Molecular imaging shows enormous clinical potential

It is not difficult to find resources on the topic of molecular imaging. A number of comprehensive review articles have been published^1-5 and dedicated websites created (e.g., www.mi-central.org/). What follows is an introduction to this emerging area with radiologists' needs in mind.

Molecular imaging can be defined as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. It is performed using imaging agents and instrumentation. Studies can be 2D, 3D, or 4D and include quantification over time.

Molecular imaging agents, known as probes, may be radiopharmaceuticals, paramagnetic or fluorescent materials, or bubble-based agents. Molecular imaging probes are being used as physiological and molecular markers in a number of applications: They may be used to follow cell trafficking, apoptosis, angiogenesis, and/ or cellular metabolism in drug development or biodistribution studies. Probes may also be used in the assessment of therapeutic interventions.Another emerging application is reporter gene imaging. The aim here is to determine the location, duration, and extent of gene expression within living subjects. Nanoparticle vehicles, smart contrast agents, and target-specific optical and radiolabeled agents will add to the current success in this area, as will imaging and therapy based on stem cells.

Molecular imaging is carried out with tools that enable signals from probes to be visualized and quantified in space and over time. Techniques include radiotracer imaging/nuclear medicine, MRI, MR spectroscopy, optical imaging, and ultrasound.

Basic research leads clinical practice, but the introduction of new imaging techniques into patient management remains a challenge. Each modality has its strengths and weaknesses (Table 1), making multimodality imaging attractive and desirable. The use of different probes in multimodal systems should aid the identification of new targets, either within cells or associated with cell membranes. Quantification of treatment effects will also increase with the development of new technology.

AVAILABLE OPTIONS

PET and SPECT use radioactive tracers to provide imaging information in a sensitive, noninvasive, and quantitative manner. Both modalities have been used primarily for clinical imaging rather than preclinical research, owing to the relatively low spatial resolution achieved when imaging small animals on a clinical system.

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Dedicated micro-PET and micro-SPECT systems offering good spatial resolution and sensitivity have now been developed, allowing small-animal studies. We can now image a mouse just as we would a patient (Figure 1). This makes SPECT and PET highly valuable tools for translational research.

A good clinical example is the use of fluorine-18 FDG with PET and PET/CT. The metabolic information provided by F-18 FDG-PET imaging is based on the increased rate of glycolysis exhibited by most malignant tumors. Work to evaluate and validate clinical applications for F-18 FDG-PET/CT is ongoing in oncology (for diagnosis and staging, treatment planning and response, detection of recurrent or residual disease, and restaging), for myocardial perfusion (coronary artery disease and myocardial viability), and in neurology (brain tumors, epilepsy, stroke, movement disorders, and dementias). PET is not synonymous with F-18 FDG-PET. Many alternative PET tracers have already entered clinical practice or will shortly (Table 2).

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MRI is playing an increasingly important role in molecular imaging. This powerful technique, when combined with contrast agents, is highly suited to imaging, for example, atherosclerotic plaques, myocardial injury, tumors, angiogenesis, and stem cells (Figure 2).

Groups of imaging agents used frequently for molecular MRI are magnetic nanoparticles and gadolinium constructs. In this latter group, large payloads of gadolinium are delivered via vehicles such as liposomes, micelles, and lipoproteins. Magnetic nanoparticles have a sensitivity in the nanomolar range and can be detected with many sequences. Targeted imaging with magnetic nanoparticles is an active area of research. This can be achieved through surface modification or through the attachment of affinity ligands to the nanoparticles.^11,12

Micron-sized encapsulated gas bubbles used to enhance contrast in ultrasound images can also be used in a number of molecular imaging applications. These small gas bubbles oscillate when exposed to an ultrasonic pulse, and they can be deflected to a vessel wall or broken into nanosized particles. This fragmentation may facilitate single-session molecular imaging of multiple targets. Microbubble agents could also be used to transport therapeutic drugs or genes to target sites. Once in position, the microbubble carriers could be ruptured by a focused ultrasound beam. The action of focused ultrasound on blood vessel walls could also aid drug penetration.¹³

Optical imaging techniques use photons in the ultraviolet to near-infrared range for in vivo diagnosis. A number of different approaches exist; fluorescence, absorption, reflectance, and/or bioluminescence may be used as the source of contrast. The techniques are developing quickly. Whole-body fluorescent imaging and bioluminescent imaging are now applied widely in small-animal models to study cell- and tissue-specific promotors, apoptosis, angiogenesis, protein-protein interaction, and gene transfer and to follow trafficking and differentiation.

A main limitation with optical imaging is the exponentially decreasing intensity of light with increasing target depth. Near-infrared fluorescent signals and newer dyes, however, provide better deep tissue imaging characteristics. If these can propagate through human tissue, then they may be suitable for noninvasive medical imaging applications. These advances will help scientists reach important goals for optical molecular imaging: improvement of light penetration, improvement of image resolution, and the localization and quantification of disease.

COMBINATION POTENTIAL

As already mentioned, no single imaging modality currently provides sufficiently high sensitivity and high spatial and temporal resolution for diagnostic purposes. The trend is consequently to combine modalities that offer different strengths. PET and SPECT, for example, are being used in combination with CT and/or MRI. Although the latter techniques lack the very high sensitivity of PET and SPECT, the high spatial resolution they offer allows important structural and anatomical information to be visualized. MRI also produces high soft-tissue contrast, provides spectroscopic information, and can be used for functional imaging (fMRI).

An increasing number of PET/CT and SPECT/CT systems are being used worldwide. PET/CT in particular has shown enormous potential for cancer imaging. Clinical and preclinical experience of combined modality imaging is growing exponentially.¹⁴ Combinations of fMRI and MR spectroscopy with PET or SPECT are predicted to offer a new perspective on molecular imaging in the future.

Another possibility is the combination of diagnosis and therapy in probes-so-called theranostics. The idea here is to use a diagnostic test to select patients who will benefit from the therapeutic intervention and identify those who will not respond or are at risk of side effects. The development of theranostics has great potential for the advancement of personalized treatment.

Molecular imaging, as practiced in nuclear medicine, could have great potential as a theranostic tool. Radionuclide molecules used for diagnostic imaging are also applicable in radionuclide therapy. One good example is the visualization, staging, and treatment of thyroid abnormalities with iodine isotopes (I-123 to I-131). Another is the use of radiolabeled peptides for tumor imaging and therapy. Somatostatin analogs labeled with diagnostic radionuclides are being used for imaging; the same or similar peptide molecules labeled with therapeutic radionuclides can be applied for therapeutic purposes (Figure 3).^15,16

CLINICAL APPLICATIONS

Molecular imaging has tremendous clinical potential. This noninvasive visualization of biological markers allows characteristic molecular events in the human body to be detected, leading to the early diagnosis and treatment of cancer and disorders of heart, brain, and other organ systems.

Molecular imaging is already leading to personalized patient care in cardiovascular disease. Noninvasive imaging of enzyme and cellular activity and interaction with cell surface markers can be used to guide treatment for ischemic injury, heart failure, atherosclerosis, vulnerable plaque, and apoptosis.

Molecular imaging is playing an increasing role in the visualization of neurological conditions, such as dementia, and psychiatric disorders. It is becoming integral to the diagnosis and staging of cancer, the assessment of therapeutic targets, treatment selection, dosimetry, and therapy monitoring.

Drug discovery and development is also benefiting from molecular imaging-led assessments of pharmacokinetics and pharmacodynamics.³

PROF. DE JONG is a professor of nuclear biology, and PROF. KRENNING is a professor of nuclear medicine, both at the Erasmus Medical Centre in Rotterdam, the Netherlands.

References

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