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Published online before print May 16, 2007, 10.1148/radiol.2441060773
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(Radiology 2007;244:39-47.)
© RSNA, 2007

Molecular Imaging Series

Molecular Imaging: The Vision and Opportunity for Radiology in the Future1

John M. Hoffman, MD and Sanjiv S. Gambhir, MD, PhD

1 From the Departments of Radiology and Neurology, University of Utah School of Medicine, 2000 Circle of Hope, Suite 2121, Salt Lake City, UT 84112-5550 (J.M.H.); and Departments of Radiology and Bioengineering, Molecular Imaging Program at Stanford, Bio-X Program, Stanford University, Stanford, Calif (S.S.G.). Received May 2, 2006; revision requested June 21; revision received October 28; final version accepted December 11. Address correspondence to J.M.H. (e-mail: john.hoffman{at}hci.utah.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
 CURRENT RECOGNITION OF MOLECULAR...
 MOLECULAR IMAGING IN THE...
 SUMMARY
 References
 
Molecular imaging is being hailed as the next great advance for imaging. This introductory article in the molecular imaging series to be published over the next several months in Radiology sets the stage for the subsequent set of articles by providing relevant definitions and background information and traces the evolution of molecular imaging to its current state of research and clinical practice. It discusses in detail the evolution of molecular imaging and the role that the National Cancer Institute and the National Institutes of Health have had in the funding and development of many of the important molecular imaging research programs that are in existence today. The article also provides basic information about the complex biology of the cell and details of the pathogenesis of cancer and how molecular imaging will be critical for earlier detection and management of cancer in the future. The article lays the foundation for the subsequent articles in the series and describes how and why molecular imaging will be critical and integral for clinical care of patients in the future. The introductory article also discusses the relevance of molecular imaging to clinical radiology practice and why it is critical for the practicing radiologist to understand these evolving techniques, as they will be the future of imaging.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
 CURRENT RECOGNITION OF MOLECULAR...
 MOLECULAR IMAGING IN THE...
 SUMMARY
 References
 
This is the introduction to a series of articles on molecular imaging to be published over the next several months in Radiology and intended to show how molecular imaging will become an integral and important part of clinical radiology practice in the future. The articles will provide the practicing radiologist with the necessary background information to understand the basic terminology, definitions, and methods of how molecular imaging is currently performed and why it will revolutionize the practice of clinical imaging as we know it in the not too distant future.

Molecular imaging can be defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level (1,2). A clinically relevant example is the use of fluorine 18 [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) and, more recently, that of FDG PET/computed tomography (CT) in cancer diagnosis and management (3,4). Both of these modalities have shown unprecedented growth for advancing the treatment of cancer over the past several years (5). The growth is based on the fact that molecular and metabolic information are being assessed rather than only anatomic information. A molecular or metabolic imaging assessment provides information that in many instances is of more diagnostic utility than is simple anatomic information.

The metabolic and molecular information provided from PET imaging with FDG can be considered one of the first validated and clinically useful tomographic "molecular imaging" techniques. More than 70 years ago, Warburg (6) recognized that malignant tumors have an increased rate of glycolysis. The initial rate-limiting enzyme in glucose metabolism in normal tissue and tumors is hexokinase. This particular enzyme is responsible for phosphorylation of glucose to glucose-6-phosphate and is significantly overexpressed or upregulated in most malignancies (7). This is a basic molecular biologic characteristic of malignant cells and is thus a molecular signature of cancer. FDG, which is an analog of deoxyglucose, enters cells through the same pathways of facilitated diffusion as does glucose (via several glucose transporters) and is subsequently phosphorylated to FDG-6-phosphate (7). FDG-6-phosphate is only minimally metabolized and, because it is negatively charged, remains metabolically trapped within cells (Fig 1). FDG PET can therefore be considered as the imaging of the rate-limiting step of glucose metabolism, namely hexokinase activity. The imaging signal detected with PET tomography is achieved by incorporation of 18F into FDG, thus enabling detection of the trapped and phosphorylated metabolite (8) (Fig 1). FDG PET for the staging and restaging of malignancy, metabolic characterization of malignancy, and monitoring of response to therapy is an example of a molecular imaging technique that is used in daily practice (9).


Figure 1A
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  		Figure 1a: Glucose and FDG metabolism. (a) Transport and metabolism of glucose compared with FDG. The normal metabolic fate of glucose is phosphorylation to glucose-6-PO4 by hexokinase. Once phosphorylated, glucose-6-PO4 can be used as an energy source with production of CO2 and H2O or stored in the form of glycogen. FDG, on the other hand, is phosporylated to FDG-6-P and metabolically trapped. (b) A more detailed depiction of the metabolic fate of FDG only. After the facilitated transport by GLUT-1 (K1), FDG is phosphorylated by hexokinase (k3). FDG-6-phosphate can neither undergo further metabolism nor diffuse out of cells. As the dephosphorylation (k4) reaction also occurs slowly, FDG-6-phosphate is trapped intracellularly and accumulates. ADP = adenosine diphosphate, ATP = adenosine triphosphate, F-6-PO4 = fructose-6-phosphate, G-6-P = glucose-6-phosphatase. (Fig 1b reprinted, with permission, from reference 3.)

 

Figure 1B
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  		Figure 1b: Glucose and FDG metabolism. (a) Transport and metabolism of glucose compared with FDG. The normal metabolic fate of glucose is phosphorylation to glucose-6-PO4 by hexokinase. Once phosphorylated, glucose-6-PO4 can be used as an energy source with production of CO2 and H2O or stored in the form of glycogen. FDG, on the other hand, is phosporylated to FDG-6-P and metabolically trapped. (b) A more detailed depiction of the metabolic fate of FDG only. After the facilitated transport by GLUT-1 (K1), FDG is phosphorylated by hexokinase (k3). FDG-6-phosphate can neither undergo further metabolism nor diffuse out of cells. As the dephosphorylation (k4) reaction also occurs slowly, FDG-6-phosphate is trapped intracellularly and accumulates. ADP = adenosine diphosphate, ATP = adenosine triphosphate, F-6-PO4 = fructose-6-phosphate, G-6-P = glucose-6-phosphatase. (Fig 1b reprinted, with permission, from reference 3.)

 
Like any new and evolving scientific and clinical discipline, such as molecular imaging, it is important to know its relevance to the daily practice of medicine. Thus, in this series of articles we wish to show why the practicing radiologist will need to understand and appreciate the importance of the following: (a) the biological information obtained from molecular imaging studies; (b) obtaining additional knowledge or training, if necessary, in molecular biology, molecular pharmacology, and genomics; and (c) being knowledgeable and comfortable with performing diagnostic molecular imaging studies and interpreting images from them on a daily basis. Furthermore, our goal is to provide an overview of the current and future use of molecular imaging that we believe will become part of a general radiology practice in the next 5–10 years.

There have been many comprehensive review articles published on molecular imaging (1–4,10–20). These articles provide the necessary information to understand the basic molecular biology, terminology and definitions (21), and background relevant to molecular imaging. We do not intend to simply reiterate this information. Rather, we wish to emphasize the potential clinical relevance and how molecular imaging will be part of patient care and management in various areas. We also provide additional information on how molecular imaging will be critically important in the drug discovery and development process (20,22–26), with a final article on the issues of regulatory approval and reimbursement.


   THE EVOLUTION OF IMAGING
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 INTRODUCTION
 THE EVOLUTION OF IMAGING
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 THE ADVENT OF MOLECULAR...
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During the past 25 years, advancements and refinements in technology have substantially broadened the range of available imaging procedures. Current techniques provide improved resolution and much clearer and more detailed anatomic images of organs and tissues than previously possible. CT, ultrasonography (US), and magnetic resonance (MR) imaging provide important structural and anatomic information. The impact of CT imaging on the practice of oncology has been immense. Similarly, the use of MR imaging in the central nervous system, in the head and neck region, and for joint disease has improved the management of patients. Currently, therapeutic response criteria are typically based on tumor measurements made from CT scans or MR images (27). The anatomic information obtained from a CT scan or MR image helps in the planning of the surgical approach and in the definition of the extent of tumor and assists in the localization of important normal structures. The use of contrast agents in both CT and MR imaging has improved diagnostic accuracy. Despite these substantial improvements in imaging technology and methods, there is a need to obtain more relevant molecular and biochemical information from imaging. For example, FDG PET for tumor staging, cardiac perfusion imaging with various nuclear medicine and MR imaging techniques, and MR spectroscopy to characterize brain tumors and prostate cancer have had a remarkable surge in use since they provide clinically useful biologic, biochemical, or physiologic information that impacts patient management.

The next major area for exploitation is molecular imaging, where more fundamental and important molecular, biologic, and biochemical information will be obtained. Molecular imaging will allow improvement in our ability to characterize and phenotype diseases on the basis of biologic and biochemical, in addition to anatomic, information. In addition, assessment of the scope of the biologic and biochemical alterations, which include receptor numbers, pathway regulation, and signal transduction abnormalities, that are present in many disease entities and analysis of gene, enzyme, and protein abnormalities will be possible. Imaging specialists of the future will have at their disposal a set of technologies with various types of intrinsic value in the information they provide (Fig 2).


Figure 2
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  		Figure 2: Spectrum of imaging technologies. The currently available imaging technologies, to varying degrees, are used to image anatomy, physiology, or molecular processes. Today, CT and US and to a large degree MR imaging are used primarily for anatomic imaging purposes, even though there is the capability for all three of these modalities to be used, to varying degrees, for physiologic assessments. MR imaging has the capability to make some molecular imaging assessments. PET and optical imaging, on the other hand, provide less anatomic information and are primarily molecular and, to a lesser degree, physiologic imaging techniques.

 

   ADVANCES IN OUR UNDERSTANDING OF THE GENETICS AND MOLECULAR BIOLOGY OF HEALTH AND DISEASE
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 INTRODUCTION
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THE ADVENT OF MOLECULAR...
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Over the past decade, there has been a revolution in our basic biologic understanding of disease. We have witnessed the elucidation of the human genome (28), mouse genome (29), and the description of the genetic abnormalities responsible for numerous diseases. There is now a much better understanding of the basic molecular pathways, proteins, and signal transduction processes that are present in the normal cell (Fig 3) (30). Scientists are also beginning to elucidate, as well, those altered processes responsible for numerous human diseases. Associated with these developments in basic molecular and cellular biology, the imaging sciences have made advances in technologies including MR imaging, PET, and optical imaging.


Figure 3
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  		Figure 3: The emergent integrated circuit of the cell. Progress in dissecting signaling pathways has begun to lay out a circuitry that will likely mimic electronic integrated circuits in complexity and finesse, where transistors are replaced by proteins (eg, kinases and phosphatases) and the electrons by phosphates and lipids, among others. In addition to the prototypical growth signaling circuit centered around Ras and coupled to a spectrum of extracellular cues, other component circuits transmit antigrowth and differentiation signals or mediate commands to live or die by apoptosis. As for the genetic reprogramming of this integrated circuit in cancer cells, some of the genes known to be functionally altered are in red. (Reprinted, with permission, from reference 30.)

 

   THE ADVENT OF MOLECULAR IMAGING
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 ABSTRACT
 INTRODUCTION
 THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
CURRENT RECOGNITION OF MOLECULAR...
 MOLECULAR IMAGING IN THE...
 SUMMARY
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The term molecular imaging came into use in the mid to late 1990s. Yet, the subspecialty of nuclear medicine has been providing for many years what might be considered molecular imaging information. With a thyroid uptake and scan for assessment of benign and malignant thyroid disease, a radioactive substrate such as iodine 131 (131I) or 123I is used for determination of a biologically relevant abnormality that is imaged. Other examples include 123I- and 131I-MIBG, indium 111 (111I) pentetreotide (OctreoScan; Mallinkrodt, Hazelwood, Mo) and 111I–capromab pendetide (ProstaScint; Cytogen, Princeton, NJ) imaging for cancer detection.

Much of the promise of imaging of molecular events can be traced to the efforts of the National Cancer Institute (NCI). In 1998, the NCI began describing the potential power of imaging techniques and molecular imaging, in particular, in the yearly NCI Bypass Budget (31–36). The NCI Bypass Budget is a public document produced annually by the NCI to identify for the Administration and Congress of the U.S. government those scientific priorities on which the budget appropriation should be spent. Imaging was identified as an area of "extraordinary opportunity" in the NCI budgets from 1998–2003. Several Requests for Applications were subsequently announced at various points during that time period for In Vivo Cellular and Molecular Imaging Centers, known as ICMICs (35–37), and Small Animal Imaging Resource Programs, also called SAIRPs (38–40). A substantial financial investment has been made by the NCI in providing this important infrastructure to promote molecular imaging and small animal imaging centers. The goals of the NCI (34–36) included the following: (a) to develop and validate imaging technologies and agents (eg, probes, radiopharmaceutical agents) that have the sensitivity to detect precancerous abnormalities or very small cancers; (b) to develop imaging techniques that can help to identify the biological properties of precancerous or cancerous cells that will aid the prediction of clinical course and response to interventions (Fig 4) (41,42); (c) to develop minimally invasive imaging technologies that can be used in interventions and in assessment of treatment outcomes; (d) to foster interaction and collaboration among imaging scientists and basic biologists, chemists, and physicists to help advance imaging research; and (e) to create infrastructures to advance research in development, assessment, and validation of new imaging tools, techniques, and assessment methods.


Figure 4
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  		Figure 4: Carcinogenesis timeline. The process of carcinogenesis is long and variable. Depending on the type of cancer, the timeline from initial genetic alterations in the cell to development of clinical cancer can be 40 years or more. Molecular imaging has the potential to be used much earlier than conventional anatomic imaging techniques in assessment of at-risk populations for altered pathways and proteins that are typically overexpressed and occur long before the development of the tumor that is detectable by using standard imaging techniques. CIS = carcinoma in situ, DCIS = ductal carcinoma in situ, CIN = cervical intraepithelial neoplasia, TIS = tumor in situ, PIN = prostate intraepithelial neoplasia. (Reprinted, with permission, from reference 41.)

 
During the past several years, the NCI and many other institutes at the National Institutes of Health—the National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Biomedical Imaging and Bioengeneering, and the National Institute of Mental Health—have put in place programs to promote molecular imaging. The NCI has provided a program to facilitate the development of imaging probes and contrast agents that will facilitate molecular imaging assessments of pathways in cancer. The Development of Clinical Imaging Drugs and Enhancers (43), known as DCIDE, program facilitates and promotes preclinical development and validation of important imaging agents, probes, and ligands. On a competitive basis, NCI will assist with the synthesis, testing, and distribution of probes that are used to image the molecular, physiologic, and functional status of tumor tissue in the human body. These infrastructure programs continue to the present at the NCI. A Network for Transitional Research for Optical Imaging, also called NTROI, is a recently funded initiative (44). The Network will develop consensus and validation processes for translational research in the newly evolving discipline of optical imaging, including optimization of emerging optical imaging systems and targeted or activatable probes. Long-term goals include development and delivery of common or similar platforms for measuring and extracting quantitative signatures from endogenous molecules or molecular probes that are cancer specific.

Soon after becoming the director of the National Institutes of Health in May 2002, Elias A. Zerhouni, MD, convened a series of meetings to chart a "roadmap" for medical research in the 21st century (45–48). The purpose was to identify major opportunities and gaps in biomedical research that no single institute at the National Institutes of Health could tackle alone but that the agency as a whole must address to have the biggest impact on the progress of medical research. The opportunities for discoveries have never been greater, but the complexity of biology remains a challenge. The National Institutes of Health is uniquely positioned to catalyze changes that must be made to transform our new scientific knowledge into tangible benefits for people (45). Several of the roadmap initiatives have components that are imaging related. In the roadmap, specific areas of interest to imagers include (a) development of high specificity and sensitivity probes to improve detection and (b) a molecular imaging and contrast agent database (MICAD) (49). With regard to a, this technology development program seeks to ultimately achieve a 1000-fold improvement in imaging probe detection sensitivity and optimal specificity for basic research and clinical applications. With regard to b, this comprehensive database of imaging probes, with their specificities, activities, and applications will be integrated with the Molecular Libraries Cheminformatics database. For more information in regard to the specific roadmap initiatives, the appropriate Web site at the National Institutes of Health (46,50) may be viewed.


   CURRENT RECOGNITION OF MOLECULAR IMAGING
TOP
 ABSTRACT
 INTRODUCTION
 THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
 CURRENT RECOGNITION OF MOLECULAR...
MOLECULAR IMAGING IN THE...
 SUMMARY
 References
 
Most major U.S. academic medical centers have realized the potential impact and importance of molecular imaging in both basic and translational research, as well as in eventual clinical care of patients (51–54). Molecular imaging programs have been set up at most academic medical centers in the United States. Many of these programs are due to funding from the NCI (35–37).

There are now two societies devoted to molecular imaging: the Society for Molecular Imaging (55) and the Academy of Molecular Imaging (56). Each of these societies has a respective molecular imaging journal, Molecular Imaging (57) and Molecular Imaging and Biology (58). Another medical journal, the former European Journal of Nuclear Medicine, is now the European Journal of Nuclear Medicine and Molecular Imaging (59). The Society of Nuclear Medicine, which publishes the Journal of Nuclear Medicine, also now uses the phrase Advancing Molecular Imaging as a byline in its name (60). Another indicator that molecular imaging is assuming increasing and critical importance in imaging occurred in January 2004 when the widely read and respected journal Radiology (61) made molecular imaging one of its new sections, with the addition of three associate editors who have expertise in molecular imaging. These changes have all occurred within the past 5 years.

There are now Web sites, such as Molecular Imaging Central (62), that allow an individual interested in molecular imaging to find the most up-to-date information on molecular imaging instrumentation, meetings, research funding opportunities, and relevant review articles. This site also provides a searchable database of molecular imaging terms.


   MOLECULAR IMAGING IN THE NEAR FUTURE
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Molecular imaging will allow the imaging scientist and clinician to visualize physiology and cellular or molecular biological processes in living tissue. Currently available techniques allow visualization and quantitation of potentially relevant physiologic and oftentimes molecularly controlled variables such as blood flow, oxygen consumption, glucose metabolism, proliferation, and tissue hypoxia as they take place in living cells and tissues. As basic scientists gain a better understanding of the fundamental molecular biologic and biochemical nature of various diseases, molecular imaging will be an important adjunct in translating this knowledge into clinical practice. Molecular imaging has the potential to help to identify important and key molecular pathway, signal transduction, and receptor alteration abnormalities in disease. This important information may elucidate how the disease behaves and will respond to certain drugs, treatments, and therapies. The development of new contrast agents and pathway-specific imaging probes will allow the in vivo elucidation of disease-altered molecular, metabolic, and specific cell cycle functions. These developments will continue to occur across all of the conventional disciplines of imaging, including CT, MR imaging, nuclear medicine, PET, and US. Newer techniques such as optical imaging hold much promise for the detection and elucidation of disease and pathogenesis at the microscopic level, potentially even in situ. With continued evolution of technology, it will be possible to visualize and quantitate the intracellular changes as the cell transforms from normal to diseased.

With the advent of new molecular imaging technologies and probes, it should become possible to evaluate at-risk populations earlier in the disease process before the typical clinical presentation. Eventually it is anticipated that, with molecular imaging techniques, the actual molecular signatures of many diseases will be visualized in vivo. The molecular imaging specialist will be able to visualize and determine which genes are being expressed as abnormal RNA and proteins in a specific disease and be able to translate this information directly into better clinical treatment of the patient. These advancements in molecular imaging capabilities will allow for individualized and personalized patient treatment based on the molecular characterization or phenotype of the disease process in vivo. This ability to detect, through imaging, the molecular changes associated with many diseases should vastly improve our ability to detect, diagnose, stage, select appropriate treatments, monitor the effectiveness of a targeted treatment, and determine prognosis in many diseases.

To facilitate the development of molecular imaging technologies, there will be associated developments in image enhancement agents, probes, and ligands. These developments will improve our ability to capture changes in the biochemical makeup of cells and other living structures. Imaging agents, which include contrast agents, probes, and ligands, will contribute to improved image formation in one of three ways: (a) They will localize in certain body organs or structures (anatomic localization); (b) they will attach to specific molecules in the body (receptor localization); or (c) they will become activated by certain biochemical or physical conditions, such as the presence of a specific enzyme in the cell (activatable agents) (1,2) (Figs 5, 6). Studies using these various molecular imaging probes are being done now in animal models, and it is only a matter of time before these techniques and probes will be tested in man. It is anticipated that contrast agents and imaging probes of the future will be capable of revealing the functional and molecular characteristics of diseases that determine clinical behavior at earlier time points. There will also be the capability to determine earlier responses to therapy and make appropriate changes if the therapy is ineffective.


Figure 5
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  		Figure 5: General principles of activatable probes. Two broad categories of molecular imaging probes. Radiolabeled probes (for PET and single photon emission computed tomography [SPECT] imaging and autoradiography) produce signal continuously, before and after they interact with their targets through the decay of the radioisotope. A time delay between injection of the probe and imaging helps to clear the untrapped probe. Activatable probes produce signal only when they interact with their targets (eg, near-infrared fluorescent probes for optical imaging). A time delay between injection and imaging helps to achieve sufficient levels of activated probe at the target site. (Reprinted, with permission, from reference 2.)

 

Figure 6A
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  		Figure 6a: Activatable fluorescent probe. (a) Schematic of near-infrared fluorescence probe activation. The initial proximity of fluorochrome molecules to each other results in signal quenching. After protease activation, fluorochromes become detectable (lightbulb effect). Cy = 5 cyanine fluorochrome, MPEG = 5 methoxy-polyethylene glycol, PL = 5 poly-L-lysine. (b) Light image of LX1 tumor implanted into the mammary fat pad of a nude mouse. The tumor is not detectable. (c) False-colored near-infrared fluorescent image superimposed on the white light image shows cathepsin B/H enzyme activity, which allows the detection of this small tumor (arrow) in the mammary fat pad. (Reprinted, with permission, from references 1 and 63.)

 

Figure 6B
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  		Figure 6b: Activatable fluorescent probe. (a) Schematic of near-infrared fluorescence probe activation. The initial proximity of fluorochrome molecules to each other results in signal quenching. After protease activation, fluorochromes become detectable (lightbulb effect). Cy = 5 cyanine fluorochrome, MPEG = 5 methoxy-polyethylene glycol, PL = 5 poly-L-lysine. (b) Light image of LX1 tumor implanted into the mammary fat pad of a nude mouse. The tumor is not detectable. (c) False-colored near-infrared fluorescent image superimposed on the white light image shows cathepsin B/H enzyme activity, which allows the detection of this small tumor (arrow) in the mammary fat pad. (Reprinted, with permission, from references 1 and 63.)

 

Figure 6C
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  		Figure 6c: Activatable fluorescent probe. (a) Schematic of near-infrared fluorescence probe activation. The initial proximity of fluorochrome molecules to each other results in signal quenching. After protease activation, fluorochromes become detectable (lightbulb effect). Cy = 5 cyanine fluorochrome, MPEG = 5 methoxy-polyethylene glycol, PL = 5 poly-L-lysine. (b) Light image of LX1 tumor implanted into the mammary fat pad of a nude mouse. The tumor is not detectable. (c) False-colored near-infrared fluorescent image superimposed on the white light image shows cathepsin B/H enzyme activity, which allows the detection of this small tumor (arrow) in the mammary fat pad. (Reprinted, with permission, from references 1 and 63.)

 
Animal models of disease will make it possible to perform certain kinds of studies that are difficult, if not impossible, to perform in humans. In addition to learning more about many diseases, research with animal models will facilitate imaging technology improvements that then can be eventually applied to the care of patients with many different diseases. The advantage of noninvasive imaging in animal models of disease is the ability to perform repetitive observations of the biological processes underlying the disease process. This factor is particularly important in the study of malignancy (38–40). Small animal imaging technologies now include micro-MR, micro-CT, micro-SPECT, micro-PET, micro-US, and various optical technologies (Fig 7). Furthermore, the level of resolution with some small animal imaging modalities is now approaching the size of individual cells. Imaging in animals also will help in the assessment of the effectiveness of new instruments and therapeutic technologies, such as radiation therapy and directed drug therapies.


Figure 7
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  		Figure 7: Small-animal imaging. Multiple imaging modalities are available for small-animal molecular imaging. Shown are views of typical instruments available and illustrative examples of the variety of images that can be obtained with these modalities. A, Coronal whole-body micro-PET image of a rat injected with FDG shows uptake of tracer in tissues that include muscle, heart, and brain and accumulation in bladder owing to renal clearance. B, Coronal micro-CT image of a mouse abdomen after intravenous injection of iodinated contrast medium. C, Coronal micro-SPECT image of mouse abdominal and pelvic regions after injection of technetium 99m–methylene diphosphonate shows spine, pelvis, tail vertebrae, femora, and knee joints owing to accumulation of tracer in bone. D, Optical reflectance fluorescence image of a mouse shows green fluorescent protein fluorescence from the liver, abdomen, spine, and brain. The mouse contains green fluorescent protein–expressing tumor cells that have spread to various sites. (Images courtesy of Dr Hoffman, Anticancer.) E, Coronal T2-weighted micro–MR image of a mouse brain. F, Optical bioluminescence image of a mouse with a subcutaneous xenograft expressing Renilla luciferase in the left shoulder region after injection of the substrate coelenterazine into the tail vein. Images were obtained using a cooled charge-coupled-device camera. The color image of visible light is superimposed on a photographic image of the mouse with a scale in photons per second per square centimeter per steradian (p/s/cm2/sr). (Reprinted, with permission, from reference 2.)

 
Molecular imaging will be a critical and an integrated part of the drug development process (20,22–26). It is envisioned that molecular imaging could potentially shorten the time line for drug approval and lessen the cost because of expedited and more direct measurement of drug effects in the body (20).

The potential importance of molecular imaging for the practice of radiology has been noted (17). Molecular imaging will assume an ever more important role in furthering our understanding of human disease and patient care in the future (10–14,17,64). Newly developed molecular imaging techniques will allow visualization and quantitation of relevant molecular and physiologic variables, such as altered cellular metabolism and proliferation (65), gene expression (66–68), protein-protein interactions (69–73), and enzymatic expression, that contribute to human disease. Clinically relevant assays, such as determination of protein-protein interactions, assessment of tissue hypoxia, noninvasive imaging assessment of gene expression, and assessment of enzymatic function, will be routinely performed noninvasively by using molecular imaging techniques.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
 CURRENT RECOGNITION OF MOLECULAR...
 MOLECULAR IMAGING IN THE...
 SUMMARY
References
 
Over the next several months, we hope to provide the readership of Radiology with a vision of why molecular imaging will be important from both a research and clinical perspective. We wish to inform the practicing radiologist about the promise of molecular imaging and how it has the potential to revolutionize clinical imaging as we know it. As radiologists and imaging scientists, it should be our goal to provide the most critical and relevant information required for the care and management of patients. Molecular imaging has the potential to provide information that will be some of the most critical and important information possible. That will be in the form of a noninvasive in vivo imaging assessment of the basic molecular biologic characterization of disease.


   FOOTNOTES
 

Abbreviations: FDG = [18F]fluoro-2-deoxy-D-glucose • NCI = National Cancer Institute

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 THE EVOLUTION OF IMAGING
 ADVANCES IN OUR UNDERSTANDING...
 THE ADVENT OF MOLECULAR...
 CURRENT RECOGNITION OF MOLECULAR...
 MOLECULAR IMAGING IN THE...
 SUMMARY
 References
 

  1. Weissleder R, Mahmood U. Molecular imaging. Radiology 2001;219:316–333.[Abstract/Free Full Text]
  2. Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003;17:545–580.[Free Full Text]
  3. Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 2005;11(8):2785–2808.[Abstract/Free Full Text]
  4. Hicks RJ. The role of PET in monitoring therapy. Cancer Imaging 2005;5(1):51–57.[Medline]
  5. The market for PET radiopharmaceuticals & PET imaging. Bio-Tech report no. 200. Bio-Tech Systems Web site. http://biotechsystems.com/reports/200/default.asp. Accessed April 9, 2006.
  6. Warburg O. The metabolism of tumors. New York, NY: Richard R. Smith, 1931; 1–129.
  7. Weber G. Enzymology of cancer cells. II. N Engl J Med 1977;296(10):541–551.
  8. Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol 1979;6(5):371–388.[CrossRef][Medline]
  9. Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med 2001;42(5 suppl):1S–93S.[Free Full Text]
  10. Jaffer FA, Weissleder R. Molecular imaging in the clinical arena. JAMA 2005;293(7):855–862.[Abstract/Free Full Text]
  11. Jager PL, de Korte MA, Lub-de Hooge MN, et al. Molecular imaging: what can be used today. Cancer Imaging 2005;5(spec no. A):S27–S32.[Medline]
  12. Cyrus T, Winter PM, Caruthers SD, Wickline SA, Lanza GM. Magnetic resonance nanoparticles for cardiovascular molecular imaging and therapy. Expert Rev Cardiovasc Ther 2005;3(4):705–715.[CrossRef][Medline]
  13. Pomper MG. Translational molecular imaging for cancer. Cancer Imaging 2005;5(spec no. A):S16–S26.[Medline]
  14. Landini L, Santarelli MF, Positano V, Leone A. Molecular imaging: its application in cardiovascular diagnosis. Curr Pharm Des 2005;11(17):2225–2234.[CrossRef][Medline]
  15. Choy G, Choyke P, Libutti SK. Current advances in molecular imaging: noninvasive in vivo bioluminescent and fluorescent optical imaging in cancer research. Mol Imaging 2003;2(4):303–312.[CrossRef][Medline]
  16. Gambhir SS. Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2002;2(9):683–693.[CrossRef][Medline]
  17. Hillman BJ, Neiman HI. Translating molecular imaging research into radiologic practice: summary of the proceedings of the American College of Radiology Colloquium, April 22–24, 2001. Radiology 2002;222:19–24.[Abstract/Free Full Text]
  18. Pomper MG. Molecular imaging: an overview. Acad Radiol 2001;8:1141–1153.[CrossRef][Medline]
  19. Luker GD, Piwnica-Worms D. Beyond the genome: molecular imaging in vivo with PET and SPECT. Acad Radiol 2001;8:4–14.[CrossRef][Medline]
  20. Kelloff GJ, Krohn KA, Larson SM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 2005;11(22):7967–7985.[Abstract/Free Full Text]
  21. Wagenaar DJ, Weissleder R, Arne Hengerer A. Glossary of molecular imaging terminology. Acad Radiol 2001;8:409–420.[CrossRef][Medline]
  22. Wang J, Maurer L. Positron emission tomography: applications in drug discovery and drug development. Curr Top Med Chem 2005;5(11):1053–1075.[CrossRef][Medline]
  23. Eckelman WC, Rohatagi S, Krohn KA, Vera DR. Are there lessons to be learned from drug development that will accelerate the use of molecular imaging probes in the clinic? Nucl Med Biol 2005;32(7):657–662.[CrossRef][Medline]
  24. Rudin M. Molecular imaging: basic principles and applications in biomedical research. London, England: Imperial College Press, 2005;
  25. Rudin M, Rausch M, Stoeckli M. Molecular imaging in drug discovery and development: potential and limitations of nonnuclear methods. Mol Imaging Biol 2005;7(1):5–13.[CrossRef][Medline]
  26. Rudin M, Weissleder R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov 2003;2:123–131.[CrossRef][Medline]
  27. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–216.
  28. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860–921. http://www.genome.gov/11006929. Published April 14, 2003; Accessed April 2, 2006.[CrossRef][Medline]
  29. Mouse Genome Sequencing Consortium; Waterston RH, Lindblad-Toh K, et al. Initial sequencing and comparative analysis of the mouse genome. Nature 2002;420:520–562. http://www.nature.com/nature/journal/v420/n6915/full/nature01262fs.html. Published December 5, 2002. Accessed April 15, 2006.[CrossRef][Medline]
  30. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.[CrossRef][Medline]
  31. Extraordinary opportunities for new investments. In: The nation's investment in cancer research: a budget proposal for fiscal years 1997/98. Bypass budget. National Cancer Institute, Financial Management Branch Web site. http://fmb.cancer.gov/financial/bypass.htm. Accessed July 15, 2006.
  32. Extraordinary opportunities for investment. In: The nation's investment in cancer research: a budget proposal for fiscal year 1999. Bypass budget. National Cancer Institute, Financial Management Branch Web site. http://fmb.cancer.gov/financial/attachments/bypass_1999.pdf. Accessed July 15, 2006.
  33. Extraordinary opportunities for investment. In: The nation's investment in cancer research: a budget proposal for fiscal year 2000. Bypass budget. National Cancer Institute, Financial Management Branch Web site. http://fmb.cancer.gov/financial/attachments/bypass_2000.pdf. Accessed July 15, 2006.
  34. Scientific priorities for cancer research: NCI's extraordinary opportunities. In: The nation's investment in cancer research: a budget proposal for fiscal year 2001. Bypass budget. National Cancer Institute, Financial Management Branch Web site. http://fmb.cancer.gov/financial/attachments/bypass_2001.pdf. Accessed July 15, 2006.
  35. Hoffman JM. Imaging in cancer: a National Cancer Institute "extraordinary opportunity". Neoplasia 2000;2(1-2):5–8.[Medline]
  36. Hoffman JM, Menkens A. Molecular imaging in cancer: future directions and goals of the National Cancer Institute. Acad Radiol 2000;7(10):905–907.[CrossRef][Medline]
  37. In vivo cancer molecular imaging centers (ICMICs). National Cancer Institute, Cancer Imaging Program Web site. http://imaging.cancer.gov/programsandresources/specializedinitiatives/icmics. Accessed April 15, 2006.
  38. Small animal imaging resource program (SAIRP). National Cancer Institute, Cancer Imaging Program Web site. http://imaging.cancer.gov/programsandresources/specializedinitiatives/SAIRP. Accessed April 15, 2006.
  39. Croft BY, Hoffman JM. NCI-funded small animal imaging programs. National Cancer Institute. Acad Radiol 2001;8:372–374.
  40. Hoffman JM, Croft B. Future directions in small animal imaging. Lab Animal 2001;30(3):32–35.[Medline]
  41. O'Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development: recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia. Clin Cancer Res 2002;8:314–346.[Abstract/Free Full Text]
  42. Kelloff GJ. Perspectives on cancer chemoprevention research and drug development. Adv Cancer Res 2000;78:199–334.[Medline]
  43. Development of clinical imaging drugs & enhancers (DCIDE). National Cancer Institute, Cancer Imaging Program Web site. http://imaging.cancer.gov/programsandresources/specializedinitiatives/dcide. Accessed April 14, 2006.
  44. Network for translational research: optical imaging (NTROI). National Cancer Institute, Cancer Imaging Program Web site. http://imaging.cancer.gov/programsandresources/specializedinitiatives/ntroi. Accessed April 14, 2006.
  45. Overview of the NIH roadmap. NIH roadmap for medical research. Office of Portfolio Analysis and Strategic Initiatives, National Institutes of Health Web site. http://nihroadmap.nih.gov/overview.asp. Accessed April 14, 2006.
  46. NIH roadmap. NIH roadmap for medical research. Office of Portfolio Analysis and Strategic Initiatives, National Institutes of Health Web site. http://nihroadmap.nih.gov/. Accessed July 14, 2006.
  47. Zerhouni E. Medicine. The NIH roadmap. Science 2003;302(5642):63–72.
  48. Zerhouni EA. US biomedical research: basic, translational, and clinical sciences. JAMA 2005;294(11):1352–1358.[Abstract/Free Full Text]
  49. Molecular imaging & contrast agent database. MICAD NIH Roadmap, National Institutes of Health. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowTOC&rid=micad.TOC&depth?pi26>2. Accessed April 14, 2006.
  50. NIH roadmap initiatives. NIH roadmap for medical research. Office of Portfolio Analysis and Strategic Initiatives, National Institutes of Health. http://nihroadmap.nih.gov/initiatives.asp. Accessed April 14, 2006.
  51. Center for molecular imaging research. Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard University Web site. http://www.mgh-cmir.org/. Accessed April 15, 2006.
  52. Molecular imaging program at Stanford (MIPS). Molecular Imaging Program, Stanford University Web site. http://mips.stanford.edu/. Accessed April 14, 2006.
  53. Background on the Center for Advanced Biomedical Imaging Research. News backgrounders. The University of Texas MD Anderson Cancer Center Web site. http://www.mdanderson.org/departments/newsroom/display.cfm?id=ffd8860c-7f0c-49c5-b7ff27d9deecdc45&method=displayfull&pn=7816f628-61d7-4b3c-88e76eac5072a6fe. Accessed April 15, 2006.
  54. Integrated science, innovative technology: this is the Crump institute. Crump Institute for Molecular Imaging Web site. http://www.crump.ucla.edu/. Accessed April 15, 2006.
  55. The Society for Molecular Imaging Web site. http://www.molecularimaging.org/. Accessed April 15, 2006.
  56. Academy of Molecular Imaging Web site. http://www.ami-imaging.org/public/journal.htm. Accessed April 15, 2006.
  57. Molecular Imaging Web site. http://www.journalsoft.com/molecularimaging/journal/index.php. Accessed April 15, 2006.
  58. Molecular Imaging and Biology Web site. http://www.ami-imaging.org/public/journal.htm. Accessed April 15, 2006.
  59. European Journal of Nuclear Medicine and Molecular Imaging Web site. http://www.springer.com/sgw/cda/frontpage/0,11855,4-0-70-1038116-detailsPage%253Djournal%257Cdescription%257Cdescription,00.html?referer=www.springer.com%2Fjournal%2F00259%2Fabout. Accessed April 15, 2006.
  60. Society of Nuclear Medicine Web site. http://interactive.snm.org/. Accessed April 15, 2006. The Journal of Nuclear Medicine Web site. http://jnm.snmjournals.org/. Accessed April 15, 2006.
  61. Radiology Web site http://radiology.rsnajnls.org/. Accessed April 15, 2006.
  62. Molecular Imaging Central Web site. http://www.mi-central.org/. Accessed April 15, 2006.
  63. Weissleder R, Tung CH, Mahmood U, Bogdanov A Jr. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol 1999;17:375–378.[CrossRef][Medline]
  64. Blasberg RG. Molecular imaging and cancer. Mol Cancer Ther 2003;2(3):335–343.[Abstract/Free Full Text]
  65. Krohn KA, Mankoff DA, Eary JF. Imaging cellular proliferation as a measure of response to therapy. J Clin Pharmacol 2001;(suppl):96S–103S.
  66. Gambhir SS, Barrio JR, Herschman HR, Phelps ME. Imaging gene expression: principles and assays. J Nucl Cardiol 1999;6(2):219–233.[CrossRef][Medline]
  67. Sharma V, Luker GD, Piwnica-Worms D. Molecular imaging of gene expression and protein function in vivo with PET and SPECT. J Magn Reson Imaging 2002;16(4):336–351.[CrossRef][Medline]
  68. Blasberg R. Imaging gene expression and endogenous molecular processes: molecular imaging. J Cereb Blood Flow Metab 2002;22(10):1157–1164.[CrossRef][Medline]
  69. Luker GD, Sharma V, Pica CM, et al. Noninvasive imaging of protein-protein interactions in living animals. Proc Natl Acad Sci U S A 2002;99:6961–6966.[Abstract/Free Full Text]
  70. Luker GD, Sharma V, Piwnica-Worms D. Visualizing protein-protein interactions in living animals. Methods 2003;29(1):110–122.[CrossRef][Medline]
  71. Paulmurugan R, Massoud TF, Huang J, Gambhir SS. Molecular imaging of drug-modulated protein-protein interactions in living subjects. Cancer Res 2004;64(6):2113–2119.[Abstract/Free Full Text]
  72. Paulmurugan R, Umezawa Y, Gambhir SS. Noninvasive imaging of protein-protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc Natl Acad Sci U S A 2002;99(24):15608–15609.[Abstract/Free Full Text]
  73. Ray P, Pimenta H, Paulmurugan R, et al. Noninvasive quantitative imaging of protein-protein interactions in living subjects. Proc Natl Acad Sci U S A 2002;99(5):3105–3110.[Abstract/Free Full Text]



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