Chemistry Reference
In-Depth Information
taBle 7.1
details of Ga
67
and In
111
radioisotopes.
Isotope
Half-life
Decay Emissions
Production
67
Ga
78 h
γ-emissions at :
93, 185, 300, 393 KeV
Auger 7.2-9.7 KeV
Decay 100% by EC
Cyclotron
68
Zn (p,2n)
67
Ga
111
In
68 h
γ-emissions at 172 and 245 KeV
Auger 19-23 KeV
Decay 100% by EC
Cyclotron
111
Cd (p,n)
111
In
of a
68
Zn target. Its relatively long half-life means that it can be readily transported to radiopharmacies distant from the cyclo-
tron. It is also relatively inexpensive at approximately $20/mCi. It decays entirely by electron capture with 10 γ emissions, the
four most intense being shown in Table 7.1. There is accompanying Auger electron emission that in energy terms is comparable
to that of
99m
Tc. It can be supplied in HCl solution or as the citrate following addition of citrate and neutralisation.
While
110
In,
110m
In, and
114m
In have been investigated for radiopharmaceutical applications,
111
In has been by far the most
widely used. It is made from
111
Cd by proton bombardment in a medium energy cyclotron. Decay occurs exclusively via
electron capture to give excited states of
111
Cd and then photons of 175 and 245 KeV are emitted en route to the ground state.
There is also some internal conversion generating Auger electron emissions in the range 19-23 KeV, which are suitable for
therapeutic applications.
7.2
GallIum and IndIum complexes and related BIoconjuGates
In recent times, the use of
67
Ga has decreased substantially with a much increased emphasis on the positron-emitting
68
Ga.
We have here focused on ligands that have been used with
67
Ga or
111
In but have included some recent examples involving
68
Ga to illustrate what may also be possible with
67
Ga. The following section follows the format used for technetium and
rhenium (Chapter 6) with ligands organised according to the donor atoms available.
7.2.1 o
6
donor ligands
67
Gallium citrate has been used for many years as an imaging agent [5, 6] sold under the name Neoscan
Tm
by GE Healthcare.
It targets metastatic tumours and focal sites of infection but cannot distinguish reliably between these. The gallium is readily
trans
-chelated from the citrate complex
1
to iron transport systems, so high concentrations of
67
Ga tend to reflect areas of
high iron turnover. This is an interesting case where imaging capabilities depend on the complex being labile to provide
67
Ga
for biological Fe sequestering agents. The X-ray crystal structure is shown in Figure 7.1
(1)
and reveals a distorted octahe-
dral coordination about gallium [7]. The similarities of Ga and Fe coordination chemistry means that biological ligands for
iron such as deferrioxamine (DFO) form extremely stable complexes with both metals. The X-ray structure of a Ga complex
(
2
) (Figure 7.1) with a model hydroxamate has been determined and shows octahedral O
6
coordination. In contrast to
Zirconium-89, there have been few, if any, examples of the use of bioconjugates based on DFO with radioactive gallium or
indium. Interestingly, a
67
Ga transferrin complex has found use as a tumour imaging agent [8] and is incorporated in cells by
clathrin-mediated endocytosis.
Two groups have independently synthesised the capped tris(hydroxypyridone) ligands
3, 4
(Figure 7.1). The C-capped
ligand
3
radiolabels in extremely high yield at room temperature, pH 6.5 with
68
Ga and can readily be derivatised at the cap-
ping carbon for attachment of biomolecules. A variant with a pendant maleimide group has been used to label C2Ac protein
for the potential imaging of apoptosis [9]. The N-capped ligand
4
does not appear to be as well pre-organised for coordination
to gallium, but nevertheless it has been labelled with
67
Ga and showed promising biodistribution
in vivo
with no binding to
blood protein and rapid renal clearance [10].
7.2.2 n
2
o
x
s
4-x
donor ligands
The classic hexadentate ligand EDTA (x = 4) forms very stable (log K = 24.9) octahedral complexes with Ga and the
7-coordinate complexes formed with In are even more stable. Replacement of two carboxyl substituents in EDTA by thiolato
groups, for example,
5
(x = 2), causes an impressive increase in stability of the Ga complex, increasing log K to 41 (Figure 7.2).
This ligand has been labelled with
67
Ga in good yield, and
in vivo
studies showed high stability with excretion occurring
