Chemistry Reference
In-Depth Information
SO
2
NH
2
O
M=Tc, Re
OC
O
N
N
O
HN
N
O
OC
M
M
O
OC
S
O
S
SO
2
NH
2
83
84
fIgure 6.31
Conjugates of metal complexes with aromatic sulphonamides for CAIX targeting.
interesting report that a
99m
Tc-labelled bis(thiosemicarbazone) complex (Figure 6.5) also shows selective uptake in the
myocardium in an isolated rat heart ischemic model [277]. Uptake studies in Hela cancer cells also showed selective uptake
under hypoxic conditions, but
in vivo
studies in mice with CanT hypoxic tumours revealed only small retention of
99m
Tc in
the tumour [278].
There is now data to suggest that it is possible to have a
99m
Tc hypoxia agent based on conjugation to a nim molecule, but
further biological evaluation will be required. The complex TcHl-91 is definitely hypoxic selective and of perhaps of more
interest than the nim derivatives because it appears to operate by a very different mechanism. This raises the possibility that
it is providing information on hypoxia that is complementary to that from a nim-based agent such as F-mISo.
An alternative approach to imaging hypoxia is to utilise the hif controlled increase of expression on the external surface of
cancer cells of carbonic anhydrase IX (CAIX) [279], which may play a role in the control of pH within the cancer cell [280].
CAIX therefore acts as an indirect marker for hypoxia [281], and
18
F-labelled aromatic sulphonamides (inhibitors of CAIX) or
radioiodine-labelled antibodies to the CAIX enzyme have been used to image CAIX expression
in vivo
. Aromatic sulphon-
amides have been coupled to
99m
Tc or Re complexes as shown in
83
and
84
(Figure 6.31). The Re analogue of
83
was an
effective inhibitor of the CAIX enzyme
in vitro,
but the
99m
Tc derivative showed little uptake in mice with xenografted CAIX-
expressing tumours [282]. Similarly, the Re complex
84
was an effective enzyme inhibitor
in vitro
but showed only marginal
uptake in cells with CAIX over expression [276]. Enzyme inhibition studies are evidently not a reliable guide to the behaviour
in cells or animals. It appears that the sulphonamide class of CAIX inhibitors may be rather sensitive to the bulk and structure
of the appended radionuclide and that an approach using labelled antibodies or fragments may be more productive, although
the comparatively short half-life of
99m
Tc may be an issue and a pre-targeting approach might be necessary.
6.7
technetIum and rhenIum dIphosphonate complexes
It has been known for a long time that
99m
Tc polyphosphate compounds can be used to detect calcification in bone [283], and
the
99m
Tc complex of hydroxyethyldiphosphonate HEDP (
85)
is sold commercially as medronate
Tm
for the imaging of
bone metastases in cancer patients. The coordination chemistry of this type of ligand with both Tc and Re is complex, and
a mixture of oligomers of unknown structures and metal oxidation states are formed from reaction of diphosphonate with
[Tco
4
]
−
with stannous chloride as reductant. only one X-ray structure has been reported of a polymeric product from
[
99
TcBr
6
]
2−
and methylene diphosphonate; a portion of the structure is shown in
86
(Figure 6.32) [284].
The bone-targeting ability of these complexes is believed to be due to the uncoordinated phosphate oxygen atoms binding
to exposed calcium ions at the bone surface. EXAFS studies on the ReHEDP species show Re-o bonding and also some
Re-Re interactions [285]. This Re complex is in clinical use for the palliation of pain accompanying bone metastases. The
complex [
188
Reo(DmSA)] that was discussed earlier in the context of therapy of medullary carcinoma is also taken up in
bone metastases and can also be used for pain relief [86, 286].
6.8
the future for technetIum and rhenIum radIopharmaceutIcals
The chemistry described above illustrates that the coordination chemistry for radiopharmaceuticals of these two elements is
very much alive and flourishing with significant advances having been made over the past two decades. At first sight it is
perhaps surprising that so few of the many new compounds have been widely adopted for clinical use. This in part reflects
the advent of PET imaging, which is perceived to offer advantages over SPECT. This issue was discussed in the introduction
to this section. However, it has to be said that many of the new bifunctional chelators provide alternative ways of targeting
the same classes of biomolecule with improvements in imaging performance that are sometimes relatively small. This does
