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

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).

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (25K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (59K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (79K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   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.)

View larger version (97K): [in this window] [in a new window] [Download PPT slide]   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.)