TOWARD IMAGING GLYCOTOOLS BY CLICK COUPLING - Click Chemistry in Glycoscience: New Developments and Strategies - page 190

method involved the CuAAC between the free -azido glucose and the homopropar-

gyl [ 18 F]fluoride 52 prepared from the corresponding tosylate 51 by treatment with
K[ 18 F]F, K 222 in acetonitrile at 100 ◦ C for 20 minutes. The biological evaluation of
compound 50 showed a good in vitro stability but was not a substrate of hexokinase,
the enzyme responsible for the phosphorylation of [ 18 F]FDG, for example. Moreover,
in contrast to [ 18 F]FDG, compound 50 was not taken up by human colon carcinoma
cells limiting its use in PET.

7.3.3.2 Nucleosides Among labeled carbohydrates, 3 -deoxy-3 -[ 18 F]fluoro-
thymidine (FLT) is currently the most widely used proliferation imaging agent in
PET. The uptake of this tracer is dependent on the presence of thymidine kinase-1
(TK1), an enzyme implicated in the salvage pathway of nucleotides. In cells FLT
is monophosphorylated by TK1 and this phosphate accumulates in the cell. TK1
activity can be upregulated by treatment and FLT could be of interest in the treatment
assessment of tumor response to treatment. However, high FLT uptake in the liver
and bone marrow limits its use in cancer diagnostic and prompted the search for new
analogs [62, 63].
New thymidine derivatives have recently been prepared taking advantage of the
CuAAC reaction (Scheme 7.11). New analogs of FLT have been described in the
patent literature [64]. The synthesis has recently been improved and the compound
used in testings [65]. The known uridine derivative 53 [66] was submitted to CuAAC
with 2-[ 18 F]fluoroethylazide to provide the labeled thymidine derivative 54 in about
75% radiochemical yield. The reaction was carried out in the presence of copper
iodide and ascorbic acid in water at 80 ◦ C for 10 minutes. Compound 54 was stable in
human plasma but is taken up by myocardis suggesting in vivo metabolism. It should
be a useful probe for tumor cell proliferation.
The CuAAC reaction has been developed for the labeling of glucose and 3-azido-
thymidine as model reactions. As shown in Scheme 7.12, Chi and coworkers proposed
the labeled acetylenic derivative 56 as a prosthetic group [67]. This compound, pre-
pared from mesylate 55 , reacted in good yields with acetylated or free azidoglucose,
to provide the expected adducts 58 within 10 minutes. Classic reaction conditions,

18 F

N

O O

N

N

HN HN

18 F

N 3

O N O N

HO HO

O O

HO HO

54

53

SCHEME 7.11 Synthesis of 18 F labeled triazolyl-thymidine.