Chemistry Reference
In-Depth Information
O
OC
HO
PhCH
2
N
3
O
OC
M
H
2
O
′M(CO) ′
M=Tc, Re
NH
2
OC
N
N
N
CH
2
Ph
63
fIgure 6.23
The 'click to chelate' approach with the Tc(I) tricarbonyl core.
COOH
COMe
M
M
CO
CO
OC
OC
HOOC
OC
OC
COOH
66
65
64
fIgure 6.24
m(I) cyclopentadienyl complexes and precursor.
affibodies [230-232], folate for cancer imaging [233, 234], bombesin analogues for cancer imaging [234, 235], cyclophenil
for imaging estrogen receptor-positive breast cancer [236], recombinant Annexin(V) for apoptosis imaging [237], nitro-l-
arginine for targeting and imaging inducible nitric oxide synthetase [238], and vitamin B
12
for cancer imaging [239, 240].
The majority of the bioconjugates discussed above have been made via some form of peptide coupling reaction between
the bifunctional chelator and bioactive molecule. An interesting alternative approach has been developed by Schibli et al.,
the so called 'click to chelate' strategy. This exploits Cu-catalysed click chemistry to couple an azide to an acetylene group
to create a link between complex and biomolecule; the triazole group created also functions as donor to the tricarbonyl unit.
An example of a model system using benzyl azide is shown in
63
(Figure 6.23). Thence derivatisation of thymidine with
azide generates a conjugate potentially capable of imaging proliferation in cancer by acting as a substrate for hTK1 (human
cytosolic thymidine kinase). The radiolabelling with
99m
Tc proceeded in high yield to give a single species. Specific activity
for hTK1 was achieved by identification of up to 20% of the phosphorylated thymidine conjugate [241, 242]. The click to
chelate approach was subsequently modified to produce bistriazole-based ligands to bind to the m(Co)
3
core [243].
6.5.3
cyclopentadienyl and carborane complexes
The high stability of metal cyclopentadienyl complexes even in aqueous media suggested their possible role in Tc-based
imaging. The first approach was by Wenzel et al., who prepared complexes of the type [RCp
99m
Tc(Co)
3
] (Cp = C
5
H
4
, R = Come,
Co
2
me, CoPh, etc.) by a ligand transfer reaction involving [
99m
Tco
4
]
−
and (RCp)
2
Fe and mnCl(Co)
5
as Co provider. The
reagents were heated in a sealed tube in meoH at 120-150°C to give acceptable yields of the technetium complex. The same
procedure was later adapted to the labelling of octreotide with
99m
Tc, and the observed uptake in pancreas and adrenals was
shown to be receptor specific by blocking with excess octreotide [244]. Cyclofenilcyclopentadienyltricarbonyltechnetium-
94m and rhenium complexes were also prepared and their estrogen receptor binding properties studied [245, 246].
Although the synthetic routes above give the required
99m
Tc cyclopentadienyl complexes, they are not appropriate for
routine radiopharmaceutical use. However, Alberto et al. have shown that acetylcyclopentadiene reacts rapidly with
[
99m
Tc(Co)
3
(H
2
o)
3
]
+
in water under mild conditions to give
64
(Figure 6.24). Also Thiele's acid
65
is cleaved by reaction
with the tricarbonyl aquo ion to give the carboxylcyclopentadienyl derivative
66.
Clearly, this new synthetic approach
means that cyclopentadienyl systems could form the basis of another method for labelling biomolecules for imaging, but it
remains to be seen whether these offer any significant advantages over the many alternatives. Carborane clusters of the type
R
1
R
2
C
2
B
9
H
9
2−
(l; R
1
= CH
2
CH
2
CooH, R
2
= H) are isoelectronic and isolobal equivalents of the cyclopentadienyl anion.
Valliant et al. have shown that these can be used to prepare complexes of the type [lm(Co)
3
]
−
(m = Re,
99m
Tc) by reaction
of the carborane anion with the Isolink kit with fluoride as catalyst [247-249]. Derivatives with R = C
6
H
4
oH-4 have been
evaluated for binding to estrogen receptors [250]. Borane clusters have been investigated for boron neutron capture therapy
(BnCT), and the incorporation of a SPECT probe will enable their exact location
in vivo
to be identified.
