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(Radiology. 1999;212:609-614.)
© RSNA, 1999

Editorial

Molecular Imaging: Exploring the Next Frontier1

Ralph Weissleder, MD, PhD

1 From the Center for the Molecular Imaging Research, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129. Received January 22, 1999; revision requested March 16; revision received March 18; accepted March 23. Supported in part by National Institutes of Health grants RO1CA54886, RO1NS35258, ROCA174424, and RO1CA59649. Address reprint requests to the author (e-mail: weissleder@helix.mgh.harvard.edu).

Index terms: Editorials • Genes and genetics • Magnetic resonance (MR), utilization, **.121492 • Radionuclide imaging, **.12172

Important developments in molecular sciences in the past decade have provided unprecedented opportunities in genome research (1), an understanding of the molecular mechanisms of disease, and the development of innovative therapies at the genetic level (2). These developments have been made possible, in part, because of automated and accelerated sequencing (3), progress in combinatorial drug development (4,5), the creative use of nonmammalian cells (insect, bacteria, phages, etc) to produce recombinant proteins or peptides, and the development of transgenic animal models (6). In parallel, imaging sciences have undergone remarkable advances over the past 2 decades. Image resolution is constantly improving for virtually all imaging modalities, and some experimental imaging systems already have microscopic-resolution capabilities (7,8). These advances have brought in vivo imaging to the basic sciences, and a flurry of program announcements from the National Institutes of Health (NIH) and other biomedical organizations reflect this progress.

Most traditional cross-sectional imaging techniques such as magnetic resonance (MR) imaging, computed tomography (CT), and ultrasonography (US) are reliant on physical (eg, absorption, scattering, proton density, relaxation rates) and physiologic (eg, blood flow) properties as the main source of contrast for the purposes of disease detection and characterization. Molecular imaging is built on these and other imaging techniques (nuclear, optical imaging) and is aimed at the exploitation of specific molecules as the source of image contrast. This paradigm shift from nonspecific physical to specific molecular sources is the underlying tenet for many of the current molecular imaging research efforts.

The impact of the developing molecular imaging technology is an entire new universe (9) that provides potential for earlier detection and characterization of disease, understanding of biology, and evaluation of treatment. For example, relatively gross parameters of disease (eg, in the case of cancer: tumor burden, anatomic location) could be improved by using more specific parameters (eg, detection of premalignant molecular abnormalities, growth kinetics, angiogenesis growth factors, tumor cell markers, or genetic alterations) (Fig 1). This imaging assessment, in combination with innovative targeted therapies, would allow assessment of therapeutic effectiveness at a molecular level, long before phenotypic changes occur. Molecular in vivo imaging could allow the study of pathogenesis in intact microenvironments of living systems. Finally, molecular imaging has the potential to provide three-dimensional information much faster than is currently possible with time-consuming, labor-intensive, invasive conventional techniques such as histologic analysis.



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  		Figure 1. Diagrams show mechanisms for molecular imaging at the organ, tissue, cellular, and genetic levels.

 
Overall, it has become clear that our specialty will play an increasingly important role as we develop and apply techniques to image genetic manipulations, to perform in vivo screening of novel drugs, and to understand functional molecular events in living organisms at the cellular and molecular levels (10,11). The aim of this communication is to summarize the prerequisites, recent accomplishments, and challenges in the development of molecular imaging techniques and to illustrate some of the potential applications.

Approaches to Molecular Imaging
The key elements (Fig 2) to sampling molecular information are (a) the use of special imaging probes with high specificity, (b) appropriate amplification strategies, and (c) sensitive systems capable of producing images with high resolution (12). For example, in vitro demonstration of messenger RNA requires the use of a complementary probe, an amplification method such as polymerase chain reaction (PCR), and detection systems (Fig 2). Likewise, demonstration of a given protein with immunohistologic methods requires a specific probe (usually an antibody), amplification (avidin-biotin, horseradish peroxidase, etc), and a visualization system such as a microscope. Acquisition of in vitro information has become relatively easy, because thousands of specialty reagents, ligands, protocols, and devices have been commercially developed over the past decade.



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  		Figure 2. Diagrams show comparison of key elements for in vitro and in vivo molecular imaging.

 
In vivo molecular imaging is more challenging than in vitro detection, primarily because of the need for probes to be biocompatible, the presence of additional delivery barriers, and the necessity for developing special in vivo amplification strategies. There are four broad areas in which considerable research efforts will thus be necessary: development of (a) suitable in vivo affinity ligands ("molecular probes"); (b) efficient organ and intracellular targeting strategies; (c) amplification strategies, because typical target concentrations are in the pico- to nanomolar range; and (d) imaging systems with high spatial resolution and sensitivity (Fig 2). Since the recognition of these requirements (12), considerable developments already have occurred, and the NIH and other national funding agencies have made a considerable commitment to support innovative research in this field.

The most commonly used imaging techniques for extraction of molecular information are nuclear (13–19), MR (20-23), and optical techniques (24–26). Each of these techniques has its particular advantages and disadvantages, and use of one or another technique is mostly dependent on the specific research question and hypothesis to be tested. Positron emission tomography (PET) is frequently used when a substrate to a given target exists that can easily be labeled with a positron emitter, for example labeled 2'-fluoro-5-iodovinyl-1-ß-D-arabinofuranosyl-uracil (FIAU) or ganciclovir for imaging of viral thymidine kinase gene expression (13,14,15,19,27). Nuclear imaging techniques also are especially suited to track small amounts of labeled therapeutic drugs (28) and to investigate multiple drug resistance (29,30) or delivery systems such as viral vectors (31).

MR imaging has two particular advantages over techniques that involve the use of isotopes: higher spatial resolution (micrometer rather than several millimeter) (7,32) and the fact that physiologic and anatomic information can be extracted simultaneously. Microscopic MR imaging, in particular, is expected to have a substantial influence in developmental biology, in imaging of transgenic animals, and in cell trafficking (33,34). In comparison with isotope techniques, however, MR imaging is several magnitudes less sensitive (millimolar rather than picomolar), which is why reliable signal ampli-fication strategies must be developed. Recently, cell labeling techniques have been developed (35) that will allow efficient in vivo tracking of stem cells, progenitor cells, or cell lines expressing transgenes (Fig 3), potentially at the single-cell level (33).



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  		Figure 3. Three-dimensional T1-weighted gradient-echo MR imaging reconstruction (repetition time, 150 msec; echo time, 3.6 msec; flip angle, 34°; voxel size, 39 x 39 x 78 µm) shows tracking of immune cells with magnetically labeled lymphocytes homed to a human glioblastoma tumor (9L tumor model) xenograft in a mouse. Cell were labeled ex vivo by using a magnetic particle with membrane translocation signals (35). Approximately 10,000 cells are distributed throughout the elongated tumor (outlined in red) and cause low MR signal intensity, which is readily detectable. (Imaging was performed in collaboration with Helene Benveniste, MD, PhD, Center for In Vivo Microscopy, Duke Medical Center, Durham, NC.)

 
Finally, optical imaging techniques have already been developed for applications in molecular and cellular biology (eg, fluorescence microscopy) and in vivo surface imaging (25,36,37). Newer approaches have been advocated that may ultimately lead to the development of tomographic optical imaging systems in the near-infrared spectrum (38,39). One of the appealing advantages of near-infrared optical imaging is that quenched fluorescent labels that become brightly fluorescent after specific molecular interaction with their target can be used (26). Such "beacons" with molecular specificity would be suitable in applications to image enzymes, DNA and/or RNA targets (40), and a variety of other cellular and subcellular targets in vivo. Another notable advantage of optical techniques is the fact that multiple probes with different spectral characteristics can be used for multichannel imaging, similar to in vitro karyotyping (41).

Imaging of Gene Delivery and Expression
There are more than 250 ongoing clinical gene therapy trials in the United States. Radiologic techniques that can assist in such therapies include minimally invasive interventional help in delivering genetic material to its target, determination of the distribution of gene delivery, and imaging of gene expression in vivo (42–44).

Several investigators (43,45) have described the use of stereotactic delivery of viral vectors and subsequent anatomic changes after gene delivery. Direct imaging of gene delivery still is at an experimental level, but methods to label viral vectors such as replication-deficient herpes simplex virus (31) or adenovirus (46) have recently been described. Figure 4 is an example of the first in vivo image of a replication-conditioned herpes simplex virus encoding for ß-galactosidase in an animal model. Viral labeling techniques are currently used to help estimate gene delivery to different target organs or cancers and to help evaluate treatment modifiers to improve gene delivery in vivo. Other techniques to track nonviral gene delivery systems also are under development (47).



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  		Figure 4. Viral gene delivery. Planar scintigraphic image of the whole-body distribution of a genetically engineered herpes simplex virus utilized for gene delivery in a rat. The indium 111-labeled replication-conditioned virus encoding for ß-galactosidase was injected intravenously (150 µCi [5.6 MBq]). Image acquisition time was 5 minutes. Note the predominant viral distribution to liver (white and red areas), which should be useful for gene therapy in this organ (31).

 
Imaging of gene expression refers to the depiction of successfully expressed proteins in vivo. Several different types of imaging marker genes have been described and are summarized in the Table. Of all the different systems, the herpes simplex virus–thymidine kinase system has received the greatest attention and, at the time of this writing, is closest to being used in clinical trials (19). This system is based on the observation that intracellularly expressed viral thymidine kinase (but not endogenous mammalian thymidine kinase) acts to phosphorylate therapeutic (eg, ganciclovir) or imaging prodrugs (eg, FIAU labeled with fluorine 18, 18F-ganciclovir), which are no longer cell membrane permeable and thus are "trapped" in cells (Fig 5). The intracellularly converted drugs are detectable with imaging assistance after elimination of precursors.


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  		Strategies for Imaging of Gene Expression
 


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  		Figure 5. Gene expression. Summed coronal PET image of a rat injected with iodine 124-FIAU, a substrate for viral thymidine kinase. The tracer accumulates in the flank tumor (in vitro-transduced W256-Tk cells) and in the neck tumor (in vivo-transduced W256 tumor). (Reprinted, with permission, from reference 19.)

 
Similar strategies also are under development with other enzyme or substrate systems. Of particular interest is the enzyme tyrosinase, which is capable of therapeutic anticancer prodrug activation (55,56) and, at the same time, can be detected at MR imaging (20). Given the unique properties of tyrosinase, it should also be feasible to detect tyrosinase activity by means of scintigraphy (57,58), PET (59), or even optical imaging (60). Several other strategies have been proposed (17) to image gene expression with nuclear, MR imaging, and/or optical imaging techniques (Table).

Imaging of Endogenous Gene Expression
In addition to imaging of transgenes expressed after gene therapy, there is general interest in the demonstration of expression of endogenous genes. Most of the current knowledge of endogenous gene expression and regulation in mammalian systems is limited to results from in vitro studies, which may or may not reflect the in vivo scenario. Such in vitro studies (Northern blot, Western blot, etc) usually require tissue sections, and time-course studies often are impractical. One of the goals in molecular imaging research, therefore, is the development and validation of universal "imaging genes." Such generic "reporters" could then be used to facilitate direct imaging of promoter activity over time.

One specific example of this type of research is in vivo imaging of vascular endothelial growth factor promoter activity "driving" green fluorescent protein expression and imaging of the latter by means of intravital microscopy (50). Recently, variants of green fluorescence protein have been developed that contain additional ligands to bind diagnostic labels such as technetium 99m, so that their expression could also be imaged by using nuclear techniques (16). It is expected that a number of approaches and transgenic animal models will ultimately be developed to assist in the study of key regulatory genes and their expression in vivo.

Early Detection and Molecular Characterization
An exciting application of molecular imaging is the potential to base disease detection on early molecular abnormalities, before diseases become obvious with traditional imaging techniques. Although enticing in concept, examples of this type of application currently are rare. One example however, is the early detection of small breast or prostate cancers on the basis of tumoral expression of tumor-associated enzymes (26). Key enzymes under current investigation are cathepsins, prostate-specific antigen (the interstitial fraction is a protease), and matrix metalloproteases (26). Unlike with traditional targeting approaches, where antibodies or other affinity molecules are used, enzymes offer the possibility to use specific imaging precursors that are not detectable unless they become activated. One of those activation strategies is shown in Figure 6, in which an optically quenched (not detectable), enzyme-specific substrate becomes detectable after enzyme activation in the tumor. In one specific example, it has been shown that breast cancer masses with a diameter of less than 0.3 mm are detectable in xenograft models (26,61). Extensive further research is needed to facilitate development and optimization of this imaging approach.



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  		Figure 6a. Optical imaging of enzyme activity in a human LX1 tumor (2-mm diameter) xenografted into the mammary fat pad of a mouse. (a) Light image. (b) Raw near-infrared image. Note the bright tumor (arrow in b) in the chest. This appearance is due to enzymatic activation of the optically quenched cathepsin imaging probe. (For more information on this type of imaging, see reference 26.)

 


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  		Figure 6b. Optical imaging of enzyme activity in a human LX1 tumor (2-mm diameter) xenografted into the mammary fat pad of a mouse. (a) Light image. (b) Raw near-infrared image. Note the bright tumor (arrow in b) in the chest. This appearance is due to enzymatic activation of the optically quenched cathepsin imaging probe. (For more information on this type of imaging, see reference 26.)

 
Imaging of Drug Therapy
Traditional therapeutic drug development has undergone considerable changes with the introduction of different combinatorial and other chemical library approaches. In vivo testing of drug effectiveness has thus become a major bottleneck in drug testing. The use of molecular imaging could be of considerable benefit (a) by helping determine the pharmacokinetics and pharmacodynamics of newly developed drugs and (b) by facilitating development of early and objective markers before phenotypic changes become obvious. In the ideal case, the imaging technique would be used to probe for the specific molecular target against which a therapeutic drug is directed—for example, enzymes, receptors, or signal transduction pathways. Another development in which imaging will have a major effect is the objective assessment of long-term and often expensive drug regimens. Imaging as a monitoring tool could help refine such treatments, potentially leading to reduced risks and cost savings. Finally, imaging has much to offer in terms of the understanding of delivery barriers for newly developed therapeutic agents, particularly large-molecular-weight, particulate, viral, or cellular systems (62).

It is clear that the foregoing is replete with "could," "would," and "potential." On the other hand, the results of successful innovation and feasibility studies are encouraging and give credibility to expectations and theories. The combined imaging possibilities probably were unimaginable 50 years ago and will certainly expand as we enter the new millennium.

Acknowledgments

The author expresses his gratitude to A. Bogdanov, PhD, and J. Wittenberg, MD, for review of the manuscript and colleagues at the Center for Molecular Imaging Research at Massachusetts General Hospital for many helpful discussions.

Footnotes

**. Multiple body systems Back

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