Nucleophilic radiofluorination

Nucleophilic substitutions with [ F]fluoride have been largely developed both in aromatic (SNAr) and aliphatic (generally SN2) series. Nucleophilic additions remain rare. F-Nucleophilic radiofluorinations usually do not require any carrier and thus enable the synthesis of products with high specific radioactivity. The SN can be performed either directly on a suitable and generally complex precursor of the target molecule or indirectly via a small labelled precursor. Both approaches present drawbacks the first one generally leads to poor yields and the second requires multistep synthesis and more sophisticated automation processes. 

Ci/mmol (6.3 x 10" TBq/mmol), the practically achieved no-carrier-added specific radioactivity is in the region of 10 Ci/mmol (3.7 x 10 TBq/mmol). Fluoiine-18 is generally recovered from the target as [ F]fluoride anion in an aqueous solution and is then engaged in nucleophilic radiofluorinations (see Section 4.1). 

In the early days of fluorine-18-chemistry the low reactivity of p F]fluoride ion in aqueous solution constituted a major obstacle to the advance of nucleophilic radiofluorination with high specific radioactivity, a problem that would later be solved with the introduction of the cryptand Kryptofix-222 , giving the highly reactive K[ F]F-K222 complex (see Section 4.1) [3], For this reason active research for anhydrous reactive fluorine-18 labelling species continued. Scheme 1 reviews a number of these early reagents. 

Aromatic nucleophilic radiofluorinations are usually performed in aprotic polar solvents, such as dimethyl sulfoxide (DMSO), sulfolane or dimethylacetamide, and often under basic conditions (because of the presence of Kryptofix-222 / potassium carbonate). Completion of the p F]fluoride incorporation often requires moderate to high temperatures (100-170 °C) for 10-30 min. Microwave technology can be a successful application here, resulting in improved yields and shorter reaction times [29,170-173],... 

Other one-step syntheses involving aromatic nucleophilic radiofluorination... 

Multi-step syntheses of a radiopharmaceutical involving an aromatic nucleophilic radiofluorination An example of a multi-step radiosynthetic pathway is the no-carrier-added synthesis of 6-[ F]fluoro-L-DOPA (Scheme 45). The first step involves the preparation of 4,5-dimethoxy-2-[ F]fluorobenzaldehyde from the corresponding nitro-substituted benzaldehyde. The following steps involve its condensation with an asymmetric chiral inductor [206] followed by L-selectride reduction of the... 

Fig. 6. Fluorine-18-labelled heferacyclic compounds other than C Flfluoropyridines, obtained by nucleophilic radiofluorination.

A/-[4-[(4-[ F]Fluorobenzylidene)amino-oxy]butyl]maleimide ([ F]FBABM) was synthesised in two steps, involving the preparation of 4-[ F]fluorobenzaldehyde (see Section 4.3.1.1), in an overall radiochemical yield of 35% in 60 min [267], whereas A/-[2-(4-[ F]fluorobenzamido)ethyl]maleimide ([ F]FBEM) was synthesised in three steps via 4-[ F]fluorobenzoic acid (see Section 4.3.1.1) in an overall radiochemical yield of 12% in 150 min [268]. Finally, based on the successful use of nucleophilic /leferoaromatic ort/io-radiofluorination in the pyridine series (see Section 4.3.2.1), 1-[3-(2-p F]fluoropyridin-3-yloxy)propyl]pyrrole-2,5-dione was prepared in 17-20% non-decay-corrected radiochemical yield in a three-step pathway taking less than 110 min [13,269]. These three reagents have been successfully coupled to peptides and proteins (>80% radiochemical yield in 10 min). 

A/-[3-(2-[ F]fluoropyridin-3-yloxy)-propyl]-2-bromoacetamide (p F]FPyBrA) was recently prepared by nucleophilic / eferoaromatic radiofluorination using a three-step radiochemical pathway and obtained in 20% overall non-decay-corrected yield in less than 85 min. In this reagent, the pyridinyl moiety carries the radioactive fluorine and the 2-bromoacetamide function ensures the alkylation of phosphorothioate monoester groups at the 3 - or 5 -end of a single-stranded oligonucleotide [18],... 

Nucleophilic aliphatic radiofluorination with tosylate as leaving group. 

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