Medical Physics Seminar - Monday, February 4, 2008

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MRI - Molecular Imaging, from Vision to Reality

Hanns-Joachim Weinmann, Ph.D.

Head of MRI and X-Ray Research

TRG Diagnostic Imaging

Bayer Healthcare Pharmaceuticals

Berlin, Germany

Almost 20 years of experience using Magnevist® and other related gadolinium chelates has  demonstrated the safety and efficacy of this new class of imaging agent.

Such so-called extracellular contrast agents do not simply improve morphological  characterization but also provide data on the physiological status of the tissue; for example, discrimination between viable and non-viable myocardium (1). Extracellular contrast agents generate very important and highly specific information about the physiological status of the organism, for example the integrity of the blood brain barrier, blood perfusion and renal  function. Newly developed contrast agents have become tissue-specific. This means that the compound interacts with the physiological machinery of the organism. Recently, a new word became popular: Molecular Imaging (MI). One of the best definitions of MI is the in vivo characterization of biological processes at the cellular and molecular level. A tissue-specific compound binds to specific cellular components and, thus, acts as a probe for MI. Liver-specific agents (e.g. gadoxetate/Primovist®) bind to transport proteins or protein families integrated in the plasma membrane of the sinusoidal and canalicular side (2). Using this phenomenon, gadolinium labeled hepatocytes can be used as probes in gene therapy (3).

Other MI probes that are currently commercially available are Superparamagnetic iron oxides (SPIO). These small Fe oxide entities are subjected to a specific uptake by cells with macrophage activity. Thus, they accumulate in the liver and spleen but are also probes for inflammatory processes since labeled monocytes travel to such sites (4-6). Targeting well defined domains at proteins will pave the way to molecular imaging. Using phage-display technologies, EPIX researchers identified a thrombus-specific peptide. In combination with high-relaxivity gadolinium chelates, a very low dose of these labeled peptides detects tiny blood clots with high specificity (7).

The relative insensitivity of MRI limits the potential of MI compounds targeting receptors or tumor markers since they are expressed in a quantity that is too low for imaging. This is a domain for the more sensitive techniques such as Positron Emission Tomography (PET) or

Optical Imaging (OI). The use of high field instruments (> 3.0 T) opens new opportunities. Tracing of isolated cells labeled with Gd, Fe or Mn become a reality (8-11). Using very high field magnets, 19F MR localized spectroscopy demonstrated the presence of amoloid plaques in an Alzheimer mouse model (12).  

Another type of MI agent are probes that would monitor enzymatic activities. Enzymes localized in the extracellular space or within the plasma membrane of cells could activate MR probes by changing their chelate structure. This cleavage allows the exchange of water molecules with the Gd atom (13, 14). Enzymes could also polymerize paramagnetic precursors. Studies suggest that paramagnetic MR imaging agents that can be activated in vivo could be used to image enzyme activity directly (15, 16).  

These compounds need to undergo toxicological tests to be approved for clinical use: the assessment of elimination - a highly important factor when an agent becomes entrapped within a cell - and chronic toxicity are definitely the most critical issues. Sensitivity and specificity have to be demonstrated in clinical trials. Furthermore, the high costs of such compounds has to be considered. Certainly, the growing number of MR imaging applications with novel substances and goals point to a fascinating future for MR imaging in molecular imaging.

References:  

1. Shan K, Constantine G, Sivananthan M, Flamm SD. Circulation. 2004;109(11):1328-1334.  

2. van Montfoort JE, Stieger B, Meijer DK, Weinmann HJ, Meier PJ, Fattinger KE. J Pharmacol Exp Ther. 1999;290(1):153-7.  

3. Lewin M, Clement O, Belguise-Valladier P, et al. Invest Radiol. 2001;36(1):9-14.  

4. Schmitz SA, Coupland SE, Gust R, et al. Invest Radiol. 2000;35(8):460-71.  

5. Stoll G, Wesemeier C, Gold R, Solymosi L, Toyka KV, Bendszus M. J Neuroimmunol. 2004;149(1-2):142-6.  

6. Ho C, Hitchens TK. Curr Pharm Biotechnol. 2004;5(6):551-66.  

7. Botnar RM, Buecker A, Wiethoff AJ, et al. Circulation. 2004;110(11):1463-6. 

8. Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP. Proc Natl Acad Sci U S A. 2004;101(30):10901-6.  

9. Aoki I, Takahashi Y, Chuang KH, et al. NMR Biomed. 2006;19(1):50-9.  

10. Bulte JW, Arbab AS, Douglas T, Frank JA. Methods Enzymol. 2004;386:275-99.  

11. de Vries IJ, Lesterhuis WJ, Barentsz JO, et al. Nat Biotechnol. 2005;23(11):1407-13. 

12. Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido TC. Nat Neurosci. 2005;8(4):527-33.  

13. Aime S, Barge A, Cabella C, Crich SG, Gianolio E. Curr Pharm Biotechnol. 2004;5(6):509-18.  

14. Aime SN, R. Grandi, M. Invest Radiol. 1988;23(1):267-270.  

15. Chen JW, Pham W, Weissleder R, Bogdanov A, Jr. Magn Reson Med. 2004;52(5):1021-8. 

16. Bogdanov AA, Jr., Chen JW, Kang HW, Weissleder R. Ernst Schering Res Found Workshop. 2005(49):147-57.  

Location: 1335 Health Sciences Learning Center (HSLC)

Time:  4:00pm-5:00pm

Refreshments will be provided prior to the talk

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