Fluorinated Radiopharmaceuticals

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... 

Scheme 13.15 Substituent effects in the microwave-enhanced nucleophilic fluorination of bifunctional radiopharmaceutical intermediates.

Aromatic fluorination can be carried out by a regiospecific destannylation process shown in reaction 69. This is an effective method for producing fluorinated m-tyrosine and other radiopharmaceuticals, as shown in reaction 70. The process can be applied for radiolabelling with 18F, denoted as F in these reactions, and the products used as radioactive tracers for clinical and fundamental investigations318-321. 

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]. 

The direct exchange of a leaving group for a fluorine-18 is often the preferred method for routine preparation of radiopharmaceuticals. Scheme 14 presents the one-step synthesis of [ F]altanserin [30,115], one of the most used ligand for mapping 5-HT2 receptors. 

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

The next two chapters are dedicated to radiopharmaceutical contrast agents starting with a detailed description of the chemistry of p -emitting compounds based on fluorine-18. Particular emphasis is laid on the different radiolabeled precursors and their suitability for the rapid synthesis of compounds useful for positron emission tomography. 

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

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]. 

Another example is the radiosynthesis of )S-[ F]CFT (p F]WIN-35,428) [121,122] (Scheme 31). This radiopharmaceutical was prepared in 0.9-2.0% radiochemical yield using acetyl p Fjhypofluoiite as the fluorination reagent. 

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. 

One-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination... 

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. 

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G. Schrobilgen, G. Firnau, R. Chirakal, E.S. Garnett, Synthesis of xenon difluoride-18F, a novel agent for the preparation of fluorine-18 radiopharmaceuticals, J. Chem. Soc. Chem. Comm. 4 (1981) 198-199. 

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. 

T. J. Hewson, Procedures, pitfalls and solutions in the production of [,sF]2-deoxy-2-fluoro-D-glucose A paradigm in the routine synthesis of fluorine-18 radiopharmaceuticals, NucL Med. Biol. 16 533 (1989). 

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