Chemistry Reference
In-Depth Information
CO
2
H
R
N
N
CO
2
H
N
OMe
HO
N
3
HO
2
C
R=H, CH
2
C
6
H
4
NCS, CH
2
CH
2
CO
2
H
8
7
fIGure 7.3
Hexadentate N
3
O
3
donor NOTA and Schiff base ligands.
O
O
P
P
OH
N
R
N
HO
R
N
OH
P
R
O
9
fIGure 7.4
Structure of TRAP ligand system, where R = H, Ph, OH.
cationic complex with Ga that has been investigated as a myocardial agent. Two stereoisomers are possible depending on the
disposition of the chelate ring systems. The (+) and (-) forms of the
67
Ga complex have been separated on a chiral HPlC
column and biodistributions studied in wild type and mDRIa knockout mice.
The biodistributions of the two isomers were significantly different, particularly with respect to liver uptake [19]. Thus
the stereoisomerism of octahedral Ga complexes, although different in nature to those of the technetium and rhenium oxo
complexes discussed earlier, should be taken into account when considering their biological behaviour. The issue of isom-
erism in gallium complexes has been well summarised in a review covering their X-ray crystal structures [20].
To avoid compromising the stable N
3
O
3
coordination core, conjugation of NOTA to biomolecules is achieved by addition of
a functional group at a backbone carbon. The derivative of NOTA with R = CH
2
CH
2
COOH is designated NODA and has been
used to label (Tyr
3
)-octreatide, TOC, with
67
Ga,
68
Ga, and
111
In for the imaging of somastatin-receptor-expressing tumours. Both
the
67
Ga and
111
In complexes showed good stability with IC
50
values in the low nm range for binding to the receptor. The bio-
distribution of the
67
Ga complex is very favourable with rapid clearance from all non-target organs [21]. NOTA derivatised with
an isothiocyanatobenzyl group has been used to conjugate
68
GaNOTA to cyclic RGD peptides for angiogenesis imaging [22].
This RGD peptide labelling approach appears not to have been used for
67
Ga. The same isothiocyanato NOTA derivative
labelled with
67
Ga has been conjugated to human epidermal growth factor hEGF and showed good stability and specific binding
following injection of an anti EGFR affibody [23]. Conjugation of
68
GaNOTA to a nitroimidazole molecule has been investi-
gated as a possible route to PET imaging of hypoxia.
In vivo
studies of the conjugates showed increasing retention of
68
Ga in
the tumour with time. However, this has not been correlated with immuno-histochemical staining of hypoxia, and the integrity
of the complex
in vivo
has not been explored [24]. A comparison of NOTA and DOTA derivatives with
68
Ga has been made that
revealed that the NOTA complexes were formed in higher radiochemical yield and showed superior stability. moreover, the
NOTA derivatives
in vivo
were more rapidly cleared from the blood and muscle, permitting better contrast in images [25].
more recently, gallium(III) complexes with TRAP (1,4,7-triazacyclononane phosphinic acid) l and 1,4,7-triazacyclonon-
ane-1,4,7-triacetic acid were reported (Figure 7.4) [26]. Complexes of several phosphinic acid 1,4,7-triazacyclononane
derivatives bearing methylphosphinic (TRAP-H), methyl(phenyl)phosphinic (TRAP-Ph), or methyl(hydroxymethyl)phos-
phinic acid (TRAP-OH) pendant arms were investigated by potentiometry, multinuclear NmR, and DFT calculations, and a
new family of efficient Ga
3+
chelators was established. TRAP ligands were shown to exhibit high thermodynamic selectivity
for Ga
3+
over the other metal ions (log
K
Gal
- log
K
ml
= 7-9).
