Chemistry Reference
In-Depth Information
When compared to the abovementioned dual-modality PET/optical and SPECT/optical imaging agents, where most of
the agents developed were specifically directed to a certain protein or other targets of interest, most of the dual-modality
MRI/optical agents are not molecularly targeted. In many cases, these MRI/optical agents take advantage of the enhanced
permeability and retention effect [131] for tumour accumulation or certain lymphatic drainage patterns for SlN mapping.
One major reason for this phenomenon is that gd-based MRI has low sensitivity (in the millimolar range); therefore, it
is very challenging to achieve high enough local concentration of a MRI contrast agent for noninvasive imaging using a
targeted approach.
15.5
pet/MrI agents
The dual-modality PET/CT scanner, already being used on a routine basis in clinical oncology, greatly facilitated pinpoint-
ing the regions of increased activity on PET, which does not provide anatomical information by itself [132, 133]. However,
accurate localisation of PET probe uptake, even with PET/CT, can be very difficult in some cases due to the absence of
identifiable anatomical structures, particularly in the abdomen [134-136]. Because of the exquisite soft tissue contrast of
MRI, combination of PET and MRI can have many synergistic effects. For example, highly accurate image registration can
offer the possibility of using the MRI image to correct for PET partial volume effect (i.e., image blurring introduced by the
finite spatial resolution of the imaging system [137]) and aid in PET image reconstruction. In addition, PET/MRI also has
greatly reduced radiation exposure than PET/CT.
PET/MRI systems have been developed for small animal imaging as well as human studies [136, 138]. PET/MRI,
acquired in one measurement, has the potential to become the imaging modality of choice for various clinical applications
such as neurological studies, certain types of cancer, stroke, and the emerging field of stem cell therapy. The future of PET/
MRI scanners will greatly benefit from the use of dual-modality PET/MRI agents, which are currently being investigated
[7]. Recently, a PET/MRI probe was synthesised through partial exchange of gd
3+
for
64
Cu in EP-2104R [139], a fibrin-
specific MRI contrast agent for thrombus detection [140]. This agent was successfully utilised for simultaneous MRI and
PET imaging of thrombus in a rat arterial thrombus model.
15.6
conclusIons
The synergy of combining multiple imaging modalities is well recognised by the imaging community, and one of the best
examples is the development of PET/MRI scanners that recently became commercially available. This chapter aims to
give a comprehensive summary of the dual-modality imaging agents that have been reported to date, which are not based
on nanoparticles. When compared to other dual-modality agents reported in the literature, dual-modality MRI/optical
agents are among the most intensively studied, which can be partly attributed to the wide availability of the imaging
agents (a representative list of fluorescent dyes that have been used for the development of dual-modality imaging agents
is shown in Figure 15.11) as well as the imaging systems. However, whether MRI/optical combination is the most
optimal dual-modality approach is questionable because neither modality is highly quantitative. Because PET has signif-
icantly higher sensitivity than SPECT (at least an order of magnitude) [10], dual-modality PET/optical and PET/MRI
agents deserve the dedication of significant research effort in the future. We envision that PET/MRI/optical agents may
find the most widespread use for future biomedical/clinical applications because such a combination provides extremely
high sensitivity (PET), quantitation capability (PET), excellent anatomical information and soft tissue contrast (MRI), as
well as a means for
ex vivo
validation (optical), which itself can also be useful for highly sensitive imaging in certain sites
of the human body.
Robust chemistry for both radiolabelling and targeting ligand conjugation is of critical importance to the potential clinical
applications of dual-modality imaging agents. For example, one major challenge in antibody labelling is to minimise the
potential interference with its antigen binding affinity/specificity, hence overconjugation of the image tags should be avoided.
One of the key requirements for accurate PET/SPECT imaging with radiolabelled imaging probes is that the tracer should
be sufficiently stable during the imaging period, because the PET/SPECT scanner detects the distribution of the radioiso-
topes instead of the targeting ligand itself (e.g., peptide, antibody). a number of chelators can be used for complexation of
certain radiometals for PET/SPECT applications (Figure 15.12).
In preclinical studies,
64
Cu is one of the most widely used radioisotopes for PET, and a variety of chelators have been
explored for
64
Cu-labelling [141]. Recently, it has been generally recognised that NOTa is one of the most suitable chelators
for
64
Cu-labelling [55, 65], even though several other chelators also exhibit similar
in vitro
stability and comparable tumour
uptake in animal models.
