Biomed Imaging Interv J 2006; 2(4):e28
© 2006 Biomedical Imaging and
Molecular imaging: spawning a new melting-pot for biomedical imaging
BJJ Abdullah*, MBBS, FRCR
Department of Biomedical Imaging (Radiology), Faculty of
Medicine, University of Malaya, Kuala Lumpur, Malaysia
Predicting the future is a dangerous undertaking at best,
and not meant for the faint-hearted. However, viewing the advances in molecular
medicine, genomics and proteomics, it is easy to comprehend those who believe
that molecular imaging methods will open up new vistas for medical imaging. The
knock on effect will impact our capacity to diagnose and treat diseases.
Anatomically detectable abnormalities, which have historically been the basis
of the practice of radiology, will soon be replaced by molecular imaging
methods that will reflect the under expression or over expression of certain
genes which occur in almost every disease. Molecular imaging can then be
resorted to so that early diagnosis and characterisation of disease can offer
improved specificity. Given the growing importance of molecular medicine,
imagers will find it profitable to educate themselves on molecular targeting,
molecular therapeutics and the role of imaging in both areas. � 2006 Biomedical
Imaging and Intervention Journal. All rights reserved.
Keywords: Molecular imaging, genomics, proteomics,
While medicine has taken on a molecular character and the
Human Genome Project has yielded a wealth of information for mapping the human
body, nothing really explains how the body works. Molecular imaging will play a
key role in delivering molecular medicine since it defines many cellular and
biochemical mechanisms . It must be said that although the term "molecular
imaging" is relatively new, the underlying concept has been the basis of many
nuclear medicine procedures for over half a century. In fact the imaging of
biological processes is central to the scientific method in natural sciences
. The term molecular imaging can be broadly defined as the
"visualisation and characterisation of biologic processes at the cellular
and molecular level in vivo". And this has been primarily catalysed by two
concurrent developments, namely the understanding of the molecular basis of
disease, and the development of drugs directed at these molecular targets.
Molecular imaging is a growing research discipline (and
increasingly a clinical discipline too) aimed at developing and testing novel
tools, reagents, and methods to image specific molecular pathways with whole
body imaging instruments in vivo. The pathways targeted play a key role in
disease processes. Molecular imaging holds the unique potential of being able
to find, diagnose and treat disease in vivo simultaneously (i.e., inside the
body), as well as depict how well a particular treatment is working i.e.,
theragnostics. This is in contrast to "classical" diagnostic imaging
where most of diseases are diagnosed based on the manifestation of signs and
symptoms following which remedial therapy is then applied to modify or
ameliorate those symptoms. In most diseases, since the origins are often
unknown and even in those instances where it is known, the treatments are meant
at best to keep things under control.
Molecular imaging exploits specific molecules as the source
of image contrast. This paradigm shift from non-specific physical to specific
molecular sources underlies many of the current molecular imaging research efforts.
It is this search for the "holy grail" of modern medicine that may make it
possible eventually to manipulate an individual's genetic constitution
appropriately, to get rid of disease processes.
Molecular imaging is to a certain extent technology driven
since molecular information can be obtained with some "high-end"
imaging technologies. To do more would require newer equipment. However, on a
conceptual level, molecular imaging is neither about technology nor about a
change in the practice but essentially another revolution in the way medicine
is viewed. One underlying premise of molecular imaging is that this emerging
field is not defined by the imaging technologies that underpin acquisition of
the final image per se but rather by the underlying biological questions of
medicine. The ramifications will be felt in every nook and cranny of medical
practice and then extend into the legal, social and ethical aspects of society.
No concept and basis of medicine, currently practiced will be spared.
As a consequence, a new approach to wellness, disease
prevention and treatment needs to be developed to counter the effects of poor
health and illness, especially in the world�s less developed countries. To
enhance such an approach, the potential contributions of biomedical imaging,
bioengineering, and bioinformatics to emerging research areas, such as
functional genomics, proteomics, molecular biomechanics and drug delivery
systems, tissue and cell engineering, quantitative biology and computer
modelling, molecular and computational imaging, computer-aided diagnosis,
metabolic imaging, ultra fast and integrated imaging systems are of prime
importance. In the current phase of the increasingly complex and ever changing
health care environment, governments, medical speciality organisations,
researchers, vendors, and providers are finding it hard to cope with these
challenges alone. Partnerships are critical to face any new concept. It is
therefore imperative that new relationships sharing the risk of adopting new
technological innovation, programmes, services and processes designed to
improve overall patient care be worked at.
Increasingly, the power of molecular imaging comes from the
capacity to harvest vast amounts of knowledge gained from molecular biology.
Currently we can theoretically design a molecular imaging agent to target each
step in the sequence from DNA replication to protein synthesis and subsequently
all the steps of protein metabolism. To begin investigating molecular signals
in vivo, researchers have already developed and characterised methods for
imaging endogenous proteins, such as receptors, transporters, or enzymes and
their respective functions. More recently, methods have also been validated to
analyse specific expression of transgenes of interest. This is typically
performed by quantifying the activity of reporter genes delivered by a viral
vector, as used in gene therapy, or through use of exogenous reporter genes in
genetically engineered cells  and transgenic mouse models .
Processes in the human body are extremely complex and depend
on a multitude of factors. As such, they are much more difficult to analyse
than a laboratory sample. In fact, metabolic processes can only be truly
understood in vivo. If we could improve the analysis of metabolic reactions in
living organisms, it would lead to immense savings for the pharmaceutical
companies and open a promising market. Methods that produce visual images are
being used with increasing frequency to study metabolic processes, e.g., to
find out when individual genes become active (are expressed). Here, highly
specific molecules (probes) are employed, which often are customised with
genetic engineering. These special molecules search for a specific substance
and, when they have found it, link with it and emit signals that can be
depicted visually to provide a diagnosis of changes to a patient's metabolism.
The key elements to sampling molecular information are :
The use of special imaging probes with high specificity. In fact due to
the advances in chemistry and screening it is possible to have increased
specificity without sacrificing sensitivity.
The availability of appropriate amplification strategies
High resolution images from systems with increased sensitivity, and
Capability of overcoming biological barriers to delivery of probes
With regard to the strategy for imaging these probes:
Direct imaging uses a probe specific for cell surface receptors,
intracellular molecules or gene expression, which interacts directly with the
target providing an image intensity correlating to the amount of target
Indirect imaging is more complicated as it often uses both a reporter
gene and a reporter probe which interacts within specifically targeted cells to
produce a metabolite trapped in the cells that is visualised when scanned.
Surrogate imaging detects downstream effects of endogenous
molecular-genetic processes using established radiopharmaceuticals and clinical
Regarding the imaging probes there are three basic types
The compartmental probe typically assesses physiological parameters (i.e.,
flow and perfusion) and as mentioned above the probe does not directly image
the molecular process but a surrogate.
Targeted probes act directly against a specific moiety targeted to the
molecule, receptor or enzyme of interest or an imaging component that provides
the physical contrast.
Finally, "smart" probes activate exclusively in the presence
of their intended target and since there is no significant background signal, smart
probes have a significant signal advantage over simple targeted agents.
Primarily because probes need to be biocompatible, the presence of additional
delivery barriers , and the necessity for developing special in vivo
amplification strategies , in vivo molecular imaging is more challenging
than in vitro detection.
Optical imaging technology (including diffuse optical
tomography, phase-array detection, photon counting, near-infrared fluorescence
imaging), high-spatial-resolution MR and nuclear imaging techniques (e.g.,
positron emission tomography [PET]), fusion imaging and micro imaging systems
(micro CT, micro MR, micro US) play an important role in the field. Each of
these techniques has its particular advantages and disadvantages, and the use
of one or the other technique is mostly dependent on the specific research
question and hypothesis to be tested .
Radionuclide imaging devices visualise very low
concentrations of radionuclide probes (nano- to femtomolar) in real-time 
and provide quantitative information , but with low image resolution. They
can be used for whole body imaging. PET is frequently used when a substrate to
a given target exists that can easily be labelled with a positron emitter, for
example labelled 2'-fluoro-5-iodovinyl-1-�-D-arabinofuranosyl-uracil (FIAU) or
ganciclovir for imaging of viral thymidine kinase gene expression. Radio
nucleotide imaging combined with a computed tomography (CT) or a magnetic
resonance imaging (MRI) scan provides high anatomic definition along with
functional imaging for precise location of the selected molecular activity.
Nuclear imaging techniques are suited to track small amounts of labelled therapeutic
drugs, and to investigate multiple drug resistance, or delivery systems such as
viral vectors. However the downside is the need for a cyclotron and high cost.
Magnetic Resonance Imaging�s (MRI) ability was enhanced
significantly with the development of functional MRI. The revival of interest
in molecular imaging has expanded the frontiers of MRI even further. MR imaging
has two particular advantages over techniques that involved the use of
isotopes, namely the higher spatial resolution (micrometer rather than several
millimetres), and the simultaneous extraction of physiologic and anatomic
In comparison with isotope techniques, however, MR imaging
is several magnitudes less sensitive (millimolar rather than picomolar), which
is why reliable signal amplification strategies must be developed. MR
techniques in cell imaging are also maturing where cells are induced to take-up
superparamagnetic iron oxide formulations .
Ultrasound in molecular imaging allows real-time imaging
with resolution of less than 50 �m. With the developments of microbubble
technology  and harmonic imaging, ultrasound is increasingly being used to
translate molecular processes in vivo. Even though CT is often not
recognised as a modality for molecular imaging, it has a role especially for
the study of soft tissue tumours in bone and lung because of its low cost,
reasonable resolution and fast scanning times.
Finally, optical imaging techniques have already been
developed for applications in molecular and cellular biology (e.g.,
fluorescence microscopy) and in vivo surface imaging . One of the appealing
advantages of near-infrared optical imaging is that quenched fluorescent labels
that become brightly fluorescent after specific molecular interactions with
their targets, can be used.
Another notable advantage of optical techniques is multiple
probes with different spectral characteristics can be used for multichannel
imaging, similar to in vitro karyotyping . In addition, it is reasonably
cheap, has good spatial resolution and possesses nanomolar sensitivity. Newer
approaches have been advocated that may ultimately lead to the development of
tomographic optical imaging systems in the near-infrared spectrum. These have
been suggested to overcome depth penetration.
Today's scientists are not just looking at specific
molecules, but are also evaluating the components within the nucleus of their
cells. They are learning what causes the cells to turn on and off, what makes
them do what they do and how their fundamental function can be boosted or shut
down. While molecular imaging has significantly advanced oncology, cardiology,
neurology, infectious disease detection and therapy, drug development, and
disease treatment, even more is expected. Here is what molecular imaging
In the future, advances in molecular imaging will lead to
the development of a broader array of imaging probes that will cover all the
body's major systems and associated disease types, making even earlier
detection of disease possible. Our capacity to image these molecular changes
will directly affect patient care by allowing much earlier detection of
diseases, e.g. image molecular changes that we currently define as
"predisease states". If such a situation came to pass, then we would
allow intervention when the outcome can be significantly altered. Because of
the greater specificity of the imaging probes and techniques we would be able
to look for specific cell types, e.g., cancer cells have an increase in
metabolic activity in comparison with normal cells. This fact makes it possible
to image cancer cells in vivo using deoxyglucose, a metabolic substance that is
voraciously glycolised and trapped by targeted cancer cells. By labelling
deoxyglucose with a radioactive agent and injecting the resulting molecular
imaging agent into patients, scientists can make nuclear images of the primary
tumour as well as metastatic sites throughout the body.
When a cell is dying (apoptosis), it turns inside out,
presenting an otherwise unexposed protein binding site. The body responds by
producing a protein called annexin, which seeks out and connects to the binding
site of these dying cells to "tag" them for destruction by the immune system.
By creating a human annexin, attaching it to the imaging agent technetium and
injecting it into the patient, scientists can "seek and illuminate" dying
cells. Physicians can use this information to decide whether to change or keep
a patient�s therapy regimen. For example, when chemotherapy or radiotherapy is
used to kill cancer cells, apoptosis occurs. Apoptosis is the necessary death of
cells to make way for new cells and to remove cells where DNA has been damaged
to the point at which cancerous change is likely to occur. If the chosen
therapy is effective, apoptosis can be demonstrated within 24 to 48 hours.
Physicians can use molecular imaging to determine whether apoptosis has
occurred and can change the therapy if it does not. Not only does this ability
mean that the treatments used will be more effective, but further costs
associated with ineffective therapy can be avoided. This can be done using
SPECT (single photon emission computed tomography) or MRI. In the example
quoted above if therapy is proving effective, then, annexin could be used as a
delivery vehicle to further enhance cell death. Physicians would add a payload
of radioactive toxin to annexin. When injected, the "loaded" annexin will
deliver the toxic agent to the site of the dying cancer cells to cause even
more cells to die. This process creates a cycle of cell death because the more
cells that die, the more toxin-loaded annexin will be attracted to the cancer
site. This molecular chain of events helps accelerate the therapy�s
With the US Food and Drug Administration's (FDA) approval of
Avastin (Bevacizumab; Genentech, Inc., San Francisco, CA) asa
first-line treatment for patients with metastatic colorectalcancer,
it was a major landmark in the field of angiogenesis. With the development of
an image based angiogenetic marker, it would help select patients forappropriate
therapeutic regimens including the most appropriatecombination of
angiogenic and other therapeutic agents, helpto identify the
optimal time window and the appropriate dosageof the different
therapeutic agents, assist in monitoring theeffects of such
treatments, and provide functional informationfor adjusting the
therapeutic regimens over time in an interactivebasis . Since
imaging can potentially provide morphologic,functional and
molecular information in a spatially and temporallyresolved manner,
many investigators have incorporated imaginginto pre-clinical
studies and clinical trials of angiogenesistherapies.
Further developments are occurring where imaging and
therapeutic agents are tagged with a targeted molecular agent are being
developed and this may enhance treatment e.g. Zevalin (Ibritumomab tiuxetan,
IDEC Pharmaceuticals, Cambridge, MA), a therapeutic regimen for treatment of
relapsed or refractory low grade, follicular or transformed B-cell
non-Hodgkin's lymphoma. Indium-111 labelled Zevalin scanning allows
visualisation of disease and calculation of dose to be delivered by Yittrium-90
labelled anti-CD 20 monoclonal antibodies .
Current evidence suggests that one course of anti-CD20 radio
immunotherapy is as efficacious as six to eight cycles of combination
Decreased tissue oxygen tension is a component of many
diseases. Although hypoxia can be secondary to a low inspired P02 or
a variety of lung disorders, the commonest cause is ischemia due to an oxygen
demand greater than the local oxygen supply. In tumours, low tissue p02
is often observed, most often due to a blood supply inadequate to meet the tumour's
demands. Decreased tissue oxygen tension is a component of many diseases. In
the heart tissue hypoxia is often observed in persistent low-flow states, such
as hibernating myocardium. In patients with stroke, hypoxia has been associated
with the penumbral region, where an intervention could preserve function. In
some tumours the efficacy of conventional radiotherapy is limited by thepresence
of a hypoxic, radioresistant, and repair-proficientsubset of tumour
Despite the potential importance of oxygen levels in tissue,
difficulty in making this measurement in vivo has limited its role in clinical
decision making. This has led to the development and testingof
hypoxic imaging techniques and agents. An ideal hypoxia imaging agent should
have high membrane permeability foreasy access to intracellular
mitochondria and low redox potential to conferstability in normal
tissue, but it should be able to be reduced bymitochondria with
abnormally high electron concentrations in hypoxic cells. Imaging with some of
these agents can provide direct evidence of tissue with low oxygen levels that
is viable. In the experimental setting this information is useful to plan a
more aggressive approach to treating tumours, or revascularise a heart
suffering ischemic dysfunction. Oxygen electrode measurements in animal
experiments have demonstrated a strong correlation between low tumour pO2
and excess 60Cu-diacetyl-bis(N(4)-methylthiosemicarbazone (60Cu-ATSM) accumulation. Some studies have suggested that
pretreatment imaging with 18F-2-fluoro-2-deoxy-D-glucose(FDG) and 64Cu-ATSM
would allow stratification of tumour phenotypessuch that those tumours
that are most susceptible would be selectedfor treatment .
Aiding and assessing response to therapy
Currently treatment instituted for most diseases is based on
"one size fits all". This is based on our inability to separate the responders
from those who are either not likely to respond or those that may actually
develop more complications from the treatment offered. But increasingly many
new-generation therapeutic drugs are designed with highly specific molecular
targeting capabilities and delivery mechanisms. By directly imaging the
underlying alterations of diseases, we have the potential to be able to
directly image the effects of therapy. This would provide an opportunity to
play a direct role in determining the efficacy of treatment. Further, response
to therapy could be assessed shortly after therapy has been initiated and not
in the many months subsequently as required today to determine whether
pharmacological or biological intervention has been beneficial.
In addition the toxic effects of treatment on the patient's
healthy tissue can be avoided. In the future, molecular imaging is expected to
aid in identifying the presence of drug-resistant genes that will enable
clinicians to pre-determine which treatment regimens will be most effective
within an hour of initiating treatment and avoid delays in optimizing a
Furthermore, molecular tracers, or radiopharmaceuticals,
will be used to create diagnostic images which visually indicate whether cancer
patients are susceptible to multi-drug resistance, a condition in which the
defensive response to one type of chemotherapy also diminishes the potency of
other chemo agents. With this information, physicians can make accurate and
fairly rapid diagnoses and provide patients with more precise treatment.
Others are working onnanoparticle delivery
platforms that can potentially deliverboth imaging and therapeutic
agents to endothelial targets.Using a vascular targeted imaging
agent for selecting patientsto be treated and for monitoring
response with the therapeuticagents delivered via the same delivery
vehicle satisfies therequirements for "personalised
It may seem like the movie, Osmosis Jones (Warner Bros) where
researchers are working to integrate molecular imaging with nanotechnologies
(human-made, molecular-size structures or machines) to detect disease and
enable even more precise therapy in many instances eliminating if not
minimising the need for surgery entirely. Some of envisioned scenarios may
include the development of biosensors providing the exact location of disease,
and new nanotechnologies which can be dispatched into the body that can deliver
drug therapies directly to cancerous cells by affixing themselves to those
specific cells and releasing cancer-killing agents.
Just like nano-robots, these nanotechnologies shall be
designed to self-assemble themselves at the appropriate place and time
following which they are able to repair bones or tears and if necessary
stimulate the growth of new blood vessels or tissue. There would additionally
be imaging technologies which could monitor the process, ensure that it is
working properly, and measure the results, the ultimate of image guided
minimally invasive surgery!
Drug discovery cycle
Molecular imaging will facilitate the development of new drugs, by providing early
stage chemical compounds that will enable researchers in the public and private
sectors to validate new drug targets, which could then move into the
drug-development pipeline. This is particularly true for rare diseases, which
may not be attractive for development by the private sector. Three key
technological advances drive NIH's effort to build small molecule libraries.
The successful completion of the Human Genome Project has provided an
enormous cache of human biology to be studied and potential drug targets to be
Developments in chemistry have given researchers in the public sector
the ability to synthesise large numbers of related molecules, a capability
previously available only to researchers in pharmaceutical and biotechnology
Advances in robotic technology and informatics now allow scientists to
screen hundreds of thousands of compounds in a single day, an orders of
magnitude greater capacity than was available a decade ago .
Molecular imaging is a powerful concept that envisions the
promise of disease characterisation / phenotyping and early assessment of
therapeutic efficacy. From this, it is a logical step to envisaging
"personalised medicine," where disease phenotyping will be used to tailor the
most optimum therapeutic regimen patient by patient and not the usual one size
fits all. This is already happening but is not directly related. Imaging
entails the use of Her-2/neu gene expression as an indicator of whether breast
cancer patients will respond to the drug Herceptin, a monoclonal antibody.
Today the power of imaging is so sophisticated that we now
have the capacity to identify unresolved biological and clinical questions and
focus on how imaging techniques might be used to solve these problems. Emphasis
continues to be on minimising invasiveness, reducing image processing time,
lower cost, less radiation dose but at the same time maximising resolution and
contrast as well as easy interpretation of data. Future advancements lie in not
only in new modalities e.g. optical imaging but also in improved imaging
modalities as well in producing displays that intelligently combine structural,
chemical, electrical, magnetic, acoustic, and motion information.
However though in the past, diagnostic imaging tests were
designed to be stand alone investigations with specialised imageacquisition,
analysis and display, it is important that we donot continue to
utilise diagnostic imaging tests in this same manner, but ratherexploit
the synergies between each individual i.e. the sum of the parts is larger than
each alone! For example, the development of PET/CT systems allows the synthesis
of the rich metabolic andfunctional information gained from PET
with the morphologic information provided by CT, new informationcan
be gained that cannot be obtained with each modality alone.These
multi-modality systems (together or image fusion from two separate systems) is
only the beginning of what may prove to be a significantparadigm
shift in medical imaging device design and manufacturing .
Molecular imaging promises to become a powerful addition to
the ammunition of medical imaging. "Who controls and gives direction to that
growth remains arguably an open question. Today�s imaging research defines the
practice of the future" . Leaders in imaging generally will be well served
to acquire the knowledge necessary to incorporate these new methods into their
practices, including knowledge of fundamental principles in molecular biology.
They should also promote education and research that will undoubtedly impact
the future of imaging.
The 21st century will witness further innovation, growth and
clinical utility imaging and therapy. These challenges are already formidable
enough for imaging community in the developed world but be daunting for those
in the developing countries where meeting the current imaging needs is at most
times, barely sufficient. Despite these challenges, we in the Southeast Asian region
must make a concerted and co-ordinated effort to ensure that we are not left
behind. The following are some of the actions that will help ensure that the
imaging community here does not lag behind.
Firstly, leaders in imaging generally should recognise the
importance of this new and rapidly expanding field. They need to encourage
acquisition of knowledge necessary to incorporate these new methods into their
practices, including knowledge of fundamental principles in molecular biology.
They should also promote education and research that will undoubtedly impact
the future of imaging.
Although we may not be able to change the current line of
thinking of the current practitioners; the future generations however, must be
aware of the developments in molecular imaging and so there must be changes in
the curriculum with introduction of subjects like biochemistry, immunology, as
well as oncology. This is being incorporated in the new integrated curriculum
implemented in some institutions.
Thirdly, there should be greater co-operation as well as
coordination between the regional societies, e.g., ASEAN Association of
Radiology and Asian-Oceania Society of Radiology, in promoting greater
awareness of biomolecular imaging. This is being done by the introduction of
specific seminars and conferences , and would certainly go a long way in ensuring
greater awareness and interest. Greater co-operation with other regional
societies, e.g., the European Congress of Radiology (ECR), will also facilitate
this process with the availability of online teaching materials  from the
Finally, the setting up of local, national or regional
centres of excellence in biomolecular imaging would be another initiative to
ensure and maintain the lead. These centres are also important since the
disease patterns and demographics are very different from that in the West.
However, setting up such centres is intensive: both financially and in terms of
human resource and is probably beyond the reach of many countries but Singapore
, Thailand and Malaysia would surely be able to do so if they have not already
done so. Such centres should be involved in the training of the new generation
of imaging specialists and should provide for cross training and fellowships.
This potential requires interdisciplinary partnerships and
collaborative efforts between physicians, medical physicists, biomedical
engineers and computer scientists. We will all need to learn each others�
technical language to move forward. The setting up of a regional journal such
as biij (www.biij.org) is also essential in putting all these different aspects
together. It also provides a forum for publication, dissemination, and
discussion as well as networking between the different groups and organisations
in the region.
In view of these changes, as well as the increasing emphasis
on imaging at the cellular level or even at the genetic level, research in the
field of biomedical imaging is set to explode.
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|Received 2 September 2005; received in revised form 20 June 2006, accepted 21 June 2006
Correspondence: Department of Biomedical Imaging (Radiology), Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel.: +603-79492069; Fax.: +603-79581973; E-mail: [email protected] (Basri J.J. Abdullah).
Please cite as: Abdullah BJJ,
Molecular imaging: spawning a new melting-pot for biomedical imaging, Biomed Imaging Interv J 2006; 2(4):e28
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