Table 2 Substrate scope of the reaction at 75 1C in DMSO
We have demonstrated a novel, versatile methodology for
the nucleophilic radiosynthesis of [18F]trifluoromethyl-labelled
compounds which have not been accessible so far. Direct
nucleophilic 18F-fluorination of CF3 groups in high specific
activity opens up a wide range of potential candidates for
radiotracer studies. Furthermore, accessing such ‘‘native’’
functionalities in biologically well characterised molecules
will be highly favourable for the invasive introduction of
additional fluorine atoms or fluorinated prosthetic groups into
radiotracer candidates.
Precursor
R1
R2
Product
RCY/%
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
OTs
OTs
OBn
NBn2
4-MeOPh
4-Me2NPh
4-O2NPh
4-FPh
PhCH2
6-MeOC10H6
H
CH3
H
H
H
H
H
H
H
CH3
[
[
[
[
[
[
[
[
[
[
18F]1b
18F]2b
18F]3b
18F]4b
18F]5b
18F]6b
18F]7b
18F]8b
18F]9b
18F]10b
93
52
82
79
69
67
89(81)4
79
65
63
In addition to direct labelling under mild conditions,
secondary labelling agents such as [18F]1b provide a novel route
for the introduction of metabolically insensitive 18F-labels in
heteroatom bound prosthetic groups.6d Due to the high stability
of C–F bonds in CF3-groups, these are less susceptible to
oxidative defluorination than aliphatic 18F fluorides. This is to
the best advantage of brain imaging studies, where uptake of
[18F]fluoride ions into the skull will seriously confound PET
data. We conclude that our novel approach is an advancement
of utmost utility in the field of PET radiochemistry.
For the investigation of the substrate scope of our reaction,
several labelling precursors7,8 were synthesized and reacted
with [K+K222][18F]FÀ cryptate under optimized conditions
(Table 2).
Difluorovinyl-functionalised labelling precursors are easily
accessible from a variety of established methods. In our case,
the model compounds were obtained in good yields using
known transformations by either elimination or Wittig–Horner
reactions.8 Interestingly, all model compounds were labelled in
good radiochemical yields except the tetra-substituted olefin 2a
which was obtained in considerably lower yield. These findings
suggest that the direct addition of [18F]fluoride ions to
2,2-difluorovinyl groups is a practicable way for the synthesis
of diversely functionalised 18F-labeled compounds.
As a prosthetic group, the 2-[18F]trifluoroethyl group
provides great potential as a metabolically insensitive, readily
available supplement to PET chemistry. With n.c.a [18F]1b in
hand we briefly examined the reactivity of this alkylating agent
towards different nucleophiles. For this reason, [18F]1b was
reacted with the N and O nucleophiles 11a–13a in DMF using
Cs2CO3 as a base. Moderate to good yields were obtained
within 10 minutes for 11b–13b (Table S1)12. [18F]1b was also
used to synthesise radiotracer candidates 14b and 15b as a
proof of concept for radiotracer synthesis.10
Notes and references
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J. Ermert and H. H. Coenen, Org. Biomol. Chem., 2011, 9, 765;
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3 G. J. Meyer, S. L. Waters, H. H. Coenen, A. Luxen, B. Maziere and
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Compound 14b, an alleged imaging agent for neurofibrillar
tangles formed by hyperphosphorylated human t-protein in
Alzheimer’s disease, was obtained in a radiochemical yield of
91% (Scheme 3). Compound 15b was formed in relatively low
yield, however this is a common finding in N-alkylation of
tropanes. Nevertheless, these findings show that [18F]1b is well
suited as a labelling agent.
5 (a) H. L. Yale, J. Med. Chem., 1959, 1, 121.
6 (a) M. R. Kilbourn, M. R. Pavia and V. E. Gregor, Int. J. Radiat.
Appl. Instrum., Part A, 1990, 41, 823; (b) O. Josse, D. Labar,
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Y. Li, Y. Zhao and J. Hu, Tetrahedron Lett., 2010, 51, 6150.
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Chem., 2004, 125, 1481; (b) G. K. S. Prakash, J. Hu, Y. Wang and
G. A. Olah, Angew. Chem., 2004, 116, 5315; (c) M. Obayashi,
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9 Sigma-Aldrich 41647 DMSO puriss., absolute, over molecular
sieve (H2O r 0.005%), Z 99.5% (GC) was used. Higher water
concentrations were prepared by adding water. See ESIw.
10 Carrier added [18F]7a has been synthesised via18F/19F isotopic exchange
and used to prepare compound 6 in low specific activity. See: (6d).
11 Characterisation of 19b and 20b as radiotracers for brain imaging
studies will be reported elsewhere.
Scheme 3 Radiotracer synthesis.
12 See ESIw for detailed experimental procedures and analytical data.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11873–11875 11875