Chemistry Reference
In-Depth Information
3.4
the radIofluorInatIon
3.4.1
electrophilic reactions
Reactive [
18
F]fluoride is practically always applied in a nucleophilic substitution reaction. Before looking at this in more
detail, we should mention recent progress in the conversion of [
18
F]fluoride into electrophilic fluorine-18 with a SRA
intermediate between that of [
18
F]fluoride and the habitual low value of [
18
F]F
2
. Gaseous methyl [
18
F]fluoride, made by
nucleophilic substitution on methyl iodide, was made to react with a small amount of F
2
in an electric arc to give [
18
F]
F
2
by a radical exchange process [62]. This 'high SRA' [
18
F]F
2
was converted into [
18
F]selectfluor bis(triflate), which
was successfully used in electrophilic aromatic model destannylations [63]. High SRA [
18
F]F
2
itself has been used in the
synthesis of 6-[
18
F]fluoro-L-DOPA (
4
) [64]. Xenon [
18
F]fluoride of relatively high SRA was made by an exchange reac-
tion on a small amount of XeF
2
in a microfluidic reactor and used in electrophilic model reactions [65]. very recently a
palladium-based method was proposed to convert no-carrier-added [
18
F]fluoride into an electrophilic form for aromatic
radiofluorination [66] (Scheme 3.1).
[
18
F]Fluoride is captured (by reaction with complex
13
) to give a specially designed Pd(Iv) complex (
14
). The oxidation
state Iv is high for palladium, and nucleophilic attack on the fluorine atom is possible. The palladium atom together with its
other ligands acts as a leaving group recovering the more comfortable oxidation state Pd(II). In the presented method, this
nucleophilic attack is performed by another palladium(II) complex
15
carrying the aromatic precursor, resulting in a transfer
of the [
18
F]fluoride onto the Pd atom of the precursor complex
15
giving
16
, in its turn in the Pd(Iv) state. The latter gives
a fast reductive elimination to the desired [
18
F]aryl fluoride
17
. various relatively complex radiofluorinated compounds, for
example, [
18
F]fluorodeoxyestrone, were labelled in radiochemical yields of more than 30%. Further experience should show
whether this is perhaps the long-sought-after grail of no-carrier-added electrophilic radiofluorination.
3.4.2
nucleophilic reactions
The vast majority of radiofluorination reactions are nucleophilic substitution reactions with a carbon atom as the reaction centre
similar to the above CH
3
[
18
F]F synthesis. Other reaction centres that are being explored are silicon, boron, and aluminium.
These centres are especially finding application in bioconjugation, which is not surprising because these elements lend them-
selves primarily to prosthetic labelling because they normally are foreign to biomolecules. Reactions can often be carried out
in aqueous media, which is an advantage in the chemical manipulation of proteins. The substitution reactions at a carbon centre
are usually done in an organic solvent, most often of an aprotic dipolar character such as MeCN,
N
,
N
-dimethylformamide
(DMF), or dimethylsulphoxide (DMSO). Carbon-centred nucleophilic radiofluorination can be divided into an aliphatic [23]
and an aromatic [24-26, 67] field.
3.4.2.1 Nucleophilic Aliphatic Substitution
Leaving Groups
In the aliphatic field, the leaving group is often a sulphonate group such as, in decreasing nucleofugacity,
triflate, mesylate, or tosylate with the highest incidence of the last one because of the stability of tosylate esters. The reaction
takes place with inversion of configuration, which is important for the design of the precursor when the reaction centre is
an asymmetric carbon such as in the radiosynthesis of all four optically pure stereoisomers of 4-[
18
F]fluoroglutamines [41].
For the frequently encountered radiofluorinated sugar derivatives, of which [
18
F]FDG (
2
) [68] and [
18
F]FLT (
3
) [23, 69]
(Scheme 3.2) are emblematic, this is naturally also an important issue.
The two-step radiosynthesis of [
18
F]FMAu (
23
) is a more recent example [70] (Scheme 3.3). The Boc protecting group
on the pyrimidine ring of
22
is necessary to avoid neighbouring group participation of the pyrimidine carbonyl oxygen atom
at the 2-position (as in
20
, Scheme 3.2) through electron-pair donation by the 3-nitrogen, which could result in an unwanted
15
[Pd]
18
F
2+
+
18
F
L
1
18
F
R
[Pd]
L
2
L
4
L
2
L
4
18
F
-
Pd
L
6
Pd
L
6
R
R
L
3
L
5
L
3
L
5
Pd(II)
Pd(IV)
13
Pd(IV)
14
Pd(IV)
16
17
scheme 3.1
Schematic representation of creating electrophilic [
18
[18F]fluorine as a Pd(Iv) complex (
14
) reacting with another Pd(II)
complex (
15
) bearing the aromatic precursor.
