Chemistry Reference
In-Depth Information
O
O
HO
2
C
HO
NH
2
HO
N
N
HN
R
HO
2
C
CO
2
H
CO
2
H
HO
N
N
Thr
HO
2
C
CO
2
H
Citrate
DOTA-
R
NH
2
HO
HO
Thr(ol)
R
1
O
N
N
NH
O
R
2
R
=
O
NH
2
O
H
2
N
S
S
HN
HO
O
N
Thr(NH
2
)
NH
2
H
R
3
O
O
HO
NH
2
HO
R
1
R
2
R
3
BFC-conjugate
Phe
Phe
Phe
DOTA-TOC
DOTA-TATE
DOTA-NOC
DOTA-lanreotide
Thr(ol)
Tyr
Tyr
Thr
Thr(ol)
Nal-1
Nal-1
L-1-naphthylalanine
Tyr
Thr(NH
2
)
Nal-1
fIgure 5.8
67
Ga-citrate (FdA-approved for sPECT imaging purposes), and various dOTA-
r
octreotide-based BFC-conjugates that
are currently being investigated with
67/68
Ga (
r
= octreotide derivative as defined above).
BFCs dOTA-TOC, dOTA-nOC, dOTA-TATE, and dOTA-lanreotide are examples of other
68
Ga-dOTA somatostatin-
targeting peptide conjugates in clinical trials (Figure 5.8) [53, 88, 90, 94].
68
Ga-dOTA-bombesin is another peptide BFC
conjugate in clinical trials that is used for imaging prostate cancer [53, 95].
The short half-life of
68
Ga is not suitable for imaging with antibodies, due to their slow localisation (imaging with anti-
bodies typically is performed 24-72 hours post injection) [26]. To overcome this limitation, small antibody fragments are
used as biovectors with faster localisation times for use with short-lived isotopes. Affibodies are similar to F(ab′)2 fragments
(Fab = fragment antigen binding), diabodies, and minibodies, which are all fragments of antibodies, that due to their smaller
size of ~6.5 kda, are well below the ~70,000 kda threshold for renal filtration [26]. They are able to quickly localise, bind
their target receptors, and have the unbound population clear the blood through the kidneys, making imaging studies feasible
with short half-life isotopes like
68
Ga [96, 97]. The
68
Ga-based agent
68
Ga-F(ab')2-trastuzumab (hERscan) is currently
finishing clinical trials for breast cancer imaging [53, 98]. A similar example to hERscan is the
68
Ga-dOTA-Z
hER2:2891
-
affibody conjugate, which has also been successfully used for imaging hER2/neu positive tumours and targets the same
breast cancer receptors as the full antibody herceptin (trastuzumab), but localises in hours instead of days [96]. One universal
flaw amongst all antibody fragments is exceptionally high kidney uptake [96, 99], which greatly limits the possible injected
dose of activity due to radiation burden on the kidneys; however, high kidney uptake can be reduced by co-administration of
the amino acid lysine, often both pre- and post-therapy [100].
5.5.2
recent
68
gallium work
Although the most commonly used chelate system for
68
Ga radiopharmaceuticals is dOTA, its close relative nOTA and its
derivatives have actually been shown to have far superior coordination properties (Figure 5.9) [101].
nOTA forms a very stable macrocyclic complex with gallium; however, contrary to dOTA, it is able to label quantita-
tively at room temperature and is therefore suitable for conjugation with sensitive biomolecules. dOTA has lower thermo-
dynamic stability with Ga(III), as demonstrated by its stability constant (log
K
Ml
= 21.3) [102]; however, nOTA shows
exceptional thermodynamic stability with Ga(III) (log
K
Ml
= 31.0) [37]. dOTA forms a large macrocyclic cavity that is not
