Chemistry Reference
In-Depth Information
-
O
P
O
O
OH
O
HO
O
O
HO
HO
HO
F
F
HO
HO
67
68
fIgure 6.25
FDG before and after phosphorylation.
+
O
N
OC
OC
O
N
HO
N
N
O
NH
OH
HO
Tc
N
O
Tc
OH
S
HO
OC
N
O
O
OH
HO
HO
S
S
OH
HO
OH
HO
69
70
fIgure 6.26
Glucose-derived conjugates of technetium complexes.
6.5.4
carbohydrate conjugates
Cancer cells have less efficient metabolism than normal cells, and there is increased glucose uptake to compensate, using
glycolysis as an energy source. This has led to the extensive use of radiolabelled glucose derivatives for cancer diagnosis.
Glucose is taken into cells via the GlUT-1 uptake pathway and then undergoes glycolysis, the first step of which is phos-
phorylation via hexokinase (HK). The most widely used derivative is
18
F-labelled glucose FDG
67,
which after cell uptake
is phosphorylated at the 6 position to give
68
(Figure 6.25). The next step in the glycolytic pathway is dehydration by
6-phosphate dehydrogenase, but this is blocked by the fluoride, and phosphorylated FDG accumulates in the cell by virtue
of its negative charge.
A
99m
Tc-based equivalent of
18
FDG would be a highly attractive alternative due to the low cost and wide availability of
99m
Tc.
However, the challenge is to make a technetium complex that is both taken up by the GlUT-1 pathway and can act as a substrate
for HK. This area was very comprehensively reviewed by orvig et al. in 2008 [251], thus this account is restricted to a few
selected examples. many compounds containing a form of glucose linked to
99m
Tc or Re have been prepared over the past 20
years. Although radiolabelling and
in vivo
studies have been conducted with many of these, they have generally been restricted
to measuring tumour uptake without determining GlUT-1 or HK activities; the tumour uptake could therefore be non-specific.
Glucosamine is a convenient functionalised glucose molecule; two of these have been attached to ECD as shown in
69
(Figure 6.26).
In vitro
cellular uptake was suppressed by D- but not l-glucose, suggesting the use of the GlUT-1 pathway.
The
99m
Tc derivative was proposed to also act as a substrate for HK, but this was based on nADH detection rather than
identification of the phosphorylated product [252]. overall, the tumour uptake of the
99m
Tc complex
69
was comparable to
18
FDG. As with many other labelling targets, the
99m
Tc tricarbonyl core has been used to link to glucose in compounds such
as
70
. Here the thioether group has been introduced to minimise the possibility of loss of the glucose molecule by enzymatic
cleavage. The radiolabelling yield and stabilities were high but there was no evidence for HK activity or use of the GlUT-1
uptake route [253]. Clear evidence for glucose conjugates with a
99m
Tc core that truly mimic FDG is therefore sparse, but this
is a rapidly evolving field and there is enough evidence to suggest that a SPECT alternative to FDG is a realistic possibility.
Although glucose surrogates bearing
99m
Tc have been elusive, sugar groups can also be extremely useful to modify the
biological behaviour of complexes and to act as linker groups to other targeting molecules.
