Chem. Rev. 1999, 99, 2293−2352 2293 Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications Peter Caravan,* Jeffrey J. Ellison, Thomas J. McMurry, and Randall B. Lauffer EPIX Medical, Inc., 71 Rogers Street, Cambridge, Massachusetts 02142 Received February 22, 1999 (Revised Manuscript Received June 24, 1999) Contents D. Other Agents 2347 E. Bioactivated Agents 2348 I. Introduction 2293 X. Conclusion 2348 A. Signal Intensity in MRI 2294 XI. Acknowledgments 2348 B. The Nature of Gadolinium(III) Chelates 2295 XII. References 2348 C. This Review 2295 II. Solution and Solid State Structures 2295 A. Solid State Structures 2296 I. Introduction B. Solution Methods 2308 C. Solution Structures/Dynamics 2310 Gadolinium, an obscure lanthanide element buried D. Gadolinium(III) Chelate Stabilty 2314 in the middle of the periodic table, has in the course of a decade become commonplace in medical diag- E. Solution Equilibria and Contrast Agent 2314 Dissociation in Vivo nostics. Like platinum in cancer therapeutics and technetium in cardiac scanning, the unique magnetic F. Kinetic Inertness and in Vivo Dissociation of 2316 Gadolinium(III) Complexes properties of the gadolinium(III) ion placed it right in the middle of a revolutionary development in G. New Compounds 2316 medicine: magnetic resonance imaging (MRI). While H. Summary/Future Directions 2320 it is odd enough to place patients in large supercon- III. Relaxation Theory 2320 ducting magnets and noisily pulse water protons in A. Introduction 2320 their tissues with radio waves, it is odder still to B. Inner-Sphere Relaxation 2320 inject into their veins a gram of this potentially toxic C. Outer-Sphere Relaxation 2325 metal ion which swiftly floats among the water D. Data Fitting of NMRD Curves 2325 molecules, tickling them magnetically. IV. Physical Properties of Small Molecule 2326 The successful penetration of gadolinium(III) che- Gadolinium Complexes lates into radiologic practice and medicine as a whole A. Water Exchange 2326 can be measured in many ways. Since the approval 2- B. Proton Exchange 2327 of [Gd(DTPA)(H2O)] in 1988, it can be estimated C. Electronic Relaxation 2327 that over 30 metric tons of gadolinium have been D. Relaxivity 2331 administered to millions of patients worldwide. Cur- rently, approximately 30% of MRI exams include the E. Outer- and Second-Sphere Relaxivity 2334 use of contrast agents, and this is projected to F. Methods of Improving Relaxivity 2336 increase as new agents and applications arise; Table V. Macromolecular Conjugates 2336 1 lists agents currently approved or in clinical trials. A. Introduction 2336 In the rushed world of modern medicine, radiologists, B. General Conjugation Methods 2336 technicians, and nurses often refrain from calling the C. Synthetic Linear Polymers 2336 agents by their brand names, preferring instead the D. Synthetic Dendrimer-Based Agents 2338 affectionate “gado.” They trust this clear, odorless E. Naturally Occurring Polymers (Proteins, 2339 “magnetic light”, one of the safest class of drugs ever Polysaccharides, and Nucleic Acids) developed. Aside from the cost ($50-80/bottle), ask- F. Targeted Agents 2340 ing the nurse to “Give him some gado” is as easy as VI. Relaxivity of Noncovalently Bound Adducts of 2341 starting a saline drip or obtaining a blood sample. Gadolinium(III) Complexes Gadolinium is also finding a place in medical VII. General Physicochemical Properties 2344 research. When one of us reviewed the field in its 1 VIII. Safety 2345 infancy, in 1987, only 39 papers could be found for A. Low Molecular Weight Chelates 2345 that year in a Medline search for “gado-” and MRI. Ten years later over 600 references appear each year. B. Macromolecular Agents 2345 And as MRI becomes relied upon by different special- IX. Applications 2346 ties, “gado” is becoming known by neurologists, A. Extracellular Agents 2346 B. Blood Pool Agents 2346 * To whom correspondence should be addressed: Tel.: +1 617 250 C. Hepatobiliary Agents 2346 6127. Fax: +1 617 250 6127. E-mail: [email protected]. 10.1021/cr980440x CCC: $35.00 © 1999 American Chemical Society Published on Web 08/20/1999 2294 Chemical Reviews, 1999, Vol. 99, No. 9 Caravan et al. Peter Caravan grew up in Bay Roberts, Newfoundland. He received a Thomas J. McMurry received his B.S. in Chemistry from Penn State in B.Sc. degree in Chemistry from Acadia University in Nova Scotia, Canada, 1979. He did his graduate work with John T. Groves at the University of in 1992. He was awarded an NSERC postgraduate scholarship which he Michigan (Ph.D., 1984) where he studied the structure and reactivity of took to the University of British Columbia where he studied the coordination high valent iron porphyrinate models for cytochrome P-450. Tom then chemistry of podand complexes of trivalent metal ions with Chris Orvig. moved to Berkeley as an NIH Postdoctoral Fellow in Kenneth N. After receiving his Ph.D. in 1996, Peter was awarded an NSERC Raymond’s laboratory to work on the synthesis and coordination chemistry postdoctoral fellowship to work in the group of Andre´ Merbach at the of macrobicyclic catechol-based siderophore analogues. In 1987, he joined Universite´ de Lausanne. There he probed the dynamics of metal the NIH as a Staff Fellow in the late Otto Gansow’s laboratory and was complexes utilizing paramagnetic NMR. In 1998 Peter joined EPIX Medical, involved with the development of bifunctional chelating agents for use in Inc., where he is currently investigating various biophysical chemistry radioimmunotherapy. Tom has been employed at EPIX Medical (formerly problems. Metasyn, Inc.) since 1993, where he is currently Senior Director, Chemistry. Jeff Ellison came to EPIX Medical in 1997. He received a B.S. degree in Dr. Lauffer received his Ph.D. in Chemistry from Cornell University in chemistry from the University of California, Irvine. He earned his Ph.D. at 1983. At the Massachusetts General Hospital, Boston, MA, he served as the University of California, Davis, studying the kinetic stabilization of low a National Institutes of Health Postdoctoral Fellow and as director of the coordinate metal environments with Phil Power. He did his postdoctoral NMR Contrast Media Laboratory. He also held positions of Assistant research with Julie Kovacs at the University of Washington, investigating Professor in Radiology at Harvard Medical School and NIH New the role of iron in nitrile hydratase enzymes. Investigator. In 1992, Dr. Lauffer founded EPIX Medical, Inc., a developer cardiologists, urologists, opthamologists, and others of MRI contrast agents, and currently serves as Chief Scientific Officer and a member of the board of directors. in search of new ways to visualize functional changes in the body. While other types of MRI contrast agents have Contrast agents increase both 1/T1 and 1/T2 to been approved, namely an iron particle-based agent varying degrees depending on their nature as well and a manganese(II) chelate, gadolinium(III) remains as the applied magnetic field. Agents such as gado- the dominant starting material. The reasons for this linium(III) that increase 1/T1 and 1/T2 by roughly include the direction of MRI development and the similar amounts are best visualized using T1-weighted nature of Gd chelates. images since the percentage change in 1/T1 in tissue is much greater than that in 1/T2. Iron particles, on A. Signal Intensity in MRI the other hand, generally lead to a much larger increase in 1/T2 than in 1/T1 and are best seen with As described in more detail elsewhere, signal T -weighted scans. intensity in MRI stems largely from the local value 2 of the longitudinal relaxation rate of water protons, The longitudinal and transverse relaxivity values, 1/T1, and the transverse rate, 1/T2. Signal tends to r1 and r2, refer to the amount of increase in 1/T1 and increase with increasing 1/T1 and decrease with 1/T2, respectively, per millimolar of agent (often given increasing 1/T2. Pulse sequences that emphasize as per mM of Gd). T1 agents usually have r2/r1 ratios changes in 1/T1 are referred to as T1-weighted, and of 1-2, whereas that value for T2 agents, such as iron the opposite is true for T2-weighted scans. oxide particles, is as high as 10 or more. Gadolinium(III) Chelates as MRI Contrast Agents Chemical Reviews, 1999, Vol. 99, No. 9 2295 Table 1. Clinically Relevant Gadolinium(III) Chelates chemical name generic name brand name company classification 2- a [Gd(DTPA)(H2O)] gadopentetate dimeglumine Magnevist Schering (Germany) extracellular - a [Gd(DOTA)(H2O)] gadoterate meglumine Dotarem Guerbet (France) extracellular a [Gd(DTPA-BMA)(H2O)] gadodiamide Omniscan Nycomed-Amersham (U.K.) extracellular a [Gd(HP-DO3A)(H2O)] gadoteridol ProHance Bracco (Italy) extracellular a [Gd(DO3A-butrol)(H2O)] gadobutrol Gadovist Schering (Germany) extracellular b [Gd(DTPA-BMEA)(H2O)] gadoversetamide OptiMARK Mallinckrodt (U. S.) extracellular 2- a [Gd(BOPTA)(H2O)] gadobenate dimeglumine MultiHance Bracco (Italy) hepatobiliary/extracellular 2- b [Gd(EOB-DTPA)(H2O)] gadoxetic acid disodium Eovist Schering (Germany) hepatobiliary MS-325 gadophostriamine trisodium AngioMARKb EPIX/Mallinckrodt (U. S.) blood pool a Approved. b In clinical trials. Advances in MRI have strongly favored T1 agents Once the chemist makes the mental leap, however and thus gadolinium(III). Faster scans with higher difficult it is, that this exchange-labile metal ion resolution require more rapid radio frequency pulsing forms essentially inert complexes, then the chelate and are thus generally T1-weighted since the MR can be viewed as an intact drug molecule. Traveling 2- signal in each voxel becomes saturated. T1 agents over the surface of, say, [Gd(DTPA)(H2O)] , it does relieve this saturation by restoring a good part of the not look too bad. It is not hydrophobic, so it is unlikely longitudinal magnetization between pulses. At the to enter cells.