Radiopharmaceuticals nucleophilic fluorinations

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

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. 

The chemistry of fluorine-18 radiopharmaceuticals, the reagents employed in electrophilic and nucleophilic fluorination methods and in aliphatic and aromatic nucleophilic substitutions, for the period 1977-1986 have been reviewed by Berridge and Tewson1. The earlier 18F-chemistry has been reviewed by Palmer, Clark and Goulding2. 

Although the majority of radiopharmaceuticals labeled with fluorine-18 have been prepared using nucleophilic fluorination reactions, in a few instances the application of electrophilic fluorination reactions has proved quite suitable. The most significant limitation of electrophilic 18F-fluorinations is the relatively low specific activities (less than lOCi/mmol) commonly obtained for final products. This is a result of the fact that electrophilic 18F-fluorination reagents (perchloryl fluoride, acetyl hypofluorite, xenon difluoride, A-fluoro-zV-alkylsulfonamides, diethylaminosulfur trifluoride) are prepared in low specific activity from 18F-labeled fluorine gas, which in itself produced in a carrier-added fashion. A second drawback of electrophilic fluorination is that the maximum radiochemical yield obtainable is 50%, as only one of the two fluorine atoms in fluorine gas can end up in the product (or, for preparation of electrophilic reagents such as acetyl [18F]hypofluorite, the maximum yield of preparing the reagent from [18F]F2 is 50%). 

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... 

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. 

In the following sections are examples of typical methods for 18F-fluorination using nucleophilic and electrophilic reaction mechanisms, with selected examples of their use in preparation of PET radiopharmaceuticals. 

Applying this novel fluorination method to 18F-fluorination provides great improvement in radiochemical yields (Table 14.5) [101]. The use of a protic solvent in nucleophilic 18F-fluorination not only improved the radiochemical yield of widely used radiopharmaceuticals such as [18F]FLT (3 -deoxy-3 -[18F]fluorothymidine) [101, 102], [18F]FP-CIT (3-[18F]fluoropropyl-2-(3-carboxymethoxy-3-(3-(4-iodophenyl) nortropane) [101, 103], and [18F]FMISO ([18F]fhioromisonidazole) [101, 104], which were difficult to prepare in conventional methods under mild conditions. This method has advanced the availability of these important radiopharmaceuticals, and should help the development of new pharmaceuticals for research and clinical application in the future. 

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