From anatomy to the target: Contributions of magnetic resonance imaging to preclinical pharmaceutical research

In recent years, in vivo magnetic resonance (MR) methods have become established tools in the drug discovery and development process. In this article, the role of MR imaging (MRI) in the preclinical evaluation of drugs in animal models of diseases is illustrated on the basis of selected examples. The individual sections are devoted to applications of anatomic, physiologic, and “molecular” imaging providing, respectively, structural‐morphological, functional, and target‐specific information. The impact of these developments upon clinical drug evaluation is also briefly addressed. The main advantages of MRI are versatility, allowing a comprehensive characterization of a disease state and of the corresponding drug intervention; high spatial resolution; and noninvasiveness, enabling repeated measurements. Successful applications in drug discovery exploit one or several of these aspects. Additionally, MRI is contributing to strengthen the link between preclinical and clinical drug research. Anat Rec (New Anat) 265:85–100, 2001. © 2001 Wiley‐Liss, Inc.

[1]  Markus Rudin,et al.  Magnetic resonance angiography of the rat cerebrovascular system without the use of contrast agents , 1999, NMR in biomedicine.

[2]  L W Hedlund,et al.  Dynamics of magnetization in hyperpolarized gas MRI of the lung , 1997, Magnetic resonance in medicine.

[3]  M D King,et al.  Identification of Collaterally Perfused Areas following Focal Cerebral Ischemia in the Rat by Comparison of Gradient Echo and Diffusion-Weighted MRI , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  P M Thompson,et al.  Unfolding the human hippocampus with high resolution structural and functional MRI , 2001, The Anatomical record.

[5]  T. Reese,et al.  Cytoprotection does not preserve brain functionality in rats during the acute post‐stroke phase despite evidence of non‐infarction provided by MRI , 2000, NMR in biomedicine.

[6]  J. Lewin,et al.  Characterization of a model of hydrocephalus in transgenic mice. , 1999, Journal of neurosurgery.

[7]  M Hoehn-Berlage,et al.  Relationship between diffusion-weighted MR images, cerebral blood flow, and energy state in experimental brain infarction. , 1995, Magnetic resonance imaging.

[8]  J A Frank,et al.  Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L W Hedlund,et al.  MR microimaging of the lung using volume projection encoding , 1997, Magnetic resonance in medicine.

[10]  A Potthast,et al.  Normal and abnormal pulmonary ventilation: visualization at hyperpolarized He-3 MR imaging. , 1996, Radiology.

[11]  J M Pauly,et al.  Lung parenchyma: projection reconstruction MR imaging. , 1991, Radiology.

[12]  D. Yablonskiy,et al.  Rapid imaging of hyperpolarized gas using EPI , 1999, Magnetic resonance in medicine.

[13]  T. Reese,et al.  Regional 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 , 1995, NMR in biomedicine.

[14]  J. Fozard,et al.  Pulmonary edema induced by allergen challenge in the rat: Noninvasive assessment by magnetic resonance imaging , 2001, Magnetic resonance in medicine.

[15]  A. Sauter,et al.  Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat , 1996, Neuroscience.

[16]  W. Happer,et al.  Biological magnetic resonance imaging using laser-polarized 129Xe , 1994, Nature.

[17]  M. Rudin,et al.  Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging. , 1986, Stroke.

[18]  J. Penney,et al.  DISTRIBUTION AND KINETICS OF GABA, BINDING SITES IN RAT CENTRAL NERVOUS SYSTEM: A QUANTITATIVE AUTORADIOGRAPHIC STUDY , 2002 .

[19]  M. Rausch,et al.  Bicuculline‐induced brain activation in mice detected by functional magnetic resonance imaging , 2001, Magnetic resonance in medicine.

[20]  J. Bormann,et al.  The 'ABC' of GABA receptors. , 2000, Trends in pharmacological sciences.

[21]  H F Li,et al.  In vivo MR imaging and spectroscopy using hyperpolarized 129Xe , 1996, Magnetic resonance in medicine.

[22]  R. Peshock,et al.  Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. , 1999, Circulation.

[23]  L. Steinman,et al.  ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging , 2000, Journal of Neuroimmunology.

[24]  Ronald M Peshock,et al.  Magnetic Resonance Imaging and Invasive Evaluation of Development of Heart Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-α , 1999 .

[25]  M Hoehn-Berlage,et al.  Ultrafast Perfusion‐Weighted MRI of Functional Brain Activation in Rats During Forepaw Stimulation: Comparison with T*2‐Weighted MRI , 1996, NMR in biomedicine.

[26]  M. Rudin,et al.  In vivo magnetic resonance imaging and spectroscopy in pharmacological research: assessment of morphological, physiological and metabolic effects of drugs , 1995 .

[27]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[28]  W. R. Lieb,et al.  Background K+ channels: an important target for volatile anesthetics? , 1999, Nature Neuroscience.

[29]  Markus Rudin,et al.  MRI Analysis of the Changes in Apparent Water Diffusion Coefficient, T2 Relaxation Time, and Cerebral Blood Flow and Volume in the Temporal Evolution of Cerebral Infarction Following Permanent Middle Cerebral Artery Occlusion in Rats , 2001, Experimental Neurology.

[30]  K. Whyte The human pulmonary circulation , 1987 .

[31]  F. Sharp,et al.  Induction of c-Fos, junB, c-Jun, and hsp70 mRNA in Cortex, Thalamus, Basal Ganglia, and Hippocampus following Middle Cerebral Artery Occlusion , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  P. Barker,et al.  Diffusion magnetic resonance imaging: Its principle and applications , 1999, The Anatomical record.

[33]  N. Beckmann,et al.  Effects of Sandimmune neoral on collagen-induced arthritis in DA rats: characterization by high resolution three-dimensional magnetic resonance imaging and by histology. , 1998, Journal of magnetic resonance.

[34]  M. Rudin,et al.  Non‐invasive, quantitative assessment of the anatomical phenotype of corticotropin‐releasing factor‐overexpressing mice by MRI , 2001, NMR in biomedicine.

[35]  B R Rosen,et al.  Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: Correlation with PET, microdialysis, and behavioral data , 1997, Magnetic resonance in medicine.

[36]  F. Hyder,et al.  Activation of single whisker barrel in rat brain localized by functional magnetic resonance imaging. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  L. Hedlund,et al.  Mixing oxygen with hyperpolarized 3He for small‐animal lung studies , 2000, NMR in biomedicine.

[38]  M. Bohlooly-y,et al.  In vivo metabolic imaging of cardiac bioenergetics in transgenic mice. , 2000, Biochemical and biophysical research communications.

[39]  D. Graham,et al.  Focal Cerebral Ischaemia in the Rat: 1. Description of Technique and Early Neuropathological Consequences following Middle Cerebral Artery Occlusion , 1981, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  M. Rudin,et al.  Noninvasive 3D MR microscopy as a tool in pharmacological research: application to a model of rheumatoid arthritis. , 1995, Magnetic resonance imaging.

[41]  M. Rudin,et al.  The role of magnetic resonance imaging and spectroscopy in transplantation: from animal models to man , 2000, NMR in biomedicine.

[42]  K. Hossmann,et al.  Differences in the cerebrovascular anatomy of C57Black/6 and SV129 mice , 1998, Neuroreport.

[43]  M. Hori,et al.  Cerebral Ischemia after Bilateral Carotid Artery Occlusion and Intraluminal Suture Occlusion in Mice: Evaluation of the Patency of the Posterior Communicating Artery , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  R G Hoffmann,et al.  Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. , 1998, The American journal of psychiatry.

[45]  J R MacFall,et al.  MR microscopy of the rat lung using projection reconstruction , 1993, Magnetic resonance in medicine.

[46]  Scott E. Fraser,et al.  A SMART MAGNETIC RESONANCE IMAGING AGENT THAT REPORTS ON SPECIFIC ENZYMATIC ACTIVITY , 1997 .

[47]  Noninvasive determination of regional cerebral blood flow in rats using dynamic imaging with Gd(DTPA) , 1991, Magnetic resonance in medicine.

[48]  L. Hedlund,et al.  MR Imaging with Hyperpolarized 3He Gas , 1995, Magnetic resonance in medicine.

[49]  R. Weissleder,et al.  Asialoglycoprotein receptor function in benign liver disease: evaluation with MR imaging. , 1991, Radiology.

[50]  Sina Nasri-Chenijani Kidney Transplant Rejection: Diagnosis and Treatment , 1987, The Yale Journal of Biology and Medicine.

[51]  A Haase,et al.  Developmental changes of cardiac function and mass assessed with MRI in neonatal, juvenile, and adult mice. , 2000, American journal of physiology. Heart and circulatory physiology.

[52]  Markus Rudin,et al.  Magnetic resonance imaging for the evaluation of rejection of a kidney allograft in the rat , 1996 .

[53]  M. Viallon,et al.  Dynamic imaging of hyperpolarized 3He distribution in rat lungs using interleaved‐spiral scans , 2000, NMR in biomedicine.

[54]  M Hoehn-Berlage,et al.  Functional MRI of somatosensory activation in rat: Effect of hypercapnic tip‐regulation on perfusion‐ and BOLD‐imaging , 1998, Magnetic resonance in medicine.

[55]  L W Hedlund,et al.  In vivo He-3 MR images of guinea pig lungs. , 1996, Radiology.

[56]  T J Brady,et al.  Magnetically labeled secretin retains receptor affinity to pancreas acinar cells. , 1996, Bioconjugate chemistry.

[57]  M Hoehn-Berlage,et al.  Variation of functional MRI signal in response to frequency of somatosensory stimulation in α‐chloralose anesthetized rats , 1996, Magnetic resonance in medicine.

[58]  M. Rudin,et al.  Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory. , 1997, Magnetic resonance imaging.

[59]  J C Lindon,et al.  Pattern recognition classification of the site of nephrotoxicity based on metabolic data derived from proton nuclear magnetic resonance spectra of urine. , 1994, Molecular pharmacology.

[60]  J R Brookeman,et al.  Lung air spaces: MR imaging evaluation with hyperpolarized 3He gas. , 1999, Radiology.

[61]  N. Beckmann,et al.  High-resolution three-dimensional magnetic resonance imaging for the investigation of knee joint damage during the time course of antigen-induced arthritis in rabbits. , 1999, Arthritis and rheumatism.

[62]  K. Hossmann,et al.  Recovery of the rodent brain after cardiac arrest: A functional mri study , 1998, Magnetic resonance in medicine.

[63]  N. Beckmann,et al.  High-resolution magnetic resonance angiography of the mouse brain: application to murine focal cerebral ischemia models. , 1999, Journal of magnetic resonance.

[64]  C. Beddell,et al.  Prediction of urinary sulphate and glucuronide conjugate excretion for substituted phenols in the rat using quantitative structure-metabolism relationships. , 1995, Xenobiotica; the fate of foreign compounds in biological systems.

[65]  M. Rudin,et al.  Quantitative assessment of rat kidney function by measuring the clearance of the contrast agent Gd(DOTA) using dynamic MRI. , 2000, Magnetic resonance imaging.

[66]  Anna Moore,et al.  In vivo magnetic resonance imaging of transgene expression , 2000, Nature Medicine.

[67]  B D Ross,et al.  Magnetic resonance methods for measurement of disease progression in rheumatoid arthritis. , 1993, Magnetic resonance imaging.

[68]  J. Kucharczyk,et al.  Magnetic resonance imaging of diffusion and perfusion , 1991, Topics in magnetic resonance imaging : TMRI.

[69]  D. J. Knudsen,et al.  Mouse Strain Differences in Susceptibility to Cerebral Ischemia are Related to Cerebral Vascular Anatomy , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[70]  A H Andersen,et al.  Mapping drug-induced changes in cerebral R2* by Multiple Gradient Recalled Echo functional MRI. , 1996, Magnetic resonance imaging.

[71]  T. Reese,et al.  In vivo magnetic resonance methods in pharmaceutical research: current status and perspectives , 1999, NMR in biomedicine.

[72]  V. P. Chacko,et al.  MRI/MRS assessment of in vivo murine cardiac metabolism, morphology, and function at physiological heart rates. , 2000, American journal of physiology. Heart and circulatory physiology.

[73]  J. Borel Pharmacology of cyclosporine (sandimmune). IV. Pharmacological properties in vivo. , 1990, Pharmacological reviews.

[74]  M. Rudin Target watching with a beady eye , 2000, Nature Biotechnology.

[75]  R. Töpper,et al.  Expression of transforming growth factor-beta 1 and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. , 1993, Acta Neuropathologica.

[76]  H. Schuurman,et al.  Magnetic resonance imaging in assessment of rejection of a kidney allograft in the rat: effect of the somatostatin analogue SMS 201-995. , 1996, Transplantation proceedings.

[77]  L. Hedlund,et al.  Mechanism of Detection of Acute Cerebral Ischemia in Rats by Diffusion‐Weighted Magnetic Resonance Microscopy , 1992, Stroke.

[78]  R D Klausner,et al.  Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. , 1988, Science.

[79]  Martin D. Brand,et al.  Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean , 2000, Nature.

[80]  J. Lewin,et al.  Characterization of a model of hydrocephalus in transgenic mice , 1999 .

[81]  F. Sharp,et al.  Induction of heat shock hsp70 mRNA and HSP70 kDa protein in neurons in the ‘penumbra’ following focal cerebral ischemia in the rat , 1993, Brain Research.

[82]  M. Rudin,et al.  Chronic graft loss: dealing with the vascular alterations in solid organ transplantation. , 1998, Transplantation proceedings.

[83]  R Weissleder,et al.  Monocrystalline iron oxide nanocompounds (MION): Physicochemical properties , 1993, Magnetic resonance in medicine.

[84]  N. Beckmann,et al.  High resolution magnetic resonance angiography non‐invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo , 2000, Magnetic resonance in medicine.

[85]  Ole A. Andreassen,et al.  Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease , 2000, The Journal of Neuroscience.

[86]  T S Smith,et al.  Three‐dimensional microimaging (MRμI and μCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis , 2001, The Anatomical record.

[87]  G. Allan Johnson,et al.  Functional MR microscopy of the lung using hyperpolarized 3He , 1999 .