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Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods

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Abstract

Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug–target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.

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References

  1. M Rudin R Weissleder (2003) ArticleTitleMolecular imaging in drug discovery and development Nat Rev Drug Discov 2 123–131 Occurrence Handle10.1038/nrd1007

    Article  Google Scholar 

  2. JK Nicholson J Connelly JC Lindon et al. (2002) ArticleTitleMetabonomics: A platform for studying drug toxicity and gene function Nat Rev Drug Discov 1 153–161 Occurrence Handle10.1038/nrd728

    Article  Google Scholar 

  3. TF Massoud SS Gambhir (2002) ArticleTitleMolecular imaging in living subjects: Seeing fundamental biological processes in a new light Genes Dev 17 545–580 Occurrence Handle10.1101/gad.1047403

    Article  Google Scholar 

  4. R Weissleder CH Tung U Mahmood et al. (1999) ArticleTitleIn vivo imaging of tumors with protease-activated near-infrared fluorescent probes Nat Biotechnol 17 375–378 Occurrence Handle10.1038/7933

    Article  Google Scholar 

  5. A Becker C Hessenius K Licha et al. (2001) ArticleTitleReceptor-targeted optical imaging of tumors with near-infrared fluorescent ligands Nat Biotechnol 19 327–331 Occurrence Handle10.1038/86707

    Article  Google Scholar 

  6. M Birchler G Neri L Tarli et al. (1999) ArticleTitleInfrared photodetection for the in vivo localisation of phage-derived antibodies directed against angiogenic markers J Immunol Methods 231 239–244 Occurrence Handle10.1016/S0022-1759(99)00160-X

    Article  Google Scholar 

  7. U Mahmood CH Tung A Bogdanov et al. (1999) ArticleTitleNear-infrared optical imaging of protease activity for tumor detection Radiology 213 866–870

    Google Scholar 

  8. CH Tung U Mahmood S Bredow et al. (2000) ArticleTitleIn vivo imaging of proteolytic enzyme activity using a novel molecular reporter Cancer Res 60 4953–4958

    Google Scholar 

  9. C Bremer CH Tung R Weissleder (2001) ArticleTitleIn vivo molecular target assessment of matrix metalloproteinase inhibition Nat Med 7 743–748 Occurrence Handle10.1038/89126

    Article  Google Scholar 

  10. CH Tung Y Lin WK Moon et al. (2002) ArticleTitleA receptor-targeted near-infrared fluorescence probe for in vivo tumor imaging ChemBioChem 3 784–786 Occurrence Handle10.1002/1439-7633(20020802)3:8<784::AID-CBIC784>3.0.CO;2-X

    Article  Google Scholar 

  11. J Chen CH Tung U Mahmood et al. (2002) ArticleTitleIn vivo imaging of proteolytic activity in atherosclerosis Circulation 105 2766–2771 Occurrence Handle10.1161/01.CIR.0000017860.20619.23

    Article  Google Scholar 

  12. P Reimer R Weissleder J Wittenberg et al. (1992) ArticleTitleReceptor-directed contrast agents for MR imaging: Preclinical evaluation with affinity assays Radiology 182 565–569

    Google Scholar 

  13. DA Sipkins K Gijbels FD Tropper et al. (2000) ArticleTitleICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging J Neuroimmunol 104 1–9 Occurrence Handle10.1016/S0165-5728(99)00248-9

    Article  Google Scholar 

  14. DA Sipkins DA Cheresh MR Kazemi et al. (1998) ArticleTitleDetection of tumor angiogenesis in vivo by αv–β3-targeted magnetic resonance imaging Nat Med 4 623–626 Occurrence Handle1:CAS:528:DyaK1cXjtFKgtr4%3D Occurrence Handle9585240

    CAS  PubMed  Google Scholar 

  15. CPK Li S Guccione MD Bednarski (2002) ArticleTitleCombined vascular targeted imaging and therapy: A paradigm for personalized treatment J Cell Biochem (Suppl) 39 605

    Google Scholar 

  16. CPK Li MD Bednarski (2002) ArticleTitleVascular-targeted molecular imaging using functionalized polymerized vesicles J Magn Reson Imaging 16 388–393 Occurrence Handle10.1002/jmri.10174

    Article  Google Scholar 

  17. YCI Chen WR Galpern AL Brownell et al. (1997) ArticleTitleDetection of dopaminergic neurotransmitter activity using pharmacologic MRI: Correlation with PET, microdialysis and behavioural data Magn Reson Med 38 389–398 Occurrence Handle1:CAS:528:DyaK2sXms1Sjtrs%3D Occurrence Handle9339439

    CAS  PubMed  Google Scholar 

  18. T Reese B Bjelke R Porszasz et al. (2000) ArticleTitleRegional brain activation by bicuculline visualized by functional magnetic resonance imaging. Time-resolved assessment of bicuculline-induced changes in local cerebral blood volume using an intravascular contrast agent NMR Biomed 13 43–49 Occurrence Handle10.1002/(SICI)1099-1492(200002)13:1<43::AID-NBM608>3.0.CO;2-S

    Article  Google Scholar 

  19. H Xu SJ Li J Bodurka et al. (2000) ArticleTitleHeroin-induced neuronal activation in rat brain assessed by functional MRI NeuroReport 11 IssueID10 85–92

    Google Scholar 

  20. M Stoeckli P Chaurand DE Hallahan et al. (2001) ArticleTitleImaging mass spectrometry: A new technology for the analysis of protein expression in mammalian tissues Nat Med 7 493–496

    Google Scholar 

  21. M Stoeckli D Staab M Staufenbiel et al. (2002) ArticleTitleMolecular imaging of amyloid beta peptides in mouse brain sections using mass spectrometry Anal Biochem 311 33–39 Occurrence Handle10.1016/S0003-2697(02)00386-X

    Article  Google Scholar 

  22. CH Contag SD Spilman PR Contag et al. (1997) ArticleTitleVisualizing gene expression in living mammals using a bioluminescent reporter Photochem Photobiol 66 523–531

    Google Scholar 

  23. H Carlsen JO Moskau SH Fromm et al. (2002) ArticleTitleIn vivo imaging of NF-κB activity J Immunol 168 1441–1446

    Google Scholar 

  24. P Ciana M Raviscioni P Mussi et al. (2003) ArticleTitleIn-vivo imaging of transcriptionally active estrogen receptors Nat Med 9 82–86

    Google Scholar 

  25. P Roessel Particlevan AH Brand (2002) ArticleTitleImaging into the future: Visualizing gene expression and protein interactions with fluorescent proteins Nat Cell Biol 4 E15–E20 Occurrence Handle10.1038/ncb0102-e15

    Article  Google Scholar 

  26. M Yang E Baranov P Jiang et al. (2000) ArticleTitleWhole-body optical imaging of green fluorescent protein-expressing tumors and metastases Proc Natl Acad Sci U S A 97 1206–1211 Occurrence Handle10.1073/pnas.97.3.1206

    Article  Google Scholar 

  27. M Yang E Baranov AR Moossa et al. (2000) ArticleTitleVisualizing gene expression by whole-body fluorescence imaging Proc Natl Acad Sci U S A 97 12278–12282 Occurrence Handle10.1073/pnas.97.22.12278

    Article  Google Scholar 

  28. M Bouvet J Wang SR Nardin et al. (2002) ArticleTitleReal-time optical imaging of primary tumor growth and multiple metastatic events in a pancreatic cancer orthotopic model Cancer Res 62 1534–1540

    Google Scholar 

  29. A Novak C Guo W Yang (2000) ArticleTitleZ/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision Genesis: J Genet Dev 28 147–155

    Google Scholar 

  30. S Kawamoto H Niwa F Tashiro et al. (2000) ArticleTitleA novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination FEBS Lett 470 263–268 Occurrence Handle10.1016/S0014-5793(00)01338-7

    Article  Google Scholar 

  31. AY Louie MM Huber ET Ahrens et al. (2000) ArticleTitleIn vivo visualization of gene expression using magnetic resonance imaging Nat Biotechnol 18 321–325 Occurrence Handle10.1038/73780

    Article  Google Scholar 

  32. R Weissleder A Moore U Mahmood et al. (2000) ArticleTitleIn vivo magnetic resonance imaging of transgene expression Nat Med 6 351–355 Occurrence Handle10.1038/73219

    Article  Google Scholar 

  33. FG Blankenberg PD Katsikis JF Tait et al. (1998) ArticleTitleIn vivo detection and imaging of phosphatidylserin expression during programmed cell death Proc. Natl Acad Sci U S A 95 6349–6354 Occurrence Handle10.1073/pnas.95.11.6349

    Article  Google Scholar 

  34. M Zhao DA Beauregard L Loizou et al. (2001) ArticleTitleNon-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent Nat Med 7 1241–1244 Occurrence Handle10.1038/nm1101-1241

    Article  Google Scholar 

  35. EA Schellenberger D Hogemann L Josephson et al. (2002) ArticleTitleAnnexin V-CLIO: A nanoparticle for detecting apoptosis by MRI Acad Radiol 9 IssueIDSuppl 2 S310–S311 Occurrence Handle10.1016/S1076-6332(03)80212-X

    Article  Google Scholar 

  36. A Petrovsky E Schellenberger L Josephson et al. (2003) ArticleTitleA. Near-infrared fluorescent imaging of tumor apoptosis Cancer Res 63 1936–1942

    Google Scholar 

  37. B Laxman DE Hall MS Bhojani et al. (2002) ArticleTitleNoninvasive real-time imaging of apoptosis Proc Natl Acad Sci U S A 99 16551–16555 Occurrence Handle10.1073/pnas.252644499

    Article  Google Scholar 

  38. P Ray H Pimenta R Paulmurugan et al. (2002) ArticleTitleNoninvasive quantitative imaging of protein–protein interactions in living subjects Proc Natl Acad Sci U S A 99 3105–3110 Occurrence Handle10.1073/pnas.052710999

    Article  Google Scholar 

  39. GD Luker V Sharma CM Pica et al. (2002) ArticleTitleNoninvasive imaging of protein–protein interactions in living animals Proc Natl Acad Sci U S A 99 6961–6966 Occurrence Handle10.1073/pnas.092022399

    Article  Google Scholar 

  40. BP Eliceiri DA Cheresh (2001) ArticleTitleAdhesion events in angiogenesis Curr Opin Cell Biol 13 563–568 Occurrence Handle10.1016/S0955-0674(00)00252-0

    Article  Google Scholar 

  41. JD Hood M Bednarski R Frausto et al. (2002) ArticleTitleTumor regression by targeted gene delivery to the neovasculature Science 296 2404–2407 Occurrence Handle10.1126/science.1070200

    Article  Google Scholar 

  42. V Dousset C Delalande L Ballarino et al. (1999) ArticleTitleIn-vivo macrophage activity imaging in central nervous system detected by magnetic resonance Magn Reson Med 41 329–333 Occurrence Handle10.1002/(SICI)1522-2594(199902)41:2<329::AID-MRM17>3.0.CO;2-Z

    Article  Google Scholar 

  43. M Rausch P Hiestand D Baumann et al. (2003) ArticleTitleMRI based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE Magn Reson Med 50 309–314 Occurrence Handle10.1002/mrm.10541

    Article  Google Scholar 

  44. M Rausch A Sauter J Frohlich et al. (2001) ArticleTitleDynamic pattern of USPIO enhancement can be observed in macrophages after ischemic brain damage Magn Reson Med 46 1018–1021

    Google Scholar 

  45. M Rausch D Baumann U Neubacher et al. (2002) ArticleTitleIn-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO NMR Biomed 15 278–283 Occurrence Handle10.1002/nbm.770

    Article  Google Scholar 

  46. A Kaim T Wischer T O’Reilly et al. (2002) ArticleTitleMR imaging with ultrasmall superparamagnetic iron oxide particles in experimental soft-tissue infections in rats Radiology 225 808–814

    Google Scholar 

  47. N Beckmann C Cannet M Fringeli-Tanner et al. (2003) ArticleTitleAnalysis of a rat model of kidney transplantation by morphological and functional MRI: Search for early markers of allograft chronic rejection Magn Reson Med 49 459–467 Occurrence Handle10.1002/mrm.10387

    Article  Google Scholar 

  48. N Beckmann R Falk S Zurbrügg et al. (2003) ArticleTitleMacrophage infiltration into the rat knee detected by magnetic resonance imaging in a model of antigen-induced arthritis N Magn Reson Med 49 1047–1055 Occurrence Handle10.1002/mrm.10480

    Article  Google Scholar 

  49. M Hoehn E Kustermann J Blunk et al. (2002) ArticleTitleMonitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat Proc Natl Acad Sci U S A 99 16267–16272 Occurrence Handle10.1073/pnas.242435499

    Article  Google Scholar 

  50. JW Bulte S Zhang P Gelderen Particlevan (1999) ArticleTitleNeurotransplantation of magnetically labeled oligodendrocyte progenitors: Magnetic resonance tracking of cell migration and myelination Proc Natl Acad Sci U S A 96 15256–15261 Occurrence Handle10.1073/pnas.96.26.15256

    Article  Google Scholar 

  51. GL Costa MR Sandora A Nakajima et al. (2001) ArticleTitleAdoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit J Immunol 167 2379–2387

    Google Scholar 

  52. A Nakajima CM Seroogy MR Sandora et al. (2001) ArticleTitleAntigen-specific T-cell-mediated gene therapy in collagen-induced arthritis J Clin Invest 107 1293–1301

    Google Scholar 

  53. A Wetterwald G Pluijm Particlevan der I Que et al. (2002) ArticleTitleOptical imaging of cancer metastasis to bone marrow: A mouse model of minimal residual disease Am J Pathol 160 1143–1153

    Google Scholar 

  54. M Zhao M Yang E Baranov et al. (2001) ArticleTitleSpatial-temporal imaging of bacterial infection and antibiotic response in intact animals Proc Natl Acad Sci U S A 98 9814–9818 Occurrence Handle10.1073/pnas.161275798

    Article  Google Scholar 

  55. C Dijke Particlevan RC Brasch TP Roberts et al. (1996) ArticleTitleMammary carcinoma model: Correlation of macromolecular contrast-enhanced MR imaging characterization of tumor microvasculature and histologic capillary density Radiology 198 813–818 Occurrence Handle8628876

    PubMed  Google Scholar 

  56. E Furman-Haran R Margalit D Grobgeld H Degani (1996) ArticleTitleDynamic contrast-enhanced magnetic resonance imaging reveals stress-induced angiogenesis in MCF7 human breast tumors Proc Natl Acad Sci U S A 93 6247–6251 Occurrence Handle10.1073/pnas.93.13.6247

    Article  Google Scholar 

  57. O Clement C Pradel N Siauve et al. (2002) ArticleTitleAssessing perfusion and capillary permeability changes induced by a VEGF inhibitor in human tumor xenografts using macromolecular MR imaging contrast media Acad Radiol 9 IssueIDSuppl 2 S328–S329 Occurrence Handle10.1016/S1076-6332(03)80219-2

    Article  Google Scholar 

  58. K Turetschek A Preda E Floyd et al. (2002) ArticleTitleMRI monitoring of tumor response to a novel VEGF tyrosine kinase inhibitor in an experimental breast cancer model Acad Radiol 9 IssueIDSuppl 2 S519–S520 Occurrence Handle10.1016/S1076-6332(03)80281-7

    Article  Google Scholar 

  59. JL Evelhoch RJ Gillies GS Karczmar et al. (2000) ArticleTitleApplications of magnetic resonance in model systems: Cancer therapeutics Neoplasia 2 152–165 Occurrence Handle10.1038/sj.neo.7900078

    Article  Google Scholar 

  60. TL Chevenert PE McKeever BD Ross (1997) ArticleTitleMonitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging Clin Cancer Res 3 1457–1466 Occurrence Handle1:STN:280:DyaK1M7htFSrsg%3D%3D Occurrence Handle9815831

    CAS  PubMed  Google Scholar 

  61. TL Chevenert LD Stegman JMG Taylor et al. (2000) ArticleTitleDiffusion magnetic resonance imaging: An early surrogate marker of therapeutic efficacy in brain tumors J Natl Cancer Inst 92 2029–2036 Occurrence Handle1:STN:280:DC%2BD3M3jt1eisQ%3D%3D Occurrence Handle11121466

    CAS  PubMed  Google Scholar 

  62. R Weissleder V Ntziachristos (2003) ArticleTitleShedding light onto live molecular targets Nat Med 9 123–128 Occurrence Handle10.1038/nm0103-123

    Article  Google Scholar 

  63. V Ntziachristos CH Tung C Bremer (2002) ArticleTitleFluorescence molecular tomography resolves protease activity in vivo Nat Med 8 757–760 Occurrence Handle10.1038/nm729

    Article  Google Scholar 

  64. V Ntziachristos R Weissleder (2002) ArticleTitleCharge-coupled-device based scanner for tomography of fluorescent near-infrared probes in turbid media Med Phys 29 803–809 Occurrence Handle10.1118/1.1470209

    Article  Google Scholar 

  65. M Lewin N Carlesso CH Tung et al. (2000) ArticleTitleTat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells Nat Biotechnol 18 410–414 Occurrence Handle10.1038/74464 Occurrence Handle1:CAS:528:DC%2BD3cXis1Gmt7s%3D Occurrence Handle10748521

    Article  CAS  PubMed  Google Scholar 

  66. JF Poduslo TM Wengenack GL Curran et al. (2002) ArticleTitleMolecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging Neurobiol Dis 11 315–329

    Google Scholar 

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  1. DTC/Analytical and Imaging Sciences, Novartis Institute for Biomedical Research, WSJ-386.2.02, CH-4002, Basel, Switzerland

    Markus Rudin PhD, Martin Rausch & Markus Stoeckli

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  1. Markus Rudin PhD
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  2. Martin Rausch
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Correspondence to Markus Rudin PhD.

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Rudin, M., Rausch, M. & Stoeckli, M. Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods. Mol Imaging Biol 7, 5–13 (2005). https://doi.org/10.1007/s11307-004-0954-z

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