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What is Molecular Imaging

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems.

• Molecular imaging typically includes two- or three- dimensional imaging as well as quantification over time.
• The techniques used include radiotracer imaging/nuclear medicine, MRI, MRS, optical imaging, ultrasound and others.

Molecular imaging agents are probes used to visualize, characterize, and measure biological processes in living systems.

• Both endogenous molecules and exogenous probes can be molecular imaging agents.

• What is Molecular Imaging? Patient Fact Sheet (.pdf)
• What is Molecular Imaging? Poster (.pdf)
• Optical Imaging
• MR/MRS
• A Definition of Molecular Imaging: from JNM Newsline- Vol. 48, No. 6. June 2007: pp 18N, 21N. (.pdf)

Just What is Molecular Imaging?

By Sanjiv Sam Gambhir MD, PhD

(Reprinted from MI Gateway, the MICoE newsletter, 2007-1)

New discipline: Molecular imaging is a new biomedical research discipline enabling the visualization, characterization, and quantification of biologic processes taking place at the cellular and subcellular levels within intact living subjects including patients.

New context: The images produced with molecular imaging reflect cellular and molecular pathways and mechanisms of disease present in the context of the living subject. Biologic processes can be studied in their own physiologically authentic environment instead of by in vitro or ex vivo biopsy/cell culture laboratory techniques.

New paradigm: The term molecular imaging itself encompasses a new imaging paradigm that includes multiple image-capture techniques, cell/molecular biology, chemistry, pharmacology, medical physics, biomathematics, and bioinformatics.

New purpose: Molecular imaging's key utilization is in the interrogation of biologic processes in the cells of a living subject in order to report on and reveal their molecular abnormalities that form the basis of disease. This is in stark contrast to the classical form of diagnostic imaging where documented findings show the end effects of these molecular alterations typically via macroscopic and well-established gross pathology.

Molecular Imaging and Nuclear Medicine

Molecular imaging includes the field of nuclear medicine along with various other fields that together offer an array of different strategies to produce imaging signals. Whereas nuclear medicine uses radiolabeled molecules (tracers) that produce signals by means of radioactive decay only, molecular imaging uses these as well as other molecules to image via means of sound (ultrasound), magnetism (MRI or magnetic resonance imaging), or light (optical techniques of bioluminescence and fluorescence) as well as other emerging techniques.

The founding principles of molecular imaging can be traced back to nuclear medicine procedures over the past few decades, with other technologies (e.g., optical, MRI) being adapted for molecular imaging by developing different types of molecular probes. At the widest level, there exist two classes of probes: nonspecific and specific. Nuclear medicine plays a key role in the latter class, as the signaling portion of specifically targeted probes. Probes that use antibodies, ligands, or substrates to specifically interact with protein targets in particular cells or subcellular compartments include those used in most of the conventional radiotracer imaging methods, where the emphasis is on imaging final products of gene expression with radiolabeled substrates that interact with a protein originating from a specific gene. These interactions are based on either receptor-radioligand binding (e.g., binding of ¹¹C-carfentanil to the mu opiate receptor) or enzyme mediated trapping of a radiolabeled substrate (e.g., ¹⁸F-2-fluoro-2-deoxyglucose [¹⁸F-FDG] phosphorylation by hexokinase).

However, the main limitation of most of these specific approaches is that a new substrate must be discovered and radiolabeled to yield a different probe for each new protein target. With the significant difficulty, cost, and effort involved in radiolabeling new substrates, along with the requirement for in vivo characterization of every such substrate under investigation, more generalizable methods (i.e., those that can image gene product targets arising from the expression of any gene of interest) are preferred. This issue has propelled the development and validation of molecular imaging reporter gene/reporter probe systems in recent years for use in living subjects together with other generalizable strategies.

Other Molecular Imaging Strategies

The various existing imaging technologies differ in five main aspects: (1) spatial resolution; (2) depth penetration; (3) energy expended for image generation (ionizing or nonionizing, depending on which component of the electromagnetic radiation spectrum is exploited for image generation); (4) availability of injectable/biocompatible molecular probes; and (5) the respective detection threshold of probes for a given technology. See table.

Key advantages and disadvantages of the main available imaging modalities used in molecular imaging approaches.

Given that certain imaging techniques have advantages and disadvantages over others, it becomes important to have available a variety of imaging strategies to accomplish the increasingly sophisticated biologic interrogation of cells that molecular imaging now offers.

For example, the use of MRI has two particular advantages over techniques involving radionuclides or optical probes: higher spatial resolution (micrometers as opposed to several millimeters) and the ability to extract physiologic and anatomic information simultaneously. Although MRI has a much lower sensitivity, if there are enough targets (e.g., vascular endothelial proteins), then MRI may be the best-suited tool. On the optical side, the main advantage of bioluminescence imaging lies in its ability to detect very low levels of gene expression due to its virtually background-free light emission. In addition, its quick and easy implementation facilitates rapid testing of biologic hypotheses and proofs-of-principle in living experimental models, not to mention its unique suitability for highthroughput imaging due to its ease of operation, short acquisition times (usually 10 to 60 seconds), and the capability for simultaneous measurement of several anesthetized living mice.

Future Fusion

As molecular imaging continues to advance, we should see radionuclide- based approaches, with PET/SPECT remaining an integral part of the molecular imaging toolbox. This will likely be the case because PET and SPECT are the most generalizable of all the available molecular imaging strategies, allowing interrogation of events at any tissue depth and allowing targeting of extracellular proteins, cell surface proteins, intracellular proteins, and others (e.g., mRNA). Although nuclear medicine could ignore the growth of the larger field of molecular imaging, a likely better strategy is to be more inclusive of other technologies that can also help interrogate processes at the cellular/molecular level. In addition, a fusion of different molecular imaging strategies as well as a fusion of anatomical and molecular imaging will likely be key to improved patient management. Although it is difficult to predict the future, it is likely that molecular imaging will continue to grow. We need to continue to educate ourselves and be a part of that growth.

Sam Gambhir, professor of radiology and bioengineering, is director of the molecular imaging program and head of nuclear medicine at Stanford University in Stanford, CA.

Information on Molecular Imaging Agents

MICAD

The Molecular Imaging and Contrast Agent Database (MICAD) program has been developed as a key component of the NIH Molecular Imaging Roadmap to provide freely accessible online scientific information on in vivo molecular imaging and contrast agents.

For further information, please contact the MICAD staff at micad@ncbi.nlm.nih.gov.

• Molecular Imaging and Contrast Agent Database (MICAD)