Nucleophilic displacement that is usually used for aliphatic fluorination reactions involves the S_N2 substitution of ¹⁸F ion and alkyl substrate containing good leaving groups such as halogens or sulfonic ester. Unlike aromatic substitution reactions, activating groups are not required.

Sulfonates are more reactive than halogens as a leaving group. There is a variety of sulfonate leaving groups available for aliphatic nucleophilic fluorination, such as p-toluenesulfonate (tosylate), methanesulfonate (mesylate), trifluoromethanesulfonate (triflate) and p-nitrosulfonate (nosylate). Among the sulfonates, reactivity increases from tosylate to mesylate and nosylate and to triflate that is the most reactive group for ¹⁸F-labelling. Nevertheless, due to its high reactivity, triflate compounds may be unstable during the fluorination reaction temperatures; they cannot tolerate any water and are subject to side reaction such as elimination.

Depending on the stability of the precursor for labelling, the reactivity and simplicity of the incorporation, aliphatic fluorination can be formed by either direct labelling [2, 29] or formation of ¹⁸F-fluoroalkyl agents [30, 31]. The main drawback of direct labelling method is the need to protect any potentially competing sites of nucleophilic attack in the molecule (principally acid, alcohol or amine groups), thus resulting in additional synthesis and purification steps.

A good example of aliphatic nucleophilic ¹⁸F substitution is the synthesis of ¹⁸F-FDG [2] in which the acetyl-protected sugar tetra-O-acetyl-2-triflate-β-mannose is used during the direct ¹⁸F-fluorination step. A deprotection of the ester groups completes the synthesis of ¹⁸F-FDG. The synthesis of ¹⁸F-FDG is now fully automated and can be achieved in approximately 30 min with radiochemical yields greater than 70 % (Fig. 4.3). A wide offer of synthesis modules, also equipped with disposable cassette that includes all the reagents, are available on the market.

Besides ¹⁸F-FDG, many radiopharmaceuticals have been synthesised by S_N2 fluorination reactions involving aliphatic substitution such as ¹⁸F-fluoro-3-deoxy-L-thymidine (¹⁸F-FLT) [32, 33], ¹⁸F-fluoroestradiol (¹⁸F-FES) [34, 35], ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) [36] and anti-1-amino-3-¹⁸F-fluorocyclobutane-1-carboxylic acid (¹⁸F-FACBC) [37], a promising tracer for staging prostate carcinoma.

Even if protic solvents, such as alcohols, are generally not used for nucleophilic substitution reactions because of their ability to solvate the nucleophile and retard its reactivity, the use of ionic solvents, such as tertiary alcohols, as a reaction media for the nucleophilic fluorination with alkali metal fluoride has been described [38, 39]. The protic medium is reported to suppress the formation of by-products and increase the rate of nucleophilic fluorination. An example is the significant improvement in the synthesis yield of ¹⁸F-FLT [40] compared to previously described methods using ¹⁸F-KF/K222 labelling procedure in aprotic solvents (Fig. 4.4).

¹⁸F-fluoroalkyl agents are synthesised by S_N2 reaction of ¹⁸F-fluoride with dihalo or disulfonate alkyl starting materials with no-carrier-added fluoride ion in the presence of K₂CO₃/K222 complex or tetrabutylammonium hydroxide in organic solvents such as acetonitrile, o-dichlorobenzene or tetrahydrofuran [30, 31]. ¹⁸F-fluoroalkylating agents with methyl, ethyl and propyl carbon backbones together with suitable leaving groups for reaction with nucleophilic species have been prepared (Fig. 4.5).

The large excess of the alkyl starting material compared to the ¹⁸F⁻ allows exclusive formation of the mono ¹⁸F-fluoroalkyl halide or sulfonate. After the formation of ¹⁸F-fluoroalkyl agent, it can be used for the second alkylation reaction. ¹⁸F-fluoroalkyl agents can be purified using gas chromatography separation or distillation from the reaction mixture into disposable C₁₈ cartridges [31]. Purification of ¹⁸F-fluoroalkyl agent before the next alkylation reaction provides more chemically and radiochemically pure product and eliminates non-volatile impurities, therefore increasing the radiochemical yield of the second alkylation reaction.

The most known aliphatic substitution reaction using ¹⁸F-fluoroalkyl agents is the radiosynthesis of ¹⁸F-fluorocholine, in which dibromomethane is fluorinated to generate ¹⁸F-fluorobromomethane, which reacts with dimethylethanolamine to produce ¹⁸F-fluorocholine [41]. In some cases, ¹⁸F-fluorobromomethane can be converted to the more reactive synthon ¹⁸F-fluoromethyltriflate, which would react more efficiently with 2-dimethylethanolamine to give ¹⁸F-fluorocholine [31].

Introduction of no-carrier-added ¹⁸F into aromatic ring is mostly limited to substitution on activated arenes. The presence of “activating” electron-withdrawing groups, such as cyano, trifluoromethyl, aldehydes, ketones and nitro, in the ortho and para positions on the aromatic ring decreases the electron density allowing for a sufficient activation for the nucleophilic substitution [16]. The leaving group most widely used in aromatic nucleophilic fluorination are nitro, quaternary trimethylammonium, alogens and sulphonates such as tosylate, mesylate and triflate. Due to low specific activity of the final product, isotopic exchange, ¹⁹F-fluoride to ¹⁸F-fluoride, is not used.

Direct aromatic nucleophilic fluorination has been used for obtaining high radiochemical yields and specific activities of ¹⁸F-labelled compounds by a simple one-pot method [42]; however, not all the precursors for the labelling can handle high temperature and basic conditions of the fluorination; they may decompose during radiosynthesis. More often, the labelled compounds can be obtained by milder indirect ¹⁸F-labelling methods. An example is the use of small ¹⁸F-labelled reactive precursors bearing a reactive functional group that can form part of the intrinsic structure of the molecule or act as a “prosthetic label” to the molecule of interest such as proteins or other biomolecules. These ¹⁸F-fluoroaromatic groups can be used as ¹⁸F-precursor molecules by reacting rapidly and under mild conditions after the initial direct ¹⁸F-fluorination step. A range of ¹⁸F-fluoroaromatic precursors is shown in Fig. 4.6.

Nitrobenzene derivatives and ¹⁸F-fluorobenzaldehydes are the most widely used precursors in the preparation of simple ¹⁸F-fluoroaromatic compounds. The nitro group is both an activating group (in the ortho or para positions) and a leaving group under the right conditions. The strongly electron withdrawing nature of the nitrile group provide a high radiochemical yield of ¹⁸F-fluorobenzonitrile precursors; moreover, the nitrile group can further be transformed into reactive groups such as N-(4-¹⁸F-fluorobenzyl)-2-bromoacetamide for the ¹⁸F-labelling of peptides and oligonucleotides (see Sect. 4.3.3) [43].

The increased use and versatility of palladium-catalysed cross-coupling reactions in organic chemistry have had an important effect in the field of radiochemistry. The new chemical methods hold the unrealised potential of changing radiotracer design and development since the synthesis of relatively simple ¹⁸F-fluoroaryl precursors has, until recently, been surprisingly quite problematic. Recently it has been described the process of the successful translation of a modern Pd-mediated fluorination reaction and the application to PET imaging. Transformation of ¹⁸F-fluoride into an electrophilic fluorination reagent provides access to ¹⁸F-aryl bonds that would be challenging to synthesise via conventional radiochemistry methods [44].

Aromatic nucleophilic substitution can also be done using diaryliodonium salts and, without the need of electron withdrawing groups, fluoride can be introduced into the arene. The introduction of ¹⁸F-fluoride into dihomoaryliodonium salts precursor gives ¹⁸F-fluoroarenes and the corresponding iodoarenes [45] and represents an extremely useful alternative for the synthesis of a range of simple ¹⁸F-fluoroaromatic compounds in good radiochemical yields and in short reaction times that would be otherwise unobtainable by traditional methods. Very recently, it has been demonstrated that a novel synthetic approach to synthesise ¹⁸F-DOPA via nucleophilic substitution of a diaryliodonium salt precursor with ¹⁸F-fluoride [46] yielded a product with SA of three orders of magnitude higher than the product obtained by the traditional electrophilic destannylation with ¹⁸F₂ with comparable biological behaviour and imaging properties in neuroendocrine tumour model [47]_. The simplicity of the synthesis method, compared with the conventional electrophilic approach along with the possibility of injecting a dose three orders of magnitude lower in comparison with the conventional product, thus dramatically reducing the risk of pharmacologic effects due to the co-administration of ¹⁹F-DOPA, appears very promising.