4598
D. Tang et al. / Tetrahedron Letters 51 (2010) 4595–4598
2.5. MAOS of 2-(4-(3-(2-(diethylamino)-2-oxoethyl)-5,
7-dimethylpyrazolo[1,5-a]pyrimidin-2-yl)phenoxy)ethyl-4-
methylbenzenesulfonate (8), a precursor for radiosynthesis of
and 1P50CA128323 (Vanderbilt ICMIC Program). We thank Dr(s).
Ronald Baldwin, Ph.D. and R. Adam Smith, Ph.D. for editorial input
and insightful discussion.
[
18F]DPA-714
Supplementary data
In order to produce 18F-labeled DPA-714 as a PET tracer, 8 is
commonly prepared as the precursor. Previous syntheses of this
compound were carried out at room temperature in high yield.6c,d
However, the prolonged reaction time reported (16 h) is a consid-
erable disadvantage. We found that this reaction could be opti-
mized using microwave irradiation for 30 min at 120 °C.
Following purification, we obtained 8 in a yield of 65%, comparable
to previous reports (Table 6).
Extending the utility of MAOS to the synthesis of additional pyr-
azolo-pyrimidinyl-based compounds, we performed the first and
third reactions shown in Scheme 1 using a variety of different re-
agents, mimicking a library-based synthetic approach. For example,
substitution of 1 with the corresponding p-chloro or p-methyl re-
agent results in rapid synthesis of 3a and 3b in acceptable yields
(Table 7). Similarly, application of MAOS to reactions featuring un-
ique diones also appears feasible, enabling synthesis of potential
TSPO ligands following the third reaction (Table 8). Interestingly,
in evaluating somewhat bulkier diones, we observed significantly
reduced reaction yield, presumably due to the geometric con-
straints afforded by groups in R1, R2 and R3. We anticipate that syn-
thetic optimization of the bulkier pyrazolo-pyrimidines is possible,
though beyond the scope of this focused work.
Supplementary data associated with this article can be found, in
References and notes
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In summary, a detailed optimization of the total synthesis of a
high-affinity TSPO ligand, DPA-714, utilizing MAOS, is described.
The protocol reported here significantly improves overall reaction
times while maintaining or even improving synthetic yields. We
envision that this protocol can be extended to library synthesis
of novel TSPO ligands with potential use for noninvasive visualiza-
tion of TSPO expression in vivo as well as treatment of TSPO-
expressing disease.
Acknowledgements
The authors wish to gratefully acknowledge funding from the
National Cancer Institute (NCI): 1R01 CA140628, K25 CA127349,