Chemistry Reference
In-Depth Information
mAb
HN
HO
2
C
CO
2
H
HO
2
C
NH
HN
N
N
N
N
O
NH
HN
N
N
N
N
HO
2
C
CO
2
H
HO
2
C
CO
2
H
Cyclen
DOTA
DOTA-mAb
O
NCS
O
N
HO
2
C
HO
2
C
N
N
N
N
O
O
N
N
N
N
HO
2
C
HO
2
C
CO
2
H
CO
2
H
DOTA-NHS
DO3A-SCN
fIgure 5.5
Chemical structure of the cyclen-based chelator dOTA, and the commonly used
N
-bifunctional dOTA derivatives dOTA-
mAb (where mAb = monoclonal antibody), dOTA-nhs (
N
-hydroxysuccinimide ester), and dO3A-sCn.
These microspheres may not be appropriate for
86
Y PET imaging because their mode of targeting is nonspecific; however,
86
Y may be a useful surrogate for dosimetry of these microspheres to assess radioactive dose to non-target organs and con-
firm tumour localisation. A variety of theranostic nanoparticles, found in the literature, incorporate combinations of MRI
contrast agents, PET/sPECT nuclides, fluorescent markers, and biovectors [55].
Of more relevance to
86
Y PET imaging are bifunctional chelating agents such as
90
Y-dOTA, which have been conjugated
to various biovectors (Figure 5.5).
90
Y-dOTA has been conjugated to the anti-carcinoembryonic antigen (CEA) antibody M5A and is in clinical trials for the
relatively nonspecific treatment of a variety of tumours (including colon, breast, lung, and medullar thyroid) [53]. The
90
Y-dOTA BFC system has been in clinical trials for use with many other antibodies as well, including chimeric monoclonal
antibody cG250 for treatment of renal cancer, anti-Cd45 monoclonal antibody BC8 for acute myeloid leukaemia, anti-Cd22
monoclonal antibody ll2 (epratuzumab) for lymphoma or leukaemia, monoclonal antibody CC49 for ovarian cancer,
humanised Mn-14 (anti-CEA) antibody for relapsed or refractory small cell lung cancer, and humanised monoclonal anti-
body BrE-3 for metastatic breast cancer [53]. A bioconjugate containing the cyclic peptide octreotide,
90
Y-dOTA-TOC, is in
clinical trials for treatment of neuroendocrine tumours (also being used with
111
In and
68
Ga for imaging/dosimetry) [53, 56].
86
Y might be useful as a surrogate for
90
Y in all of these agents for accurate pre-therapy imaging and dosimetry. some
specific examples of
86
Y-antibody conjugates that have been recently reported but are not in clinical trials are ChX-A″-
dTPA conjugated to cetuximab panitumumab for imaging human malignant mesothelioma tumours [1, 57], and bevaci-
zumab for imaging of tumour angiogenesis [2].
These examples of
90
Y-based BFC systems in clinical trials should emphasise the importance of a strong and well-
developed chelate system as the foundation of a radiometal-based radiopharmaceutical, because it can then be conjugated to
a variety of biovectors and applied to a large number of imaging and treatment modalities. Once a suitable chelate system is
matched with a metal ion and found to have favourable coordination and stability properties, it can then be conjugated to a
theoretically limitless number of biovectors. A quick browse of the current clinical trial offerings [53] demonstrates this
quite clearly, because a majority of investigated agents are based on the chelators dTPA and dOTA. The chelators dTPA
and dOTA are ubiquitous in radiometal and coordination chemistry and have been used to complex many metal ions, such
as indium, gallium, copper, zirconium, and lutetium. The versatile metal ion binding properties of these chelators means that
radiopharmaceutical preparations that use them can be evaluated with many different nuclides, although not all metal ions
bind with the same affinity and stability.
5.4.2
recent
86
yttrium work
As evidenced from the popularity of dOTA, the high thermodynamic stability and kinetic inertness of macrocyclic chelators
is ideal for
in vivo
radiopharmaceutical applications (they benefit from the macrocycle effect); however, sensitive biological
molecules such as antibodies (and their derivatives, such as affibodies, diabodies, nanobodies) are not ideally compatible
with the high labelling temperatures typically required for macrocycles [58, 59]. dTPA is an acyclic chelator with much
