for some important fluorine-18-labelled radiopharmaceuticals. Over the years several reviews on electrophilic fluorination were written. The reader is encouraged to seek out these works for greater detail on the subject [7,68-70]. 

Kilbourn, M.R. Fluorine-18 Labeling Radiopharmaceuticals, National Academy Washington, DC, 1991. 

Some Positron Emitters of Clinical Interest Fluorine-18 is undoubtedly the most widely used positron-emitting radionuclide. This is mainly due to the wide use of 18FDG, the PET radiopharmaceutical that has permitted PET to become an everyday clinical tool. With the exception of 18FDG and probably 18FDOPA, the use of other 18F-labeled radiopharmaceuticals is very limited. However, the chemical and physical characteristics of 18F are excellent ... 

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. 

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. 

Triflate 133 has been used94 in the course of the synthesis of 4-[18F]fluoroproline 134 according to the reaction scheme in equation 62. Positron-emitting [18F]fluorine (t1/2 = 109.7 min), a very attractive isotope used for labelling radiopharmaceuticals, has been... 

The synthesis reported by Hamacher et al. has been routinely used to prepare [ F]FDG in PET production centers around the world. The synthesis requires no HPLC purification, and the described RCY was excellent (>90%, EOB). As noted above, [ F]FDG is the most widely used fluorine-18-labeled radiopharmaceutical to date, and so the synthesis has also been adapted for solid phase. SPOR strategies for preparation of [ F]FDG, shown in Scheme 13.3, have beenreportedby Wadsworth etal. and Brady etal. and illustrate proof-of-concept. Notably, these authors used a concept based on perfluorosulfonate linker units to attach the precursor to the resin. The cleavage step used standard radiofluorination... 

The traditional routes of nucleophilic substitution, electrophilic substitution, or addition can be used to rapidly incorporate fluorine-18 into a desired molecule. Kilboum s book, Fluorine-18 Labelling of Radiopharmaceuticals [2], provides an... 

Kilboum, M R Fluorine-18 Labelling of Radiopharmaceuticals, National Academy Press Washmgton, DC, 1990... 

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]. 

Kilbourn MR (1990) Fluorine-18 labelling of radiopharmaceuticals. Nuclear Science Series, NAS-NS-3203 National Academy Press, Washington DC... 

Design of radiotracers and radiopharmaceuticals labelled with a short-lived positron emitter The case of fluorine-18... 

Aliphatic and aromatic nucleophilic substitutions with p Fjfluoride are usually performed either on an immediate precursor of the target molecule (direct labelling using a one-step process) or on an indirect precursor followed by one or more chemical steps leading to the target radiotracer. The first approach, if highly desirable, is in fact rarely practicable. The reaction conditions are often not compatible with the structure or with the various chemical functions borne by the radiopharmaceutical. It is therefore common that the radiosynthesis comprises at least two chemical steps first the introduction of fluorine-18 followed by what is often a (multi)deprotection step. It is not unusual either that fluorine-18 is first incorporated into a much simpler and chemically more robust molecule which is then coupled to a more sensitive entity under milder conditions, possibly still followed by a final deprotection step. Suchlike multi-step procedures are possible thanks to the favourable half-life of fluorine-18. However, the more complicated the process, the more chance of side reactions and complicated final purifications (see also Section 2.3), which may seriously hamper the automation of the process. 

The successful use of [ F]FDG in oncology PET imaging has prompted the design of several other radiopharmaceuticals, such as [ F]FLT ([ F]fluorothymi-dine, used as cellular proliferation marker. Scheme 36) [152-154], F-MISO ([ F] fluoromisonidazole, used to assess tissue hypoxia. Scheme 37) [155], c/s-4-[ F] fluoro-L-proline (used as abnormal collagen synthesis marker. Scheme 38) [156] and 0-(2-[ F]fluoroethyl)-L-tyrosine (used as amino acid transport and/or protein synthesis marker. Scheme 39) [157]. All these fluorine-18-labelled molecules have been prepared by aliphatic nucleophilic fluorination followed by a deprotection reaction. 

Single- or multi-step preparation of [ F]fluoroaryl-type molecular building blocks and some applications A large number of no-carrier-added fluorine-18-labelled aromatic key-intermediates have been synthesised, opening the way to the preparation of more complicated radiopharmaceuticals via multi-step approaches. Scheme 42 non-exhaustively lists a number of para-substituted [ F]fluorobenzene compounds indicating some of their possible chemical interconnections. It also shows some of the precursors for labelling (P1-P7) that have been used for their preparation. 

M.R. Kilboum, M.J. Welch, Fluorine-18 labeled receptor based radiopharmaceuticals, Appl. Radiat. Isot. 37 (1986) 677-683. 

M.R. Kilboum, Fluorine-18 Labeling of Radiopharmaceuticals, Nuclear Science Series, Washington, (1990). 

S.M. Okarvi, Recent progress in fluorine-18 labelled peptide radiopharmaceuticals, Eur. J. Nucl. Med. 28 (2001) 929-938. 

E. J. Knust, H.J. Machulla, C. Astfalk, Radiopharmaceuticals V F-Labeling with water target produced fluorine-18—Synthesis and quality control of 6- F-nicotinic acid diethylamide, Radiochem. Radioanal. Lett. 55 (1983) 249-255. 

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