Review

Nanoprobes for hybrid SPECT/MR molecular imaging

Ripen Misri

Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

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Katayoun Saatchi

Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada

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Urs O Häfeli

* Author for correspondence

Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.

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Email the corresponding author at urs.hafeli@ubc.ca

Published Online:25 May 2012https://doi.org/10.2217/nnm.12.32

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Abstract

Hybrid imaging techniques provide enhanced visualization of biological targets by synergistically combining multiple imaging modalities, thereby providing information on specific aspects of structure and function, which is difficult to obtain by a single imaging modality. Advances in the field of hybrid imaging have resulted in the recent approval of PET/magnetic resonance (MR) imaging by the US FDA for clinical use in the USA and Europe. Single-photon emission computed tomography (SPECT)/MR imaging is another evolving hybrid imaging modality with distinct advantages. Recently reported progress in the development of a SPECT/MR imaging hybrid scanner provides a cue towards the need for multimodal SPECT/MR imaging nanoprobes to take full advantage of a scanner’s simultaneous imaging capability. In this review, we present some of the latest developments in the domain of SPECT/MR hybrid imaging, particularly focusing on multimodal nanoprobes.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1 Jennings LE, Long NJ. ‘Two is better than one’ – probes for dual-modality molecular imaging. Chem. Commun. (Camb.) (24),3511–3524 (2009).▪ Provides the rationale for hybrid imaging as well as presenting an overview of the progress in the application of dual-modality molecular imaging probes.Crossref, Medline, Google Scholar
2 Delbeke D, Schoder H, Martin WH, Wahl RL. Hybrid imaging (SPECT/CT and PET/CT): improving therapeutic decisions. Semin. Nucl. Med.39(5),308–340 (2009).Crossref, Medline, Google Scholar
3 Bockisch A, Freudenberg LS, Schmidt D, Kuwert T. Hybrid imaging by SPECT/CT and PET/CT: proven outcomes in cancer imaging. Semin. Nucl. Med.39(4),276–289 (2009).Crossref, Medline, Google Scholar
4 Antoch G, Bockisch A. Combined PET/MRI: a new dimension in whole-body oncology imaging? Eur. J. Nucl. Med. Mol. Imaging36(Suppl. 1),S113–S120 (2009).Crossref, Medline, Google Scholar
5 Pichler BJ, Judenhofer MS, Wehrl HF. PET/MRI hybrid imaging: devices and initial results. Eur. Radiol.18(6),1077–1086 (2008).Crossref, Medline, Google Scholar
6 Fatemi-Ardekani A, Samavati N, Tang J, Kamath MV. Advances in multimodality imaging through a hybrid PET/MRI system. Crit. Rev. Biomed. Eng.37(6),495–515 (2009).Crossref, Medline, Google Scholar
7 Cook GJ. Oncological molecular imaging: nuclear medicine techniques. Br. J. Radiol.76(Spec No. 2),S152–S158 (2003).Crossref, Medline, CAS, Google Scholar
8 Patel CN, Chowdhury FU, Scarsbrook AF. Hybrid SPECT/CT: the end of ‘unclear’ medicine. Postgrad. Med. J.85(1009),606–613 (2009).Crossref, Medline, CAS, Google Scholar
9 Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP. MRI detection of single particles for cellular imaging. Proc. Natl Acad. Sci. USA101(30),10901–10906 (2004).Crossref, Medline, CAS, Google Scholar
10 Zhou SA, Brahme A. Development of high-resolution molecular phase-contrast stereoscopic X-ray imaging for accurate cancer diagnostics. Radiat. Prot. Dosimetry139(1–3),334–338 (2010).Crossref, Medline, CAS, Google Scholar
11 Gallagher FA. An introduction to functional and molecular imaging with MRI. Clin. Radiol.65(7),557–566 (2010).Crossref, Medline, CAS, Google Scholar
12 Dafni H, Landsman L, Schechter B, Kohen F, Neeman M. MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor. NMR Biomed.15(2),120–131 (2002).Crossref, Medline, CAS, Google Scholar
13 Weissleder R, Moore A, Mahmood U et al.In vivo magnetic resonance imaging of transgene expression. Nat. Med.6(3),351–355 (2000).Crossref, Medline, CAS, Google Scholar
14 Dodd SJ, Williams M, Suhan JP, Williams DS, Koretsky AP, Ho C. Detection of single mammalian cells by high-resolution magnetic resonance imaging. Biophys. J.76(1 Pt 1),103–109 (1999).Crossref, Medline, CAS, Google Scholar
15 Hamamura MJ, Ha S, Roeck WW et al. Development of an MR-compatible SPECT system (MRSPECT) for simultaneous data acquisition. Phys. Med. Biol.55(6),1563–1575 (2010).Crossref, Medline, Google Scholar
16 Thakur ML. Genomic biomarkers for molecular imaging: predicting the future. Semin. Nucl. Med.39(4),236–246 (2009).Crossref, Medline, Google Scholar
17 Mishani E, Hagooly A. Strategies for molecular imaging of epidermal growth factor receptor tyrosine kinase in cancer. J. Nucl. Med.50(8),1199–1202 (2009).Crossref, Medline, CAS, Google Scholar
18 Dobrucki LW, De Muinck ED, Lindner JR, Sinusas AJ. Approaches to multimodality imaging of angiogenesis. J. Nucl. Med.51(Suppl. 1),S66–S79 (2010).Crossref, Medline, Google Scholar
19 Dunn BK, Wagner PD, Anderson D, Greenwald P. Molecular markers for early detection. Semin. Oncol.37(3),224–242 (2010).Crossref, Medline, CAS, Google Scholar
20 Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer45(2),228–247 (2009).Crossref, Medline, CAS, Google Scholar
21 Catana C, Procissi D, Wu Y et al. Simultaneous in vivo positron emission tomography and magnetic resonance imaging. Proc. Natl Acad. Sci. USA105(10),3705–3710 (2008).Crossref, Medline, CAS, Google Scholar
22 Wehrl HF, Judenhofer MS, Wiehr S, Pichler BJ. Pre-clinical PET/MR: technological advances and new perspectives in biomedical research. Eur. J. Nucl. Med. Mol. Imaging36(Suppl. 1),S56–S68 (2009).Crossref, Medline, Google Scholar
23 Boss A, Bisdas S, Kolb A et al. Hybrid PET/MRI of intracranial masses: initial experiences and comparison to PET/CT. J. Nucl. Med.51(8),1198–1205 (2010).Crossref, Medline, Google Scholar
24 Mcelroy DP, Saveliev V, Reznik A, Rowlands JA. Evaluation of silicon photomultipliers: a promising new detector for MR compatible PET. Nucl. Instrum. Meth. A.571(1–2),106–109 (2007).Crossref, CAS, Google Scholar
25 Nafziger B. FDA clears first PET-MRI scanner. DotMed News, 10 June (2011).Google Scholar
26 Wagenaar DJ, Kapusta M, Li J, Patt BE. Rationale for the combination of nuclear medicine with magnetic resonance for pre-clinical imaging. Technol. Cancer Res. Treat.5(4),343–350 (2006).Crossref, Medline, Google Scholar
27 Meier D, Wagenaar DJ, Chen S, Xu J, Yu J, Tsui BM. A SPECT camera for combined MRI and SPECT for small animals. Nucl. Instrum. Methods Phys. Res. A.652(1),731–734 (2011).▪▪ Describes a magnetic resonance (MR)-compatible SPECT camera for small animals.Crossref, Medline, CAS, Google Scholar
28 Torres Martin De Rosales R, Tavare R, Glaria A, Varma G, Protti A, Blower PJ. ^99mTc-bisphosphonate-iron oxide nanoparticle conjugates for dual-modality biomedical imaging. Bioconjug. Chem.22(3),455–465 (2011).▪▪ Describes a new strategy for developing SPECT/PET-MR imaging agents in which the bisphosphonate group could be used to attach functionality to provide targeting, stealth/stability and radionuclides to Fe3O4 nanoparticles using a very simple methodology.Crossref, Medline, Google Scholar
29 Rodriguez E, Chen JW. Molecular imaging: basic approaches. In: Imaging in CNS Drug Discovery and Development. Borsook D, Beccera LR, Bullmore E, Hargreaves RJ (Eds). Springer, NY, USA, 105–119 (2009).Google Scholar
30 Liu Y, Wu C. Radiolabeling of monoclonal antibodies with metal chelates. Pure Appl. Chem.63(2),427–463 (1991).Crossref, CAS, Google Scholar
31 Mahmood A, Jones AG. Technetium radiopharmaceuticals. In: Handbook of Radiopharmaceuticals: Radiochemistry and Applications. Welch MJ, Redvanly CS (Eds). John Wiley & Sons, West Sussex, UK, 323–362 (2003).Google Scholar
32 Halpern SE. The advantages and limits of indium-111 labeling of antibodies. Experimental studies and clinical applications. Int. J. Rad. Appl. Instrum. B.13(2),195–201 (1986).Crossref, Medline, CAS, Google Scholar
33 Shiga H, Taki J, Yamada M et al. Evaluation of the olfactory nerve transport function by SPECT-MRI fusion image with nasal thallium-201 administration. Mol. Imaging Biol.13(6),1262–1266 (2011).Crossref, Medline, Google Scholar
34 Goetz C, Breton E, Choquet P, Israel-Jost V, Constantinesco A. SPECT low-field MRI system for small-animal imaging. J. Nucl. Med.49(1),88–93 (2008).Crossref, Medline, Google Scholar
35 Gianolio E, Maciocco L, Imperio D et al. Dual MRI-SPECT agent for pH-mapping. Chem. Commun. (Camb.)47(5),1539–1541 (2011).Crossref, Medline, CAS, Google Scholar
36 Cutler CS, Smith CJ, Ehrhardt GJ, Tyler TT, Jurisson SS, Deutsch E. Current and potential therapeutic uses of lanthanide radioisotopes. Cancer Biother. Radiopharm.15,531–545 (2000).Crossref, Medline, CAS, Google Scholar
37 Liu S, Edwards DS. Bifunctional chelators for therapeutic lanthanide radiopharmaceuticals. Bioconjug. Chem.12,7–34 (2001).Crossref, Medline, Google Scholar
38 Knapp FF Jr. Rhenium-188 – a generator-derived radioisotope for cancer therapy. Cancer Biother. Radiopharm.13(5),337–349 (1998).Crossref, Medline, CAS, Google Scholar
39 Van Gog FB, Visser GW, Stroomer JW, Roos JC, Snow GB, Van Dongen GA. High dose rhenium-186-labeling of monoclonal antibodies for clinical application: pitfalls and solutions. Cancer80(Suppl. 12),2360–2370 (1997).Crossref, Medline, CAS, Google Scholar
40 Aime S, Nano R, Grandi M. A new class of contrast agents for magnetic resonance imaging based on selective reduction of water-T2 by chemical exchange. Invest. Radiol.23(Suppl. 1),S267–S270 (1988).Crossref, Medline, CAS, Google Scholar
41 Laurent S, Forge D, Port M et al. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev.108(6),2064–2110 (2008).Crossref, Medline, CAS, Google Scholar
42 Kinoshita M, Yoshioka Y, Okita Y, Hashimoto N, Yoshimine T. MR molecular imaging of HER-2 in a murine tumor xenograft by SPIO labeling of anti-HER-2 affibody. Contrast Media Mol. Imaging5(1),18–22 (2010).Medline, CAS, Google Scholar
43 Glaus C, Rossin R, Welch MJ, Bao G. In vivo evaluation of (64)Cu-labeled magnetic nanoparticles as a dual-modality PET/MR imaging agent. Bioconjug. Chem.21(4),715–722 (2010).Crossref, Medline, CAS, Google Scholar
44 Weissleder R, Kelly K, Sun EY, Shtatland T, Josephson L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol.23(11),1418–1423 (2005).Crossref, Medline, CAS, Google Scholar
45 Weissleder R, Lee AS, Fischman AJ et al. Polyclonal human immunoglobulin G labeled with polymeric iron oxide: antibody MR imaging. Radiology181(1),245–249 (1991).Crossref, Medline, CAS, Google Scholar
46 Weissleder R, Lee AS, Khaw BA, Shen T, Brady TJ. Antimyosin-labeled monocrystalline iron oxide allows detection of myocardial infarct: MR antibody imaging. Radiology182(2),381–385 (1992).Crossref, Medline, CAS, Google Scholar
47 Lee JH, Sherlock SP, Terashima M et al. High-contrast in vivo visualization of microvessels using novel FeCo/GC magnetic nanocrystals. Magn. Reson. Med.62(6),1497–1509 (2009).Crossref, Medline, Google Scholar
48 Yang H, Zhang C, Shi X et al. Water-soluble superparamagnetic manganese ferrite nanoparticles for magnetic resonance imaging. Biomaterials31(13),3667–3673 (2010).Crossref, Medline, CAS, Google Scholar
49 Tromsdorf UI, Bigall NC, Kaul MG et al. Size and surface effects on the MRI relaxivity of manganese ferrite nanoparticle contrast agents. Nano Lett.7(8),2422–2427 (2007).Crossref, Medline, CAS, Google Scholar
50 Tanimoto A, Kuribayashi S. Application of superparamagnetic iron oxide to imaging of hepatocellular carcinoma. Eur. J. Radiol.58(2),200–216 (2006).Crossref, Medline, Google Scholar
51 Jain TK, Foy SP, Erokwu B, Dimitrijevic S, Flask CA, Labhasetwar V. Magnetic resonance imaging of multifunctional pluronic stabilized iron-oxide nanoparticles in tumor-bearing mice. Biomaterials30(35),6748–6756 (2009).Crossref, Medline, CAS, Google Scholar
52 Berry CC, Curtis ASG. Functionalisation of magnetic nanoparticles for applications in biomedicine. J. Phys. D. Appl. Phys.36,R198–R206 (2003).Crossref, CAS, Google Scholar
53 Kobukai S, Baheza R, Cobb JG et al. Magnetic nanoparticles for imaging dendritic cells. Magn. Reson. Med.63(5),1383–1390 (2010).Crossref, Medline, Google Scholar
54 Lind K, Kresse M, Debus NP, Muller RH. A novel formulation for superparamagnetic iron oxide (SPIO) particles enhancing MR lymphography: comparison of physicochemical properties and the in vivo behavior. J. Drug Target10(3),221–230 (2002).Crossref, Medline, CAS, Google Scholar
55 Guardia P, Perez N, Labarta A, Batlle X. Controlled synthesis of iron oxide nanoparticles over a wide size range. Langmuir26(8),5843–5847 (2010).Crossref, Medline, CAS, Google Scholar
56 Wen G, Zhang XL, Chang RM, Xia Q, Cang P, Zhang Y. Superparamagnetic iron oxide (Feridex)-enhanced MRI in diagnosis of focal hepatic lesions. Di Yi Jun Yi Da Xue Xue Bao22(5),451–452 (2002).Medline, Google Scholar
57 Wang YX, Hussain SM, Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur. Radiol.11(11),2319–2331 (2001).Crossref, Medline, CAS, Google Scholar
58 Bligh SW, Sadler PJ, Marriott JA, Latham IA, Kelly JD. Characterization and in vivo distribution of 99mTc- and 111In-labeled magnetite. Int. J. Rad. Appl. Instrum. A.40(9),751–757 (1989).Crossref, Medline, CAS, Google Scholar
59 Lewin M, Carlesso N, Tung CH et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol.18(4),410–414 (2000).▪ Describes a cell labeling approach using short HIV-Tat peptides to derivatize superparamagnetic nanoparticles. The authors developed imaging probes capable of concomitant imaging by MR, SPECT and optical imaging.Crossref, Medline, CAS, Google Scholar
60 Lee CM, Jeong HJ, Kim EM et al. Superparamagnetic iron oxide nanoparticles as a dual imaging probe for targeting hepatocytes in vivo.Magn. Reson. Med.62(6),1440–1446 (2009).Crossref, Medline, CAS, Google Scholar
61 Kaufner L, Cartier R, Wüstneck R et al. Poly(ethylene oxide)- block -poly(glutamic acid) coated maghemite nanoparticles: in vitro characterization and in vivo behavior. Nanotechnology18(11),115710 (2007).Crossref, Google Scholar
62 Baio G, Fabbi M, Salvi S et al. Two-step in vivo tumor targeting by biotin-conjugated antibodies and superparamagnetic nanoparticles assessed by magnetic resonance imaging at 1.5 T. Mol. Imaging Biol.12(3),305–315 (2010).Crossref, Medline, Google Scholar
63 Gao X, Cui Y, Levenson RM, Chung LW, Nie S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol.22(8),969–976 (2004).Crossref, Medline, CAS, Google Scholar
64 Liu S, Jia B, Qiao R et al. A novel type of dual-modality molecular probe for MR and nuclear imaging of tumor: preparation, characterization and in vivo application. Mol. Pharm.6(4),1074–1082 (2009).Crossref, Medline, CAS, Google Scholar
65 Otsuji E, Kuriu Y, Okamoto K et al. Monoclonal antibody A7 coupled to magnetic particles as a contrast enhancing agent for magnetic resonance imaging of human colorectal carcinoma. Cancer Immunol. Immunother.55(6),728–733 (2006).Crossref, Medline, CAS, Google Scholar
66 West SD, Lee YC. Management of malignant pleural mesothelioma. Clin. Chest Med.27(2),335–354 (2006).Crossref, Medline, Google Scholar
67 Renshaw AA, Dean BR, Antman KH, Sugarbaker DJ, Cibas ES. The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Chest111(1),106–109 (1997).Crossref, Medline, CAS, Google Scholar
68 Pakzad F, Groves AM, Ell PJ. The role of positron emission tomography in the management of pancreatic cancer. Semin. Nucl. Med.36(3),248–256 (2006).Crossref, Medline, Google Scholar
69 Buy JN, Ghossain MA, Sciot C et al. Epithelial tumors of the ovary: CT findings and correlation with US. Radiology178(3),811–818 (1991).Crossref, Medline, CAS, Google Scholar
70 Patz EF Jr, Rusch VW, Heelan R. The proposed new international TNM staging system for malignant pleural mesothelioma: application to imaging. AJR Am. J. Roentgenol.166(2),323–327 (1996).Crossref, Medline, Google Scholar
71 Misri R, Meier D, Yung A, Kozlowski P, Hafeli UO. Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobe. Nanomedicine doi:org/10.1016/j.nano.2011.10.013 (2011) (Epub ahead of print).▪▪ Describes the development of dual-modality molecular imaging bioprobes, in the form of magnetic nanoparticles conjugated to radiolabeled antibodies, for tumor-specific SPECT and MR imaging.Medline, Google Scholar
72 Argani P, Iacobuzio-Donahue C, Ryu B et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin. Cancer Res.7(12),3862–3868 (2001).Medline, CAS, Google Scholar
73 Muminova ZE, Strong TV, Shaw DR. Characterization of human mesothelin transcripts in ovarian and pancreatic cancer. BMC Cancer4,19 (2004).Crossref, Medline, Google Scholar
74 Yokokawa J, Palena C, Arlen P et al. Identification of novel human CTL epitopes and their agonist epitopes of mesothelin. Clin. Cancer Res.11(17),6342–6351 (2005).Crossref, Medline, CAS, Google Scholar
75 Misri R, Saatchi K, Ng SSW, Kumar U, Häfeli UO. Evaluation of 111In labeled antibodies for SPECT imaging of mesothelin expressing tumors. Nucl. Med. Biol.38(6),885–896 (2011).Crossref, Medline, CAS, Google Scholar
76 Lijowski M, Caruthers S, Hu G et al. High sensitivity: high-resolution SPECT-CT/MR molecular imaging of angiogenesis in the Vx2 model. Invest. Radiol.44(1),15–22 (2009).Crossref, Medline, CAS, Google Scholar
77 Kryza D, Taleb J, Janier M et al. Biodistribution study of nanometric hybrid gadolinium oxide particles as a multimodal SPECT/MR/optical imaging and theragnostic agent. Bioconjug. Chem.22(6),1145–1152 (2011).▪ Demonstrates the multimodal imaging properties of a gadolinium-based T1 contrast agent.Crossref, Medline, CAS, Google Scholar
78 Zielhuis SW, Seppenwoolde JH, Mateus VA et al. Lanthanide-loaded liposomes for multimodality imaging and therapy. Cancer Biother. Radiopharm.21(5),520–527 (2006).Crossref, Medline, CAS, Google Scholar
79 Koning GA, Fretz MM, Woroniecka U, Storm G, Krijger GC. Targeting liposomes to tumor endothelial cells for neutron capture therapy. Appl. Radiat. Isot.61(5),963–967 (2004).Crossref, Medline, CAS, Google Scholar
80 O’Connor JP, Jackson A, Parker GJ, Jayson GC. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br. J. Cancer96(2),189–195 (2007).Crossref, Medline, Google Scholar
81 Tofts PS, Brix G, Buckley DL et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J. Magn. Reson. Imaging10(3),223–232 (1999).Crossref, Medline, CAS, Google Scholar
82 Saatchi K, Soema P, Gelder N et al. Hyperbranched polyglycerols as trimodal imaging agents: design, biocompatibility and tumor uptake. Bioconjug. Chem.23(3),372–381 (2011).Crossref, Google Scholar
83 Maeda H. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug. Chem.21(5),797–802 (2010).Crossref, Medline, CAS, Google Scholar
84 Koba W, Kim K, Lipton ML et al. Imaging devices for use in small animals. Semin. Nucl. Med.41(3),151–165 (2011).Crossref, Medline, Google Scholar
85 Wall JS, Richey T, Williams A et al. Comparative analysis of peptide p5 and serum amyloid P component for imaging AA amyloid in mice using dual-isotope SPECT. Mol. Imaging Biol. doi:10.1007/s11307-011-0524-0 (2011).Google Scholar
86 Ducharme J, Goertzen AL, Patterson J, Demeter S. Practical aspects of ¹⁸F-FDG PET when receiving 18F-FDG from a distant supplier. J. Nucl. Med. Technol.37(3),164–169 (2009).Crossref, Medline, Google Scholar
87 Breeman WA, Verbruggen AM. The 68Ge/68Ga generator has high potential, but when can we use 68Ga-labeled tracers in clinical routine? Eur. J. Nucl. Med. Mol. Imaging34(7),978–981 (2007).Crossref, Medline, Google Scholar
88 National Research Council (US) and Institute of Medicine (US) Committee on State of the Science of Nuclear Medicine. Availability of radionuclides for nuclear medicine research. In: Advancing Nuclear Medicine Through Innovation. National Academies Press, Washington, DC, USA (2007).Google Scholar
101 Philips receives FDA clearance to market its first whole body PET/MR imaging system in the United States. www.multivu.com/mnr/53109-philips-fda-clearance-market-whole-body-pet-mr-imaging-systemGoogle Scholar

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Published online 25 May 2012

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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