Chemistry Reference
In-Depth Information
reaction with these leaving groups, especially with OH and OEt. An example with hydride as leaving group is the derivatisa-
tion of a nucleoside with a -Ph(
t
-Bu)
2
SiH moiety with subsequent incorporation into an oligonucleotide, followed by label-
ling at 165°C in DMSO [228]. The fluorosilicon approach is most often used in bioconjugation, but also small molecules
have been made, for example, silicon-based derivatives of the D
2
ligand fallypride (
18
F/
19
F exchange, 2.4 Ci/µmol) [216] and
of the hypoxia marker misonidazole (OEt and O
i
-Pr leaving groups) [227]. Finally, labelled alkyl tetrafluorosilicates present
an alternative to the prosthetic groups with bulky substituents discussed above [206]. They were made from the corresponding
triethoxysilyl precursors, and carrier fluoride was added to ensure efficient incorporation. The labelled fluorosilicates proved
to be moderately stable in aqueous media.
3.5.3
click chemistry
Organic azides (
90
) react with terminal alkynes (
89
) in a 1,3-dipolar cycloaddition to give 1,4-disubstituted 1,2,3-triazoles
(
88
) (Scheme 3.16). This so-called Huisgen cycloaddition is Cu(I) catalysed, which orientates the substituents specifically
in the 1,4 direction. It is an example of a 'click reaction,' which is a modular synthetic approach using always a same effi-
cient condensation reaction to join a pair of variable chemical moieties. Click chemistry has become highly fashionable in
18
F-PET chemistry, especially in bioconjugation because of the mild reaction conditions in water or aqueous organic mix-
tures, the high yields, and the
in vivo
stability of the triazole entity, which mimics an amide or peptide bond, and the relative
inertness of the azide and alkyne functions toward other reactions in the applied conditions [230-232]. The fluorine-18 label
can be either on the azide or on the alkyne partner, of which 2-[
18
F]fluoroethyl azide and 4-[
18
F]fluoro-1-butyne are the sim-
plest representatives. These can be easily prepared from corresponding sulphonate precursors and, if desired, isolated by
distillation [101], [233-242]. More complex
18
F-labelled click components that can contribute to an increased hydrophilicity
are known too, for example, pyridines such as compounds
58
,
59,
and
60
[174-177], reagents derived from 2-[
18
F]fluoro-
2-deoxy-D-glucose (
2
) [243] or containing PEG [244-247]. An illustration of the efficiency of the Huisgen click reaction is
a recent oligonucleotide labelling using azido([
18
F]fluoromethyl)benzenes and only 20 nmol of precursor [248].
The use of copper in the above click reaction sometimes presents a problem because of the potential risk of contamination
of an injection with this toxic metal. A copper-free variation on the above azide cycloaddition was therefore developed, in
which the driving force of the reaction is energy relief in a strained azadibenzocyclo-octyne (
91
) when the azide (
90
) adds
to the triple bond to give
92
(Scheme 3.16). Again the radioactively labelled part can be attached to either of the two reaction
partners. The alkyne partner can be labelled at the ring nitrogen in the form of, for example, a 3-(
p
-[
18
F]fluorobenzoylamino)
propionyl group (easily accessible via [
18
F]SFB (
70
)) [249] or a 3-(6-[
18
F]fluorohexanoylamino)propionyl group [250]. In
this case the biomolecule to be labelled bears the azido function, for example, Tyr
3
-octreotate [250]. Bombesin was labelled
the other way around with various azides of varying lipophilicity [251]. This click construction can be made in either
aqueous or alcoholic media and seems metabolically stable. [249] Other 1-3 dipoles potentially can be useful too, as the
recently proposed nitrone function, which adds to alkenes without catalyst [252].
Another catalyst-free bioconjugation method that is drawing attention is the inverse electron demand Diels-Alder cyclo-
addition of a
trans
-cyclo-octane (
94
) and an aryl-substituted tetrazine derivative (
93
) [253] (Scheme 3.17). This reaction,
leading to
95
, is practically immediate and can be carried out in aqueous media. The
trans
-cyclo-octene
94
, carrying a fluo-
rine-18 labelled chain, adds with expulsion of dinitrogen to the tetrazine
93
, carrying the biomolecule. The driving force is
again strain relief.
Trans
-cyclo-octenes are conveniently generated from the corresponding
cis
compounds by photochemical
means. This method has been successfully applied in the labelling of a PARP-1 inhibitor, which is a small molecule [254],
and in the labelling of a cyclic RGD peptide [255]. A similar reaction is the photoactivated addition of a dipolarophilic
alkene (
97
) to an aryl substituted tetrazole (
96
), which was applied to peptide bioconjugation with a
18
F-moiety attached to
the tetrazole and the peptide to the alkene, leading to product
98
[256] (Scheme 3.17).
R
1
N
R
1
R
1
H
N
R
1
N
91
89
-
+
NNN
N
R
2
N
Cu(I)
90
88
R
2
N
N
R
2
N
92
scheme 3.16
The Huisgen 1,3-dipolar cycloaddition (on the left) and a copper-free variation using a strained azadibenzocyclo-octyne
(on the right) in radiofluorination. The radioactive part can be either on R
1
or on R
2
.
