Dr. Bonekampis a resident and Dr. Pomper is a professor in the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD; Dr. Hammoud is a Staff Clinician, Department of Radiology and Imaging Sciences, National Institutes of Health/ Clinical Center, Bethesda, MD.
The Task Force of the Society of Nuclear Medicine (SNM) Molecular Imaging Center of Excellence (MICoE) defines molecular imaging as the “visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems.”1
In the context of translation into clinical practice, molecular imaging would perhaps better be known as “molecular diagnostic imaging,” to distinguish it from “classical diagnostic imaging.” Unlike the latter, molecular imaging goes beyond structural assessment, and probes disease-specific abnormalities at the molecular level, putting it at the frontiers of biomedical science where new genetic and molecular causes of disease are continually being discovered.
However, molecular imaging is not a new concept. For example, positron-emission tomography (PET) has proved capable of imaging molecular processes such as blood flow in the brain and other organs using O-15 water, as early as the 1970s.2 Yet, molecular imaging has only recently been defined as a separate field. This was probably instigated by the completion of the human genome project in April 20033,4 and the recognition that many diseases have molecular and cellular causes. It is now recognized that imaging of processes intrinsic to metabolism, cell signaling and gene expression is possible. The evolution of our knowledge of molecular mechanisms of disease and the progress of imaging technology are happening rapidly and in parallel, fostering their combined application in molecular imaging.
Molecular imaging systems
Simply put, a molecular imaging system typically consists of a target, an agent and an imaging modality. Molecular imaging necessitates the interaction of the target with a “labeled” agent that can be detected externally by one or more modalities.
Three major ways of agent-target interaction are recognized (Figure 1). Targeted binding: Here, the labeled agent selectively binds to its target, for a long enough period to allow external detection by an imaging modality. One example is neuroreceptor imaging in the brain, such as with 11C-raclopride, which binds to the type-2 dopamine receptor. The interaction is detected externally by PET imaging (Figure 1A).
Imaging agent accumulation in the cell: This usually results from enzymatic action that modifies the structure of the agent. The best example is 18F-fluorodeoxyglucose (FDG), which, once inside the cell, is acted upon by hexokinase, resulting in a phosphorylated version that can neither cross the cell membrane again nor undergo glycolysis. This results in the accumulation of FDG in highly metabolic cells, such as in cancer or infection/inflammation. The interaction can be detected externally by PET imaging (Figure 1B).
Activation of imaging agent by cellular components: The cellular components are usually enzymes, resulting in signal amplification. One example is bioluminescence in which the luciferase enzyme expressed by the target cell acts on injected luciferin. Emitted light is then detected externally by specialized cameras (Figure 1C).
Agent labeling and amplification strategies
Prior to agent-target interaction, substantial work goes into the labeling process of the imaging agent. The most common labeling method is probably the use of modified injectable agents adapted from known drugs/molecules.5-10 For that purpose, the in vivo characteristics of the labeled molecules need to be determined first. Favorable characteristics include, high specific activity of the label (to avoid drug toxicity and preserve tracer characteristics); high site selectivity and specificity; appropriate binding affinity; suitable hydro/lipophilicity and size (which govern transport across barriers); suitable metabolism (metabolites are likely to carry the label but exhibit altered specificity); low immediate excretion (renal, hepatic) or sequestration (drug resistance transporters, phagocytes); low non-specific binding (as the background signal reduces contrast); and, the ability to achieve high local concentrations.11-15
Limitations of the use of injectable molecular imaging agents of different modalities can be explained to a great extent by their pharmacological properties. For example, ultrasound contrast agents (in the form of microbubbles) and magnetic resonance imaging (MRI) iron nanoparticles are relatively bulky, and are restricted by body membranes such as the vascular endothelium, the blood-brain barrier or the cell membrane; they are restricted much more than low–molecular-weight agents.16-25 Radionuclide-based labeling techniques, on the other hand, provide the ability of replacing atoms of biological molecules with their radioisotopes, resulting in radiolabeled injectable agents that ideally are chemically identical (same size, chemistry and charge) to their unlabeled state. Positron-emitting radioisotopes lend themselves to these techniques, because they include the lower–mass-number elements of the periodic system, which are major components of biological molecules, such as carbon, nitrogen, fluorine and oxygen.5,7,8,26-38
Another form of labeling is indirect, using reporter genes. This constitutes the basis of molecular genetic imaging. In this case, a reporter gene (the product of which can be detected externally), is genetically linked (ex vivo) to a promoter of the gene of interest in such a way that when the gene of interest is expressed, the reporter gene product (protein) is produced, enabling imaging (Figure 2).
One such example is the use of the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) as a reporter gene. When the gene of interest is expressed in the cell, the HSV1-tk gene is simultaneously transcribed to HSV1-tk mRNA and then translated to TK. TK can then phosphorylate one of its substrates, such as iodine-124 fluorodeoxy arabinofuranosyl iodouracil (124I-FIAU). The phosphorylated 124I-FIAU cannot cross the cell membrane and is sequestered within the cell, becoming amenable to PET imaging. The phosphorylated 124I-FIAU is thus an indirect indicator of the expression of the gene of interest.39-42 Many new imaging agents for human reporter genes are subject to active research in anticipation of their use in human gene therapy.
In contradistinction to indirect labeling, direct cell-labeling techniques are also used in molecular imaging to introduce a label into cells in vitro, before transplantation. One example is the use of the highly derivatized cross-linked iron oxide nanoparticle (CLIO–HD) to label killer lymphocytes ex vivo prior to reintroduction of the labeled cells into the system.43 These iron oxide particles provide strong negative contrast when imaged with MRI. After reintroduction of the labeled cells, the 3-dimensional distribution of infiltrating T-cells across the whole tumor can be detected using MRI, with simultaneous assessment of both cellular recruitment and therapeutic efficiency.43
Molecular imaging modalities
There are 4 main categories of molecular imaging modalities: ultrasound, optical imaging, MRI and nuclear medicine techniques. The choice of the imaging modality is determined based on the temporal and spatial resolution; field of view; sensitivity of the imaging system; depth of the biological process; the molecular or cellular process to image (protein vs. cell); and, the availability of suitable probes and labels that can be delivered to the imaging target.
Molecular imaging with ultrasound commonly utilizes specialized contrast agents, usually in the form of small acoustically active gas-filled microbubbles that possess high echogenicity, sufficient to elicit signal from as little as a single microbubble (femtoliter ∼10-15 liter volume). The microbubbles are often coated with lipids, proteins or polymers, with diameters of >1µm,20 which confines them to the intravascular space. This is why relevant targets are usually those expressed on the endovascular structures or intravascular cells such as angiogenesis, inflammation and intravascular thrombi.16 The use of ultrasound in molecular imaging is largely limited to animal applications (Figure 3). Excellent reviews on the use of ultrasound in combination with targeted microbubbles and ultrasound-induced drug delivery exist.17-20
Optical techniques include 2 major classes: fluorescence and bioluminescence imaging. Fluorescence refers to the property of certain molecules (fluorophores) to absorb light at a particular wavelength and to emit light of a longer wavelength after a brief interval known as the fluorescence lifetime.44 Fluorescent reporters carry such fluorophores. Two-dimensional planar fluorescence reflectance imaging (FRI) technology has evolved into 3-dimensional fluorescence-mediated tomography (FMT),45,46 which is capable of deep tissue penetration, using sophisticated computational analysis methodology to reconstruct the in vivo distribution of intravenously injected fluorescent probes.47 Photon wavelength influences the depth resolution of optical imaging techniques. Near-infrared photons currently provide the greatest wavelengths (650 nm to 900 nm) and the best depth of penetration (>1 cm).
Bioluminescence imaging uses reporter genes that lead to expression of luciferase proteins. Upon injection of the substrate, luciferin, light is emitted as a result of a chemical reaction involving luciferase, luciferin, oxygen and ATP. The emitted light is detected externally.48 As opposed to fluorescence imaging, no excitation light is required. Luciferase proteins are derived from different organisms, such as bacteria, fireflies, red and green click beetles, and renilla reniformis (sea pansy). Firefly and red click beetle luciferases emit longer wavelength photons.49
Optical imaging techniques are characterized by their spatial resolution varying from several millimeters to micrometer resolution, and by their excellent sensitivity. However, their use is limited to small animals and surface and fiber optic imaging in nonhuman primates and humans (Figure 4).
While MRI provides very high resolution (up to 10 µm) and unlimited depth of penetration, it is, however, limited by low sensitivity, with detectabilities in the milli- to micromolar (10-3 to 10-6) range.50 Therefore, amplification techniques are often needed to image molecular processes in vivo.
The best recognized MRI amplification technique is the use of iron oxide particles as contrast agents. These provide negative MR contrast through local increase of the relaxivity (R1 and R2) of the tissue.51-55 Superparamagnetic iron oxide (SPIO) particles are becoming increasingly popular as they provide the strongest contrast available for MR imaging, while they are biodegradable by cellular enzymes. Their surface coating dextrans facilitate linking to ligands.56 Detection is possible at micromolar concentrations of iron, and sensitivity is sufficient for T2*-weighted imaging.52
Cells labeled with iron oxide are used for monitoring of cell trafficking in vivo. The labeling can be done through systemic IV injection of the particles, which are then incorporated inside macrophages through phagocytosis. The migration of macrophages can then be monitored externally using MRI (Figure 5).57-59 Labeling can also be performed through in situ injection of iron oxide particles near areas of stem-cell formation such as the subventricular zone of the brain.60,61 The most common technique though is in vitro labeling of cells prior to injection.62-64
Nuclear medicine techniques
Nuclear medicine techniques provide practically unlimited depth penetration and have very high sensitivities, in the nanomolar (10-9) range.65,66 Production of radiotracers with high specific radioactivity yields detectable radioactivity while maintaining low pharmacological doses. Although PET and single photon emission computed tomography (SPECT) cause radiation exposure and have relatively low resolution (2 mm to 5 mm for PET, 8 mm to 12 mm for SPECT),65,66 nonetheless they are the most commonly used human molecular imaging modalities. As a result of applicability of the tracer principle to radiopharmaceuticals used in human studies (only a very small quantity of the radiopharmaceutical is introduced, too small to exert any pharmacologic effect), the United States Food and Drug Administration (FDA) approval of new radiopharmaceuticals is generally much less complicated than for other modality imaging agents.
PET tracers are, in general, easier to quantify; reliable kinetic modeling is established for many tracers. PET has approximately 100 times higher sensitivity than SPECT, in large measure due to the ability to avoid using collimators during imaging.67 The most commonly used PET radionuclides are 11C (half-life ≈ 20 min) and 18F (half-life ≈ 110 min). SPECT tracers, in general, have longer half-lives, allowing the study of molecular processes that evolve over longer times. SPECT provides many readily useable radiotracers, and a local cyclotron is not needed for operation.
Small animal molecular imaging
Small animal molecular imaging represents the vast majority of molecular imaging applications at the present time. This mirrors the fact that molecular imaging is becoming an integrated and indispensable tool for modern life sciences. Medical application is expected for the most successful, least harmful and most reliable techniques, and clinical usefulness remains the true final proving ground.
Molecular imaging in small animals is facilitated by the adaptation of the imaging systems. Preclinical small-animal imaging PET, SPECT, MRI and CT scanners68-75 provide high-resolution imaging. Also, there is increasing availability of mouse models of human diseases, such as cancer, atherosclerosis and neurological diseases.76-83
Current applications of molecular imaging
Translational molecular imaging brings promising experimental therapies and diagnostic tests to the clinic, after extensive evaluation in experimental models. Frequently used modalities include PET and SPECT, as well as a few MRI applications. Optical techniques and ultrasound applications remain of limited use (for reasons outlined previously) but they retain high potential. For example, fluorescence imaging is being investigated as an enhancement of fiber-optic detection of colon cancer.84,85
FDG is the most widely used molecular imaging agent in oncology. Since its inception as a marker of metabolism in tumor cells, FDG has played a major role in the diagnosis, evaluation and follow-up of different tumors, including lymphoma, lung cancer, brain cancer, head-and-neck tumors, melanoma, and breast cancer (Figure 6).86-108 Unlike normal cells, where glycolysis is inhibited by the presence of oxygen (Pasteur effect),109,110 FDG uptake in tumors is reflective of increased glycolysis, even in the presence of oxygen (aerobic glycolysis or Warburg effect),109 which is facilitated by overexpression of glucose transporters and glycolytic enzymes in malignant cells.111-114
However, FDG-PET has limitations. For example, in brain tumors, FDG use is limited by high background uptake of the tracer, since the brain uses glucose as its main source of energy (Figure 6).115 The use of FDG-PET in prostate cancer is also limited by low tracer uptake of tumor cells which can overlap with uptake in benign prostate hyperplasia (BPH)116-118 and the anatomic location of the prostate gland in close proximity to the urinary bladder.119 Such limitations have instigated the evaluation of alternative molecular and cellular targets, such as amino acid transport, DNA synthesis, fatty acid metabolism and angiogenesis.
Proliferating tumor cells are characterized by increased amino acid transport across the cell membrane120, which can be evaluated using radiolabeled amino acids such as 11C-methionine (MET).120,121 In brain tumors, the superiority of MET over FDG in the evaluation of disease extent, surgical planning, evaluation prior to stereotactic biopsy, follow-up and evaluation for recurrence, has been demonstrated.122-130 This is probably due to the lower background uptake of MET, resulting in higher tumor-to-background ratios and better visualization of the tumor. The main limitation, however, is in the short half-life of 11C prohibiting smooth clinical translation. 18F-labeled amino acids are thus being evaluated, such as 18F-FET,131,132 18F-DOPA133,134 and 18F-ACBC.135,136
DNA synthesis is another molecular imaging target in tumors. Imaging of thymidine kinase 1 (TK1), an enzyme overexpressed during the DNA synthesis phase of the cell cycle, reflects cellular proliferation.137-140 18F-Fluorothymidine (FLT)29,30,141,142 is a radiolabeled nucleoside analog that is phosphorylated by TK1, rendering it unable to leave the cell. FLT has been successfully used in the original evaluation as well as the follow-up and assessment of treatment response in many tumors such as lung cancer143, lymphoma144, head-and-neck cancer145, and breast cancer (Figure 7).146
Besides nuclear medicine techniques, MR applications of molecular imaging in oncology exist, such as the use of coated iron oxide particles to detect metastatic disease in lymph nodes or the liver.23,147-150 When injected systemically, iron oxide particles that are phagocytosed by macrophages are then transported to the lymph nodes. A metastatic lymph node, in which the normal macrophage population has been replaced by tumor cells, will demonstrate partial or no drop in signal, while a normal lymph node, in which the iron particles have localized, will have decreased signal and provide detailed characterization independent of typically accepted size criteria (Figure 5).23
Inflammation and infection
Increased FDG uptake can be seen in infectious/inflammatory conditions since FDG-PET does not target a molecular process that is specific for neoplasia but rather uses the relative increase in glucose metabolism of neoplastic cells over normal parenchymal cells. The main limitation of using FDG in inflammation imaging, thus, is its lack of specificity. In fact, FDG uptake of benign tumors, inflammatory processes and malignant neoplasms can sometimes overlap.151-153
To improve differentiation between neoplastic and infectious/inflammatory processes, multiple molecular imaging targets of infec-tion/inflammation have been evaluated mostly in animals, with few human applications at this point. Examples of human applications include the use of monoclonal antigranulocyte antibodies, such 99mTc-fanolesomab (NeutroSpec®, Palatin Technologies, Cranbury, NJ), which binds the CD15 antigen expressed on neutrophils.154-158 Antibody fragments are slightly more popular due to lower immunogenicity and faster clearance, such as 99mTc-labelled sulesomab (LeukoScan®, Immunomedics Inc., Morris Plains, NJ) which was found to be as accurate as white blood cell scanning in osteomyelitis and soft-tissue infections159,160 as well as prosthetic joint infections.161,162 Radiolabeled antibiotics, on the other hand, have been used to directly target bacteria, rather than reactive cells. The best known is probably 99mTc-ciprofloxacin (Infecton®, DRAXIMAGE, Kirkland, Quebec, Canada)163,164 which has been evaluated in a multitude of infectious entities such as acute cholecystitis,165 spinal infections,166 and abdominal infections.167
Recently, 124I-FIAU168,169 PET-CT has been found to be useful in imaging musculoskeletal bacterial infections.170 In that study, the substrate specificity difference between bacterial TK and the major human TK was exploited to develop a new imaging technique that can detect the presence of viable bacteria (Figure 8).170
Neuroimaging and neurodegeneration
Alzheimer’s dementia (AD) is the most common cause of dementia and earlier diagnosis is sought for more accurate prognosis and education of the patients and their families. Several gene therapy trials are attempting to halt or even reverse progression of AD.171-175 In AD, decreased FDG uptake is seen, reflective of regional impairment of cerebral glucose metabolism, mostly in neocortical association areas, whereas primary visual areas, the sensorimotor cortex, basal ganglia, and cerebellum are relatively well preserved.176 FDG-PET abnormalities however are not pathognomonic of AD. Alternative molecular imaging targets are sought for higher specificity. The most intuitive targets are the pathologic associates of AD, namely neurofibrillary tangles (NFTs) and amyloid plaques (APs). Novel PET and SPECT ligands for NFTs and APs are under investigation, most of which are derived from known histologic staining agents used in AD such as DDNP,177-179 thioflavins S and T180-185, and stilbenes.178,186-188
Perhaps the best known amyloid ligand currently is the 11C-labeled Pittsburgh compound B (PIB). The development of this compound from the initial investigations in mouse models of AD189-191 to the first applications in humans was extraordinarily fast (Figure 9).192-195 In the earliest studies, AD patients showed increased retention of PIB in association cortex areas known to contain large amounts of amyloid deposits in AD, compared with controls.192 However, “cognitively normal” controls with higher-than-normal PIB uptake were noted,196-199 raising the possibility of those subjects being predisposed to develop AD. If this is proven in prospective larger studies, PIB could potentially be a useful diagnostic tool for detection of disease prior to the onset of symptoms, which can help maximize the benefits of therapy. However, PIB suffers from the short physical half-life of 11C such that 18F amyloid-binding derivatives are actively being pursued. Other ligands investigated as AP and NFT markers include 18F-FDDNP,200,201 6-iodo-2-(4’-dimethylamino) phenyl-imidazo[1,2-a]pyridine (IMPY) derivatives,202,203 and 11C-SB-13.204-205
In summary, molecular imaging is undergoing constant change and is rapidly expanding. It spans all current life sciences and is being utilized at the frontiers of modern research. For the clinical radiologist, the future will bring application of molecular imaging techniques into the standard diagnostic workflow. Radiology will continue to be enhanced as knowledge from molecular biology, genomics and proteomics, neuroscience and molecular physiology continues to be integrated into imaging research and, eventually, practice.
- Mankoff DA. A definition of molecular imaging. J Nucl Med. 2007;48:18N, 21N.
- Subramanyam R, Alpert NM, Hoop B, Jr., et al. A model for regional cerebral oxygen distribution during continuous inhalation of 15O2, C15O, and C15O2. J Nucl Med.1978;19:48–53.
- Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.
- Collins FS, Green ED, Guttmacher AE, et al. A vision for the future of genomics research. Nature. 2003;422:835–847.
- Kurdziel KA, Kiesewetter DO, Carson RE, et al. Biodistribution, radiation dose estimates, and in vivo Pgp modulation studies of 18F-paclitaxel in nonhuman primates. J Nucl Med. 2003;44:1330–1339.
- Smith-Jones PM, Solit DB, Akhurst T, et al. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nature Biotechnol. 2004;22:701–706.
- Ginovart N, Galineau L, Willeit M, et al. Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography. J Neurochem. 2006;97:1089–1103.
- Zhang MR, Suzuki K. [18F]Fluoroalkyl agents: Synthesis, reactivity and application for development of PET ligands in molecular imaging. Curr Top Med Chem.2007;7:1817–1828.
- Steiniger B, Kniess T, Bergmann R, et al. Radiolabeled glucocorticoids as molecular probes for imaging brain glucocorticoid receptors by means of positron emission tomography (PET). Mini Rev Med Chem. 2008;8:728–739.
- Kikuchi T, Okamura T, Fukushi K, et al. Cerebral acetylcholinesterase imaging: Development of the radioprobes. Curr Top Med Chem. 2007;7:1790–1809.
- Lee J, Burdette JE, MacRenaris KW, et al. Rational design, synthesis, and biological evaluation of progesterone-modified MRI contrast agents. Chem Biol. 2007;14:824–834.
- Friedman M, Orlova A, Johansson E, et al. Directed evolution to low nanomolar affinity of a tumor-targeting epidermal growth factor receptor-binding affibody molecule. J Mol Biol. 2008;376:1388–1402.
- Humblet V, Lapidus R, Williams LR, et al. High-affinity near-infrared fluorescent small-molecule contrast agents for in vivo imaging of prostate-specific membrane antigen. Mol Imaging. 2005;4:448–462.
- Horti AG, Van Laere K. Development of radioligands for in vivo imaging of type 1 cannabinoid receptors (CB1) in human brain. Curr Pharm Des. 2008;14:3363–3383.
- Doorduin J, de Vries EF, Dierckx RA, Klein HC. PET imaging of the peripheral benzodiazepine receptor: Monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des. 2008;14:3297–3315.
- Schmitz G. Ultrasonic imaging of molecular targets. Basic Res Cardiol. 2008;103:174–181.
- Klibanov AL. Ultrasound molecular imaging with targeted microbubble contrast agents. J Nucl Cardiol. 2007;14:876–884.
- Hernot S, Klibanov AL. Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev. 2008;60:1153–1166.
- Ferrara K, Pollard R, Borden M. Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng. 2007;9:415–447.
- Dayton PA, Rychak JJ. Molecular ultrasound imaging using microbubble contrast agents. Front Biosci. 2007;12:5124–5142.
- Zurkiya O, Chan AW, Hu X. MagA is sufficient for producing magnetic nanoparticles in mammalian cells, making it an MRI reporter. Magn Res Med. 2008;59:1225–1231.
- Kang HW, Josephson L, Petrovsky A, et al. Magnetic resonance imaging of inducible E-selectin expression in human endothelial cell culture. Bioconjug Chem. 2002;13:122–127.
- Feldman AS, McDougal WS, Harisinghani MG. The potential of nanoparticle-enhanced imaging. Urol Oncol. 2008;26:65–73.
- Bulte JW, Zhang S, van Gelderen P, et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: Magnetic resonance tracking of cell migration andmyelination. Proc Natl Aca Sci USA. 1999;96:15256–15261.
- Arbab AS, Yocum GT, Kalish H, et al. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood. 2004;104:1217–1223.
- Watanabe H, Inoue T, Shinozaki T, et al. PET imaging of musculoskeletal tumours with fluorine-18 alpha-methyltyrosine: Comparison with fluorine-18 fluorodeoxyglucose PET. Eur J Nucl Med. 2000;27:1509–1517.
- Ishiwata K, Kubota K, Murakami M, et al. A comparative study on protein incorporation of L-[methyl-3H]methionine, L-[1-14C]leucine and L-2-[18F]fluorotyrosine in tumorbearing mice. Nucl Med Biol. 1993;20(8):895–899.
- Ferner RE, Golding JF, Smith M, et al. [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associatedmalignant peripheral nerve sheath tumours (MPNSTs): A long-term clinical study. Ann Oncol. 2008;19:390–394.
- Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET: Comparison with 18F-FDG. J Nucl Med. 2005;46:945–952.
- Bradbury MS, Hambardzumyan D, Zanzonico PB, et al. Dynamic small-animal PET imaging of tumor proliferation with 3'-deoxy-3'-18F-fluorothymidine in a genetically engineered mouse model of high-grade gliomas. J Nucl Med. 2008;49:422–429.
- Beer AJ, Niemeyer M, Carlsen J, et al. Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET. J Nucl Med. 2008;49:255–259.
- Beer AJ, Grosu AL, Carlsen J, et al. [18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:6610–6616.
- Miller PW, Long NJ, Vilar R, Gee AD. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew Chem Int Ed Engl. 2008;47:8998–9033.
- Zhang H, Tian M, Oriuchi N, et al. 11C-choline PET for the detection of bone and soft tissue tumours in comparison with FDG PET. Nucl Med Commun. 2003;24:273–279.
- Tsuyuguchi N, Ohata K, Morino M, et al. Magnetic resonance imaging and [11C]methyl-L-methionine positron emission tomography of fibrous dysplasia—two case reports. Neurol Medi Chir (Tokyo). 2002;42:341–345.
- Pomper MG, Musachio JL, Zhang J, et al. 11C-MCG: Synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol Imaging. 2002;1:96–101.
- Hammoud DA, Endres CJ, Chander AR, et al. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol. 2005;11: 346–355.
- Kurdziel KA, Figg WD, Carrasquillo JA, et al. Using positron emission tomography 2-deoxy-2-[18F]fluoro-D-glucose, 11CO, and 15O-water for monitoring androgen independent prostate cancer. Mol Imaging Biol. 2003;5:86–93.
- Tjuvajev JG, Stockhammer G, Desai R, et al. Imaging the expression of transfected genes in vivo. Cancer Res. 1995;55:6126–6132.
- Ponomarev V, Doubrovin M, Serganova I, et al. Cytoplasmically retargeted HSV1-tk/GFP reporter gene mutants for optimization of noninvasive molecular-genetic imaging. Neoplasia. 2003;5: 245–254.
- Ponomarev V, Doubrovin M, Shavrin A, et al. A human-derived reporter gene for noninvasive imaging in humans: Mitochondrial thymidine kinase type 2. J Nucl Med. 2007;48:819–826.
- Kang KW, Min JJ, Chen X, Gambhir SS. Comparison of [14C]FMAU, [3H]FEAU, [14C]FIAU, and [3H]PCV for monitoring reporter gene expression of wild type and mutantherpes simplex virus type 1 thymidine kinase in cell culture. Mol Imaging Biol. 2005;7:296–303.
- Kircher MF, Allport JR, Graves EE, et al. In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res. 2003;63:6838–6846.
- Soubret A, Ntziachristos V. Optical Imaging and Tomography. In: Ntziachristos V, Leroy-Willig A, Tavitian B. Textbook of in vivoimaging in vertebrates. Hoboken, NJ: J.Wiley; 2007:149–182.
- Montet X, Figueiredo JL, Alencar H, et al. Tomographic fluorescence imaging of tumor vascular volume in mice. Radiology. 2007;242: 751–758.
- Ntziachristos V, Weissleder R. Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation. Opt Lett. 2001;26:893–895.
- Ntziachristos V, Ripoll J, Wang LV, Weissleder R. Looking and listening to light: The evolution of whole-body photonic imaging. Nat Biotechnol. 2005;23:313–320.
- Shields AF, Price P. In vivo imaging of cancer therapy. Totowa, N.J.: Humana; 2007.
- Moin K, McIntyre OJ, Matrisian LM, Sloane BF. Fluorescent Imaging of Tumors. In: Shields AF, Price P. In vivo imaging of cancer therapy. Totowa, N.J.: Humana;2007:281–302.
- Sosnovik D, Weissleder R. Magnetic resonance and fluorescence based molecular imaging technologies. In: Rudin M. Molecular imaging : Basic principles and applications in biomedical research. London; Imperial College Press: Distributed in the UK by World Scientific; 2005:83–116.
- Bryar TR, Daughney CJ, Knight RJ. Paramagnetic effects of iron(III) species on nuclear magnetic relaxation of fluid protons in porous media. J Magn Reson. 2000;142:74–85.
- Burtea C, Laurent S, Vander Elst L, Muller RN. Contrast agents: Magnetic resonance. Handb Exp Pharmacol. 2008;185:135–65.
- Josephson L, Lewis J, Jacobs P, et al. The effects of iron oxides on proton relaxivity. Magn Reson Imaging. 1988;6:647–53.
- Simon GH, Bauer J, Saborovski O, et al. T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning. Eur Radiol. 2006;16:738–745.
- Tanimoto A, Pouliquen D, Kreft BP, Stark DD. Effects of spatial distribution on proton relaxation enhancement by particulate iron oxide. J Magn Reson Imaging. 1994;4:653–657.
- Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004;17:484–499.
- Beckmann N, Cannet C, Fringeli-Tanner M, et al. Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation. Magn Reson Med. 2003;49:459–467.
- Zhang Y, Dodd SJ, Hendrich KS, et al. Magnetic resonance imaging detection of rat renal transplant rejection by monitoring macrophage infiltration. Kidney Int. 2000;58:1300–1310.
- Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med. 2003;348:2491–2499.
- Sumner JP, Shapiro EM, Maric D, et al. In vivo labeling of adult neural progenitors for MRI with micron sized particles of iron oxide: Quantification of labeled cell phenotype. NeuroImage. 2009;44: 671–678.
- Shapiro EM, Gonzalez-Perez O, Manuel Garcia-Verdugo J, et al. Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain. NeuroImage. 2006;32: 1150–1157.
- Suh JS, Lee JY, Choi YS, et al. Efficient labeling of mesenchymal stem cells using cell permeable magnetic nanoparticles. Biochem Biophys Research Commun. 2009;379:669–675.
- Krejci J, Pachernik J, Hampl A, Dvorák P. In vitro labelling of mouse embryonic stem cells with SPIO nanoparticles. Gen Physiol Biophys. 2008;27:164–173.
- Stuber M, Gilson WD, Schär M, et al. Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with ON-resonant water suppression (IRON). Magn Reson Med. 2007;58:1072–1077.
- Lecomte R. Molecular PET Instrumentation and Imaging Techniques. In: Pomper MG, Gelovani J. Molecular imaging in oncology. New York: Informa Healthcare;2008:67–92.
- Tsui BMW, Wang Y, Mok SP. Molecular SPECT Imaging Instrumentation and Techniques. In: Pomper MG, Gelovani J. Molecular imaging in oncology. New York: Informa
- Rahmim A, Zaidi H. PET versus SPECT: Strengths, limitations and challenges. Nucl Med Commun. 2008;29:193–207.
- De Clerck N, Postmov A. High Resolution X-ray Microtomography: Applications in Biomedical Research. In: Ntziachristos V, Leroy-Willig A, Tavitian B. Textbook of in vivo imaging in vertebrates. Hoboken, NJ: J. Wiley; 2007:57–78.
- Leroy-Willig A, Geldwerth-Feniger D. Nuclear Magnetic Resonance Imaging and Spectroscopy. In: Ntziachristos V, Leroy-Willig A, Tavitian B. Textbook of in vivo imaging in vertebrates. Hoboken, NJ: J. Wiley; 2007:1–56.
- Tavitian B, Trébossen R, Pasqualini R, Dollé F. In Vivo Radiotracer Imaging. In: Ntziachristos V, Leroy-Willig A, Tavitian B. Textbook of in vivo imaging in vertebrates. Hoboken, NJ: J. Wiley; 2007:57–78.
- Riemann B, Schäfers KP, Schober O, Schäfers M. Small animal PET in preclinical studies: Opportunities and challenges. Q J Nucl Med Mol Imaging. 2008;52:215–221.
- Rowland DJ, Cherry SR. Small-animal preclinical nuclear medicine instrumentation and methodology. Semin Nucl Med. 2008;38:209–222.
- Weber DA, Ivanovic M. Ultra-high-resolution imaging of small animals: Implications for preclinical and research studies. J Nucl Cardiol. 1999;6:332–344.
- Moats RA, Velan-Mullan S, Jacobs R, et al. Micro-MRI at 11.7 T of a murine brain tumor model using delayed contrast enhancement. Mol Imaging. 2003;2:150–158.
- Badea CT, Drangova M, Holdsworth DW, Johnson GA. In vivo small-animal imaging using micro-CT and digital subtraction angiography. Phys Medicine Biol. 2008;53:R319–R350.
- Kim CF, Jackson EL, Kirsch DG, et al. Mouse models of human non-small-cell lung cancer: Raising the bar. Cold Spring Harb Symp Quant Biol. 2005;70:241–250.
- Grimm J, Kirsch DG, Windsor SD, et al. Use of gene expression profiling to direct in vivo molecular imaging of lung cancer. Proc Natl Acad Sci USA. 2005;102:14404–14409.
- Kasper S, Smith JA, Jr. Genetically modified mice and their use in developing therapeutic strategies for prostate cancer. J Urol. 2004;172:12–19.
- Raman V, Pathak AP, Glunde K, et al. Magnetic resonance imaging and spectroscopy of transgenic models of cancer. NMR Biomed. 2007;20:186–199.
- Cryan JF, Slattery DA. Animal models of mood disorders: Recent developments. Curr Opin Psychiatry. 2007;20:1–7.
- Wensel TG, Gross AK, Chan F, et al. Rhodopsin-EGFP knock-ins for imaging quantal gene alterations. Vision Res. 2005;45:3445–3453.
- van den Buuse M, Garner B, Gogos A, Kusljic S. Importance of animal models in schizophrenia research. Aust NZ J Psychiatry. 2005;39:550–557.
- Citrin D, Camphausen K. Optical imaging of mice in oncologic research. Expert Rev Anticancer Ther. 2004;4:857–864.
- Chin WW, Thong PS, Bhuvaneswari R, et al. In vivo optical detection of cancer using chlorin e6—polyvinylpyrrolidone induced fluorescence imaging and spectroscopy. BMC Med Imaging. 2009;9:1.
- Funovics MA, Alencar H, Montet X, et al. Simultaneous fluorescence imaging of protease expression and vascularity during murine colonoscopy for colonic lesion characterization. Gastrointest Endosc. 2006;64:589–597.
- Hutchings M, Specht L. PET/CT in the management of haematological malignancies. Eur J Haematol. 2008;80:369–380.
- Lin C, Luciani A, Itti E, et al. Whole body MRI and PET/CT in haematological malignancies. Cancer Imaging. 2007;7:S88–S93.
- Agarwal V, Branstetter BF 4th, Johnson JT. Indications for PET/CT in the head and neck. Otolaryngol Cin North Am. 2008;41:23–49,v.
- Maldonado A, González-Alenda FJ, Alonso M, Sierra JM. PET-CT in clinical oncology. Clin Transl Oncol. 2007;9:494–505.
- Fukui MB, Blodgett TM, Meltzer CC. PET/CT imaging in recurrent head and neck cancer. Semin Ultrasound CT MR. 2003;24:157–163.
- Finger PT, Kurli M, Reddy S, et al. Whole body PET/CT for initial staging of choroidal melanoma. Brit J Ophthalmol. 2005;89:1270–1274.
- Kumar R, Alavi A. Clinical applications of fluorodeoxyglucose—positron emission tomography in the management of malignant melanoma. Curr Opin Oncol. 2005;17):154–159.
- Kent MS, Port JL, Altorki NK. Current state of imaging for lung cancer staging. Thorac Surg Clin. 2004;14:1–13.
- Franzius C, Schober O. Assessment of therapy response by FDG PET in pediatric patients. Q J Nucl Med. 2003;47:41–45.
- Rohren EM, Provenzale JM, Barboriak DP, Coleman RE. Screening for cerebral metastases with FDG PET in patients undergoing whole-body staging of non-central nervous system malignancy. Radiology. 2003;226:181–187.
- Henze M, Mohammed A, Schlemmer H, et al. Detection of tumour progression in the follow-up of irradiated low-grade astrocytomas: Comparison of 3-[123I]iodo-alpha-methyl- L-tyrosine and 99mTc-MIBI SPET. Eur J Nucl Med Mol Imaging. 2002;29:1455–1461.
- Stas M, Stroobants S, Dupont P, et al. 18-FDG PET scan in the staging of recurrent melanoma: Additional value and therapeutic impact. Melanoma Res. 2002;12:479–490.
- De Witte O, Lefranc F, Levivier M, et al. FDG-PET as a prognostic factor in high-grade astrocytoma. J Neurooncol. 2000;49:157–163.
- Heusner TA, Kuemmel S, Umutlu L, et al. Breast cancer staging in a single session: Whole-body PET/CT mammography. J Nucl Med. 2008;49:1215–1222.
- Hayashi M, Murakami K, Oyama T, et al. PET/CT supports breast cancer diagnosis and treatment. Breast cancer. 2008;15:224–230.
- Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med. 2008;49:480–508.
- Rosen EL, Eubank WB, Mankoff DA. FDG PET, PET/CT, and breast cancer imaging. Radiographics. 2007;27:S215–S229.
- Haug A, Tiling R, Sommer HL. FDG-PET and FDG-PET/CT in breast cancer. Recent Results Cancer Res. 2008;170:125–140.
- Kumar R, Lal N, Alavi A. 18F-FDG PET in detecting primary breast cancer. J Nucl Med. 2007;48:1751; author reply 1752.
- Avril N, Adler LP. F-18 fluorodeoxyglucose-positron emission tomography imaging for primary breast cancer and loco-regional staging. Radiol Clinics North Am. 2007;45:645–57, vi.
- Iagaru A, Masamed R, Keesara S, Conti PS. Breast MRI and 18F FDG PET/CT in the management of breast cancer. Ann Nucl Med. 2007;21:33–38.
- Mankoff DA, Eubank WB. Current and future use of positron emission tomography (PET) in breast cancer. J Mammary Gland Biol Neoplasia. 2006;11:125–36.
- Endo K, Oriuchi N, Higuchi T, et al. PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int J Clin Oncol. 2006;11:286–296.
- Lopez-Lazaro M. The Warburg effect: Why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem. 2008;8:305–312.
- Racker E. History of the Pasteur effect and its pathobiology. Mol Cell Biochem. 1974;5:17–23.
- Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–662.
- Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–8930.
- Bui T,Thompson CB. Cancer’s sweet tooth. Cancer Cell. 2006;9:419–420.
- Ashrafian H. Cancer’s sweet tooth: The Janus effect of glucose metabolism in tumorigenesis. Lancet. 2006;367:618–621.
- Wong TZ, van der Westhuizen GJ, Coleman RE. Positron emission tomography imaging of brain tumors. Neuroimaging Clin North Am. 2002;12:615–26.
- Farsad M, Schiavina R, Franceschelli A, et al. Positron-emission tomography in imaging and staging prostate cancer. Cancer Biomark. 2008;4:277–284.
- Ide M. Cancer screening with FDG-PET. Q J Nucl Med Mol Imaging. 2006;50:23–27.
- Effert PJ, Bares R, Handt S, et al. Metabolic imaging of untreated prostate cancer by positron emission tomography with 18fluorine-labeled deoxyglucose. J Urol. 1996;155:994–998.
- Takahashi N, Inoue T, Lee J, et al. The roles of PET and PET/CT in the diagnosis and management of prostate cancer. Oncology. 2007;72:226–233.
- Bénard F, Romsa J, Hustinx R. Imaging gliomas with positron emission tomography and single-photon emission computed tomography. Semin Nucl Med. 2003;33:148–162.
- Tsuyuguchi N, Takami T, Sunada I, et al. Methionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radio-surgery—in malignant glioma. Ann Nucl Med. 2004;18:291–296.
- Pötzi C, Becherer A, Marosi C, et al. [11C] methionine and [18F] fluorodeoxyglucose PET in the follow-up of glioblastoma multiforme. J Neurooncol. 2007;84:305–314.
- Van Laere K, Ceyssens S, Van Calenbergh F, et al. Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: Sensitivity, inter-observer variability and prognostic value. Eur J Nucl Med Mol Imaging. 2005;32:39–51.
- Kim S, Chung JK, Im SH, et al. 11C-methionine PET as a prognostic marker in patients with glioma: Comparison with 18F-FDG PET. Eur J Nucl Med Mol Imaging. 2005;32:52–59.
- Pirotte B, Goldman S, Massager N, et al. Comparison of 18F-FDG and 11C-methionine for PET-guided stereotactic brain biopsy of gliomas. J Nucl Med. 2004;45:1293–1298.
- Giammarile F, Cinotti LE, Jouvet A, et al. High and low grade oligodendrogliomas (ODG): Correlation of amino-acid and glucose uptakes using PET and histological classifications. J Neurooncol. 2004;68:263–274.
- Chung JK, Kim YK, Kim SK, et al. Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Eur J Nucl Med Mol Imaging. 2002;29:176–182.
- De Witte O, Goldberg I, Wikler D, et al. Positron emission tomography with injection of methionine as a prognostic factor in glioma. J Neurosurg. 2001;95:746–750.
- Sasaki M, Kuwabara Y,Yoshida T, et al. A comparative study of thallium-201 SPET, carbon-11 methionine PET and fluorine-18 fluorodeoxyglucose PET for the differentiation of astrocytic tumours. Eur J Nucl Med. 1998;25:1261–1269.
- Ogawa T, Hatazawa J, Inugami A, et al. Carbon-11-methionine PET evaluation of intracerebral hematoma: Distinguishing neoplastic from non-neoplastic hematoma. J Nucl Med. 1995;36:2175–2179.
- Floeth FW, Pauleit D, Sabel M, et al. 18F-FET PET differentiation of ring-enhancing brain lesions. J Nucl Med. 2006;47:776–782.
- Pöpperl G, Kreth FW, Herms J, et al. Analysis of 18F-FET PET for grading of recurrent gliomas: Is evaluation of uptake kinetics superior to standard methods? J Nucl Med. 2006;47:393–403.
- Nanni C, Fanti S, Rubello D. 18F-DOPA PET and PET/CT.J Nucl Med. 2007;48:1577–1579.
- Heiss WD, Wienhard K, Wagner R, et al. F-Dopa as an amino acid tracer to detect brain tumors. J Nucl Med. 1996;37:1180–1182.
- Martarello L, McConathy J, Camp VM, et al. Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC), potential PET ligands for tumor detection. J Med Chem. 2002;45:2250–2259.
- Shoup TM, Olson J, Hoffman JM, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med. 1999;40:331–338.
- Eriksson S, Kierdaszuk B, Munch-Petersen B, et al. Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs. Biochem Biophys Res Commun. 1991;176:586–592.
- Langen P, Etzold G, Hintsche R, Kowollik G. 3'-Deoxy-3'-fluorothymidine, a new selective inhibitor of DNA-synthesis. Acta Biol Med Ger. 1969;23:759–766.
- Munch-Petersen B, Cloos L, Jensen HK, Tyrsted G. Human thymidine kinase 1. Regulation in normal and malignant cells. Adv Enzyme Regul. 1995;35:69–89.
- Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem. 1988;263:8350–8358.
- Saga T, Kawashima H, Araki N, et al. Evaluation of primary brain tumors with FLT-PET: Usefulness and limitations. Clin Nucl Med. 2006;31:774–780.
- Chen W, Delaloye S, Silverman DH, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: A pilot study. J Clin Oncol. 2007;25:4714–4721.
- Ullrich RT, Zander T, Neumaier B, et al. Early detection of erlotinib treatment response in NSCLC by 3′-deoxy-3′-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET). PLoS One. 2008;3:e3908.
- Herrmann K, Wieder HA, Buck AK, et al. Early response assessment using 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin’s lymphoma. Clin Cancer Res. 2007;13:3552–3558.
- Linecker A, Kermer C, Sulzbacher I, et al. Uptake of (18)F-FLT and (18)F-FDG in primary head and neck cancer correlates with survival. Nuklearmedizin. 2008;47:80–85;quiz N12.
- Kenny LM, Vigushin DM, Al-Nahhas A, et al. Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: Evaluation of analytical methods. Cancer Res. 2005;65:10104–10112.
- Memarsadeghi M, Riedl CC, Kaneider A, et al. Axillary lymph node metastases in patients with breast carcinomas: Assessment with nonenhanced versus uspio-enhanced MR imaging. Radiology. 2006;241:367–377.
- Misselwitz B. MR contrast agents in lymph node imaging. Eur J Radiol. 2006;58:375–382.
- Will O, Purkayastha S, Chan C, et al. Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: A meta-analysis. Lancet Oncol. 2006;7:52–60.
- de Vries IJ, Lesterhuis WJ, Barentsz JO, et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol. 2005;23:1407–1413.
- Bonekamp D, Smith JD, Aygun N. Avid FDG uptake in a rapidly enlarging common carotid artery mycotic aneurysm, mimicking lymphadenopathy. Emerg Radiol. 2009;16:383–386.
- van Waarde A, Elsinga PH. Proliferation markers for the differential diagnosis of tumor and inflammation. Curr Pharm Des. 2008;14:3326–3339.
- Rosenbaum SJ, Lind T,Antoch G, Bockisch A. False-positive FDG PET uptake—the role of PET/CT. Eur Radiol. 2006;16:1054–1065.
- Klingensmith WC 3rd, Perlman D, Baum K. Intrapatient comparison of 2-deoxy-2-[F-18]fluoro-D-glucose with positron emission tomography/computed tomography to Tc99m fanolesomab (NeutroSpec) for localization of infection. Mol Imaging Biol. 2007;9:295–299.
- Love C, Palestro CJ. Radionuclide imaging of infection. J Nucl Med Technol. 2004;32:47–57; quiz 58–59.
- Love C, Tronco GG, Palestro CJ. Imaging of infection and inflammation with 99mTc-Fanolesomab. Q J Nucl Med Mol Imaging. 2006;50:113–120.
- Shanthly N, Aruva MR, Zhang K, et al. 99mTc-Fanolesomab: Affinity, pharmacokinetics and preliminary evaluation. Q J Nucl Med Mol Imaging. 2006;50:104–112.
- Tronco GG, Love C, Rini JN, et al. Diagnosing prosthetic vascular graft infection with the antigranulocyte antibody 99mTc-fanolesomab. Nucl Med Commun. 2007;28:297–300.
- Delcourt A, Huglo D, Prangere T, et al. Comparison between Leukoscan (Sulesomab) and Gallium-67 for the diagnosis of osteomyelitis in the diabetic foot. Diabetes Metab. 2005;31:125–133.
- Quigley AM, Gnanasegaran G, Buscombe JR, Hilson AJ. Technetium-99m-labelled sulesomab (LeukoScan) in the evaluation of soft tissue infections. Med Princ Pract. 2008;17:447–52.
- Iyengar KP, Vinjamuri S. Role of 99mTc Sulesomab in the diagnosis of prosthetic joint infections. Nucl Med Commun. 2005;26:489–496.
- Pakos EE, Fotopoulos AD, Stafilas KS, et al. Use of (99m)Tc-sulesomab for the diagnosis of prosthesis infection after total joint arthroplasty. J Int Med Res. 2007;35:474–481.
- Britton KE, Wareham DW, Das SS, et al. Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infecton). J Clin Pathol. 2002;55:817–823.
- Sonmezoglu K, Sonmezoglu M, Halac M, et al. Usefulness of 99mTc-ciprofloxacin (infecton) scan in diagnosis of chronic orthopedic infections: Comparative study with 99mTc-HMPAO leukocyte scintigraphy. J Nucl Med. 2001;42:567–574.
- Choe YM, Choe W, Lee KY, et al. Tc-99m ciprofloxacin imaging in acute cholecystitis. World J Gastroenterol. 2007;13:3249–3252.
- De Winter F, Gemmel F, Van Laere K, et al. 99mTc-ciprofloxacin planar and tomographic imaging for the diagnosis of infection in the postoperative spine: Experience in 48 patients. Eur J Nucl Med Mol Imaging. 2004;31:233–239.
- Artiko V, Davidovic B, Nikolic N, et al. Detection of gastrointestinal and abdominal infections by 99mTc-ciprofloxacin. Hepatogastroenterology. 2005;52:491–495.
- Nimmagadda S, Mangner TJ, Douglas KA, et al. Biodistribution, PET, and radiation dosimetry estimates of HSV-tk gene expression imaging agent 1-(2′-Deoxy-2′-18F-Fluoro-beta-D-arabinofuranosyl)-5-iodouracil in normal dogs. J Nucl Med. 2007;48:655–660.
- Tjuvajev JG, Avril N, Oku T, et al. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res. 1998;58:4333–4341.
- Diaz LA Jr, Foss CA, Thornton K, et al. Imaging of musculoskeletal bacterial infections by [124I]FIAU-PET/CT. PLoS One. 2007;2:e1007.
- Bradbury J. Hope for AD with NGF gene-therapy trial. Lancet Neurol. 2005;4:335.
- Braddock M. Safely slowing down the decline in Alzheimer’s disease: Gene therapy shows potential. Expert Opin Investig Drugs. 2005;14:913–915.
- Poirier J. Apolipoprotein E represents a potent gene-based therapeutic target for the treatment of sporadic Alzheimer’s disease. Alzheimers Dement. 2008;4:S91–S97.
- Tuszynski MH, Blesch A. Nerve growth factor: From animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Prog Brain Res. 2004;146:441–449.
- Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med.
- Trost M, Dhawan V, Feigin A, Eidelberg D. Part II Neuroimaging in neurodegeneration, PET/SPECT. In: Beal MF, Lang AE, Ludolph AC. Neurodegenerative diseases: Neurobiology, pathogenesis, and therapeutics. Cambridge, UK; Cambridge University Press; 2005:253–289.
- Agdeppa ED, Kepe V, Liu J, et al. 2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): Novel diagnostic and therapeutic tools in Alzheimer’s disease. Mol Imaging Biol. 2003;5:404–417.
- Furumoto S, Okamura N, Iwata R, et al. Recent advances in the development of amyloid imaging agents. Curr Top Med Chem. 2007;7:1773–1789.
- Shoghi-Jadid K, Small GW, Agdeppa ED, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:24–35.
- Lockhart A, Ye L, Judd DB, et al. Evidence for the presence of three distinct binding sites for the thioflavin T class of Alzheimer’s disease PET imaging agents on beta-amyloid peptide fibrils. J Biol Chem. 2005;280:7677–7684.
- Solbach C, Uebele M, Reischl G, Machulla HJ. Efficient radiosynthesis of carbon-11 labelled uncharged Thioflavin T derivatives using [11C]methyl triflate for beta-amyloid imaging in Alzheimer’s Disease with PET. Appl Radiat Isot. 2005;62:591–595.
- Thees S, Neumaier B, Glatting G, et al. Radiation dosimetry and biodistribution of the beta-amyloid plaque imaging tracer 11C-BTA-1 in humans. Nuklearmedizin. 2007;46:175–180.
- Toyama H, Ye D, Ichise M, et al. PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2005;32:593–600.
- Wu C, Cai L, Wei J, et al. Lipophilic analogs of thioflavin S as novel amyloid-imaging agents. Curr Alzheimer Res. 2006;3:259–266.
- Wu C, Pike VW, Wang Y.Amyloid imaging: From benchtop to bedside. Curr Top Dev Biol. 2005;70:171–213.
- Ono M, Wilson A, Nobrega J, et al. 11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer’s disease. Nucl Med Biol. 2003;30:565–571.
- Rowe CC, Ackerman U, Browne W, et al. Imaging of amyloid beta in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: Proof of mechanism. Lancet Neurol. 2008;7:129–135.
- Zhang W, Oya S, Kung MP, et al. F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Abeta aggregates in the brain. Nucl Med Biol. 2005;32:799–809.
- Wengenack TM, Curran GL, Poduslo JF. Targeting Alzheimer amyloid plaques in vivo. Nat Biotechnol. 2000;18:868–872.
- Klunk WE, Wang Y, Huang GF, et al. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci. 2001;69:1471–1484.
- Mathis CA, Bacskai BJ, Kajdasz ST, et al. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett. 2002;12:295–298.
- Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–319.
- Lopresti BJ, Klunk WE, Mathis CA, et al. Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: A comparative analysis. J Nucl Med. 2005;46:1959–1972.
- Price JC, Klunk WE, Lopresti BJ, et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab. 2005;25:1528–1547.
- Rabinovici GD, Furst AJ, O’Neil JP, et al. 11C-PIB PET imaging in Alzheimer’s disease and frontotemporal lobar degeneration. Neurology. 2007;68:1205–1212.
- Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509–1517.
- Jack CR Jr, Lowe VJ, Senjem ML, et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain. 2008;131:665–680.
- Pike KE, Savage G, Villemagne VL, et al. Beta-amyloid imaging and memory in non-demented individuals: Evidence for preclinical Alzheimer’sdisease. Brain. 2007;130:2837–2844.
- Villemagne VL, Pike KE, Darby D, et al. Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease. Neuropsychologia. 2008;46:1688–1697.
- Braskie MN, Klunder AD, Hayashi KM, et al. Plaque and tangle imaging and cognition in normal aging and Alzheimer’s disease. Neurobiol Aging. Nov 10, 2008; epub ahead of print.
- Noda A, Murakami Y, Nishiyama S, et al. Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP. Synapse. 2008;62:472–475.
- Newberg AB, Wintering NA, Plössl K, et al. Safety, biodistribution, and dosimetry of 123I-IMPY:A novel amyloid plaque-imaging agent for the diagnosis of Alzheimer’s disease. J Nucl Med. 2006;47:748–754.
- Qu W, Kung MP, Hou C, et al. Radioiodinated aza-diphenylacetylenes as potential SPECT imaging agents for beta-amyloid plaque detection. Bioorg Med Chem Lett. 2007;17):3581–3584.
- Henriksen G, Yousefi BH, Drzezga A, Wester HJ. Development and evaluation of compounds for imaging of beta-amyloid plaque by means of positron emission tomography. Eur J Nucl Med Mol Imaging. 2008;35:S75–S81.
- Verhoeff NP, Wilson AA, Takeshita S, et al. In vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry. 2004;12:584–595.