Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular imaging in drug discovery and development

Nature Reviews Drug Discovery volume 2, pages 123–131 (2003)Cite this article

Key Points

  • Imaging technologies exploit the interaction of various forms of energy with tissues to non-invasively visualize the body.

  • Many imaging techniques were originally developed for human use, but have recently been scaled-down to allow the high-resolution imaging of mice. This is highly relevant, because as genomics provides us with better animal models of disease, imaging readouts can be used to evaluate novel therapeutics.

  • Imaging methods offer several advantages over other current practices in drug discovery, examples of which are discussed in this article:

  • The use of imaging endpoints instead of time-consuming dissection and histology can significantly decrease the workload involved in tissue analysis and thereby speed up the evaluation of drug candidates.

  • Imaging can provide biomarkers of a disease process and thus help to define stratified study groups.

  • As imaging methods are non-invasive, they allow for longitudinal studies in a single animal. This increases the statistical relevance of a study, allows for more clinically relevant study designs and decreases the number of animals required.

  • Imaging can also provide important information on the optimal timing and dosing of drugs.

  • Emerging molecular-imaging tools can provide much earlier surrogate markers of therapy success than is currently possible.

Abstract

Imaging sciences have grown exponentially during the past three decades, and many techniques, such as magnetic resonance imaging, nuclear tomographic imaging and X-ray computed tomography, have become indispensable in clinical use. Advances in imaging technologies and imaging probes for humans and for small animals are now extending the applications of imaging further into drug discovery and development, and have the potential to considerably accelerate the process. This review summarizes some of the recent developments in conventional and molecular imaging, and highlights their impact on drug discovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Structural and functional imaging.
Figure 3: Imaging drug pharmacokinetics and pharmacodynamics.
Figure 4: Fluorescence molecular imaging.

Similar content being viewed by others

References

  1. Weissleder, R. Scaling down imaging: molecular mapping of cancer in mice. Nature Rev. Cancer 2, 11–18 (2002). Review of in vivo mouse imaging technologies.

    Article  CAS  Google Scholar 

  2. Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nature Med. 9, 123–128 (2003). This manuscript reviews emerging novel optical in vivo imaging technologies.

    Article  CAS  PubMed  Google Scholar 

  3. Rudin, M. et al. In vivo magnetic resonance methods in pharmaceutical research: current status and perspectives. NMR Biomed. 12, 69–97 (1999). Review of MR technologies in drug development.

    Article  CAS  PubMed  Google Scholar 

  4. Beckmann, N., Mueggler, T., Allegrini, P. R., Laurent, D. & Rudin, M. From anatomy to the target: contributions of magnetic resonance imaging to preclinical pharmaceutical research. Anat. Rec. 265, 85–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Jain, R. K., Munn, L. L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nature Rev. Cancer 2, 266–276 (2002).

    Article  CAS  Google Scholar 

  6. Phelps, M. E. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc. Natl Acad. Sci. USA 97, 9226–9233 (2000). Review of PET imaging applications.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fischman, A. J., Alpert, N. M. & Rubin, R. H. Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action. Clin. Pharmacokinet. 41, 581–602 (2002). Review of the role of PET in the study of drug pharmacokinetics.

    Article  CAS  PubMed  Google Scholar 

  8. Reese, T., Bochelen, D., Sauter, A., Beckmann, N. & Rudin, M. Magnetic resonance angiography of the rat cerebrovascular system without the use of contrast agents. NMR Biomed. 12, 189–196 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Villringer, A. et al. Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects. Magn. Reson. Med. 6, 164–174 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Roussel, S. A., van Bruggen, N., King, M. D. & Gadian, D. G. Identification of collaterally perfused areas following focal cerebral ischemia in the rat by comparison of gradient echo and diffusion-weighted MRI. J. Cereb. Blood Flow Metab. 15, 578–586 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Moseley, M., Wendland, M. & Kucharczyk, J. Magnetic resonance imaging of diffusion and perfusion. Top. Magn. Reson. Imaging 3, 50–67 (1991).

    CAS  PubMed  Google Scholar 

  12. Sauter, A. & Rudin, M. Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging. Stroke 17, 1228–1234 (1986).

    Article  CAS  PubMed  Google Scholar 

  13. Rausch, M., Baumann, D., Neubacher, U. & Rudin, M. In vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO. NMR Biomed. 15, 278–283 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Sauter, A. et al. Recovery of function in cytoprotected cerebral cortex in rat stroke model assessed by functional MRI. Magn. Reson. Med. 47, 759–765 (2002).

    Article  PubMed  Google Scholar 

  15. Cristofanilli, M., Charnsangavej, C. & Hortobagyi, G. N. Angiogenesis modulation in cancer research: novel clinical approaches. Nature Rev. Drug Discov. 1, 415–426 (2002).

    Article  CAS  Google Scholar 

  16. Tatum, J. L. & Hoffman, J. M. Role of imaging in clinical trials of antiangiogenesis therapy in oncology. Acad. Radiol. 7, 798–799 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Bhujwalla, Z. M. et al. The physiological environment in cancer vascularization, invasion and metastasis. Novartis Found Symp. 240, 23–38; discussion 38-45, 152-153, (2001).

    CAS  PubMed  Google Scholar 

  18. Lewin, M. et al. In vivo assessment of vascular endothelial growth factor-induced angiogenesis. Int. J. Cancer 83, 798–802 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Petrovsky, A., Weissleder, W., Shalinsky, D., Hu-Lowe, D. & Bogdanov, A. Non-invasive magnetic resonance imaging (MRI) of vascular parameters affected by VEGF–receptor tyrosine kinase inhibition in a human xenograft model. Proc. Am. Assoc. Cancer Res. 43, 1081 (2002).

    Google Scholar 

  20. Peterfy, C. G. Magnetic resonance imaging of rheumatoid arthritis: the evolution of clinical applications through clinical trials. Semin. Arthritis Rheum. 30, 375–396 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. McConnell, M. V. et al. MRI of rabbit atherosclerosis in response to dietary cholesterol lowering. Arterioscler. Thromb. Vasc. Biol. 19, 1956–1959 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Chinnaiyan, A. M. et al. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc. Natl Acad. Sci. USA 97, 1754–1759 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jennings, D. et al. Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI. Neoplasia 4, 255–262 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Evelhoch, J. L. et al. Applications of magnetic resonance in model systems: cancer therapeutics. Neoplasia 2, 152–165 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cherry, S. R. Fundamentals of positron emission tomography and applications in preclinical drug development. J. Clin. Pharmacol. 41, 482–491 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Del Guerra, A. & Belcari, N. Advances in animal PET scanners. Q. J. Nucl. Med. 46, 35–47 (2002).

    CAS  PubMed  Google Scholar 

  27. Green, L. A. et al. Noninvasive methods for quantitating blood time–activity curves from mouse PET images obtained with fluorine-18-fluorodeoxyglucose. J. Nucl. Med. 39, 729–734 (1998).

    CAS  PubMed  Google Scholar 

  28. Chatziioannou, A., Tai, Y. C., Doshi, N. & Cherry, S. R. Detector development for microPET II: a 1 microl resolution PET scanner for small animal imaging. Phys. Med. Biol. 46, 2899–2910 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Brady, F. et al. Radiolabelled tracers and anticancer drugs for assessment of therapeutic efficacy using PET. Curr. Pharm. Des. 7, 1863–1892 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Halldin, C., Gulyas, B. & Farde, L. PET studies with carbon-11 radioligands in neuropsychopharmacological drug development. Curr. Pharm. Des. 7, 1907–1929 (2001). Review of PET in the development of drugs for mental health disorders.

    Article  CAS  PubMed  Google Scholar 

  31. Fischman, A. J. et al. Pharmacokinetics of 18F fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography. Antimicrob. Agents Chemother. 40, 659–664 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fischman, A. J. et al. Positron emission tomographic analysis of central 5-hydroxytryptamine2 receptor occupancy in healthy volunteers treated with the novel antipsychotic agent, ziprasidone. J. Pharmacol. Exp. Ther. 279, 939–947 (1996).

    CAS  PubMed  Google Scholar 

  33. Aboagye, E. O. et al. Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients. Br. J. Cancer 86, 1052–1056 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gibson, R. E. et al. Non-invasive radiotracer imaging as a tool for drug development. Curr. Pharm. Des. 6, 973–989 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Fischman, A. J. et al. Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography. Antimicrob. Agents Chemother. 37, 1270–1277 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002).

    Article  CAS  Google Scholar 

  37. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Warner, R. R. & O'Dorisio T. M. Radiolabeled peptides in diagnosis and tumor imaging: clinical overview. Semin. Nucl. Med. 32, 79–83 (2002).

    Article  PubMed  Google Scholar 

  39. Becker, A. et al. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands. Nature Biotechnol. 19, 327–331 (2001).

    Article  CAS  Google Scholar 

  40. Bugaj, J. E., Achilefu, S., Dorshow, R. B. & Rajagopalan, R. Novel fluorescent contrast agents for optical imaging of in vivo tumors based on a receptor-targeted dye–peptide conjugate platform. J. Biomed. Opt. 6, 122–133 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Tung, C. H., Lin, Y., Moon, W. K. & Weissleder, R. A receptor-targeted near-infrared fluorescence probe for in vivo tumor imaging. Chembiochem 3, 784–786 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Weissleder, R. et al. In vivo magnetic resonance imaging of transgene expression. Nature Med. 6, 351–355 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Hogemann, D., Ntziachristos, V., Josephson, L. & Weissleder, R. High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes. Bioconjug. Chem. 13, 116–121 (2002).

    Article  PubMed  Google Scholar 

  44. Sipkins, D. A. et al. Detection of tumor angiogenesis in vivo by αVβ3-targeted magnetic resonance imaging. Nature Med. 4, 623–626 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Burns, H. D. et al. Positron emission tomography neuroreceptor imaging as a tool in drug discovery, research and development. Curr. Opin. Chem. Biol. 3, 388–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Hartvig, P., Bergstrom, M., Antoni, G. & Langstrom, B. Positron emission tomography and brain monoamine neurotransmission — entries for study of drug interactions. Curr. Pharm. Des. 8, 1417–1434 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Fowler, J. S. et al. Positron emission tomography studies of dopamine-enhancing drugs. J. Clin. Pharmacol. (Suppl.) 13–16 (1999).

  48. Hietala, J. Ligand–receptor interactions as studied by PET: implications for drug development. Ann. Med. 31, 438–443 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Laakso, A. & Hietala, J. PET studies of brain monoamine transporters. Curr. Pharm. Des. 6, 1611–1623 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Passchier, J. & van Waarde, A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur. J. Nucl. Med. 28, 113–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Pilowsky, L. S. Probing targets for antipsychotic drug action with PET and SPET receptor imaging. Nucl. Med. Commun. 22, 829–833 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Volkow, N. D., Ding, Y. S., Fowler, J. S. & Gatley, S. J. Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer's dementia. Biol. Psychiatry 49, 211–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Waarde, A. Measuring receptor occupancy with PET. Curr. Pharm. Des. 6, 1593–1610 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Martinez, D. et al. Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with 11C WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology 24, 209–229 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Louie, A. Y. et al. In vivo visualization of gene expression using magnetic resonance imaging. Nature Biotechnol. 18, 321–325 (2000).

    Article  CAS  Google Scholar 

  56. Perez, J. M., Josephson, L., O'Loughlin, T., Hogemann, D. & Weissleder, R. Magnetic relaxation switches capable of sensing molecular interactions. Nature Biotechnol. 20, 816–820 (2002).

    Article  CAS  Google Scholar 

  57. Bremer, C., Tung, C. H. & Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nature Med. 7, 743–748 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Mahmood, U., Tung, C. H., Tang, Y. & Weissleder, R. Feasibility of in vivo multichannel optical imaging of gene expression: experimental study in mice. Radiology 224, 446–451 (2002).

    Article  PubMed  Google Scholar 

  59. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotechnol. 18, 410–414 (2000).

    Article  CAS  Google Scholar 

  60. Sharma, V., Luker, G. D. & Piwnica-Worms, D. Molecular imaging of gene expression and protein function in vivo with PET and SPECT. J. Magn. Reson. Imaging 16, 336–351 (2002).

    Article  PubMed  Google Scholar 

  61. Zhao, M., Kircher, M. F., Josephson, L. & Weissleder, R. Differential conjugation of tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake. Bioconjug. Chem. 13, 840–844 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Tjuvajev, J. G. et al. Imaging the expression of transfected genes in vivo. Cancer Res. 55, 6126–6132 (1995).

    CAS  PubMed  Google Scholar 

  63. Gambhir, S. S. et al. Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. Proc. Natl Acad. Sci. USA 96, 2333–2338 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, X., Zhang, S., Zhao, P., Kovacs, Z. & Sherry, A. D. Synthesis and NMR studies of new DOTP-like lanthanide(III) complexes containing a hydrophobic substituent on one phosphonate side arm. Inorg. Chem. 40, 6572–6579 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Bornhop, D. J. et al. Fluorescent tissue site-selective lanthanide chelate, Tb-PCTMB for enhanced imaging of cancer. Anal. Chem. 71, 2607–2615 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Tromberg, B. J. et al. Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy. Neoplasia 2, 26–40 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chance, B. Near-infrared (NIR) optical spectroscopy characterizes breast tissue hormonal and age status. Acad. Radiol. 8, 209–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Hanlon, E. B. et al. Prospects for in vivo Raman spectroscopy. Phys. Med. Biol. 45, R1–R59 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Brown, E. B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nature Med. 7, 864–868 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Ntziachristos, V., Tung, C. H., Bremer, C. & Weissleder, R. Fluorescence molecular tomography resolves protease activity in vivo. Nature Med. 8, 757–760 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Marten, K. et al. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice. Gastroenterology 122, 406–414 (2002).

    Article  PubMed  Google Scholar 

  72. Ito, S. et al. Detection of human gastric cancer in resected specimens using a novel infrared fluorescent anti-human carcinoembryonic antigen antibody with an infrared fluorescence endoscope in vitro. Endoscopy 33, 849–853 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Zonios, G., Bykowski, J. & Kollias, N. Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy. J. Invest. Dermatol. 117, 1452–1457 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Kuroiwa, T., Kajimoto, Y. & Ohta, T. Development and clinical application of near-infrared surgical microscope: preliminary report. Minim. Invasive. Neurosurg. 44, 240–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Ntziachristos, V., Ripoll, J. & Weissleder, R. Would near-infrared fluorescence signals propagate through large human organs for clinical studies? Opt. Lett. 27, 333–335 (2002).

    Article  PubMed  Google Scholar 

  76. Contag, C. H. et al. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochemistry & Photobiology 4, 523–531 (1997).

    Article  Google Scholar 

  77. Hastings, J. W. Chemistries and colors of bioluminescent reactions: a review. Gene 173, 5–11 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Bhaumik, S. & Gambhir, S. S. Optical imaging of Renilla luciferase reporter gene expression in living mice. Proc. Natl Acad. Sci. USA 99, 377–382 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Nicholson, J. K., Connelly, J., Lindon, J. C. & Holmes, E. Metabonomics: a platform for studying drug toxicity and gene function. Nature Rev. Drug Discov. 1, 153–161 (2002).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Institute for Biomedical Research, Basel, CH-4002, Switzerland

    Markus Rudin

  2. Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Charlestown, 02129, Massachusetts, USA

    Ralph Weissleder

Authors
  1. Markus Rudin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph Weissleder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ralph Weissleder.

Related links

Related links

FURTHER INFORMATION

Academy of Molecular Imaging (AMI)

Encyclopedia of Life Sciences

Computer tomography

Magnetic resonance imaging

Molecular Imaging (MOLI) Database

Society for Magnetic Resonance in Medicine (ISMRM)

Society for Molecular Imaging (SMI)

Society for Non-invasive Imaging in Drug Discovery (SNIDD)

Society of Nuclear Medicine (SNM)

Glossary

MAGNETIC RESONANCE IMAGING

(MRI). A powerful diagnostic imaging method that uses radiowaves in the presence of a magnetic field to extract information from certain atomic nuclei (most commonly hydrogen). It is primarily used for producing anatomical images, but also gives information on the physico-chemical state of tissues, flow, diffusion, motion and, more recently, molecular targets.

X-RAY COMPUTED TOMOGRAPHY

(CT). As generated X-rays pass through different types of tissue, they are deflected or absorbed to different degrees. CT uses X-rays to obtain three-dimensional images by rotating an X-ray source around the subject and measuring the intensity of transmitted X-rays from different angles.

POSITRON EMISSION TOMOGRAPHY

(PET). A tomographic imaging technique that detects nuclides as they decay by positron emission.

SEROTONIN SYSTEM

This is an important neurotransmission network involved in aggressive and sexual behaviour, depression, anxiety, the sleep–wake cycle, moods, thermoregulation and other functions.

FLUORESCENCE-MEDIATED TOMOGRAPHY

A tomographic reconstruction method developed for in vivo imaging of fluorescent probes. Images of deep structures are mathematically reconstructed by solving diffusion equations, under the assumption that photons have been scattered many times.

FLUORESCENCE REFLECTANCE IMAGING

A simple method of image acquisition similar to fluorescence microscopy, except that different optics allow image acquisition of whole animals. Mostly suited for surface tumours or surgically exposed tumours.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rudin, M., Weissleder, R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov 2, 123–131 (2003). https://doi.org/10.1038/nrd1007

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1007

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing