Profile

Research Interests

Our primary field of interest is the design and synthesis of more effective contrast agents for magnetic resonance imaging (MRI). MRI has become a cornerstone of radiology and diagnostic medicine, offering images of soft tissue at exquisite resolution. In some instances contrast between healthy and unhealthy tissue is poor and a contrast agent is administered to accentuate differences. These contrast agents are small complexes of paramagnetic metal ions and are so successful that it has been estimated that over 30 tonnes of these metallo-pharmaceuticals have been administered since MRI was clinically approved. Despite the great success of these agents they continue to have several drawbacks, most importantly the high doses required and their lack of tisuue specificity.

The vast majority of MRI contrast agents are complexes of gadolinium. By studying the effect that ligand structure has upon the properties Gd3+ complexes were are beginning to build up a picture of how to design more effective contrast agents. Our research divides into two overlapping areas:

Fundamental studies into the coordination chemistry of lanthanide ions.

Electron spin relaxation times and water exchange rates are key parameters in the design of MRI contrast agents. The coordination chemistry of a lanthanide ion is instrumental in determining these characteristics for any given complex. Fortunately, this means that chemists can manipulate these parameters by appropriately designing the ligand systems used. Unfortunately, the relationships between these physical parameters and the structure of the ligand system are not yet well enough understood to allow us to design optimal MRI contrast agents. In particular the relationship between structure and electron spin relaxation is still far from clear.

One of the problems associated with defining the relationships between the physical characteristics of lanthanide ions and the structure of the complex has been the readiness of lanthanide complexes to adopt multiple coordination geometries, even within the same complex. We have recently reported methods by which the coordination geometry of a lanthanide complex can be constrained to a single isomer by careful substitution of the ligand framework. This approach is beginning to provide insights into the nature of different isomers and how they're physical characteristics differ. In addition to continuing this line of research into systems that are applicable to the design of conventional MRI contrast agents we are also extending this work; applying it to a new class of MRI contrast agents known as paraCEST agents.

Development of targeted MRI contrast agents

This dimension of our work seeks to bridge the chasm that separates the design of improved imaging agents described above and the practical world of MR imaging. By preparing contrast agents that comprise two components we hope to develop a new generation of MRI contrast agents that will function in a real MRI setting and greatly enhance the information that is obtained by the imaging experiment. The first component of this new generation of agents will be a Gd3+ chelate that is optimized for MRI applications. This is critical since the more effective a contrast agent a given Gd3+ centre is then the lower the contrast agent's detection limit. The second component of these new agents is a group that will target the agent to a specific cell type, protein or other biological marker of interest. This will afford the opportunity image specific targets of interest in various pathologies that cannot currently be imaged using currently available MRI contrast agents. The development of the agents will take both in the chemistry labs at Portland State and the Advanced Imaging Research Center at OHSU. Our current work in this field is focussed upon derivatives of the macrocyclic ligand DOTMA (a crystal structure of the Sm3+ complex is shown on the left) and how simple phosphonates might be useful for targeting tumours.

Representative Publications

• "The Effect of the Amide Substituent on the Biodistribution and Tolerance of Lanthanide(III) DOTA-Tetraamide Derivatives"
• M. Woods, P. Caravan, C.F.G.C. Geraldes, M.T. Greenfield, G.E. Kiefer, M. Lin, K. McMillan, M.I.M. Prata, A.C. Santos, X. Sun, J. Wang, S. Zhang, P. Zhao and A.D. Sherry, Invest. Radiol. (2008), 43, In Press.
• "Polymeric PARACEST Agents for Enhancing MRI Contrast Sensitivity"
• Y. Wu, Y. Zhou, O. Ouari, M. Woods, P. Zhao, T.C. Soesbe, G.E. Kiefer, A.D. Sherry, J. Am. Chem. Soc. (2008), 130, In Press.
• "Synthesis and Relaxometric Studies of a Dendrimer-based pH responsive MRI Contrast Agent"
• M.M. Ali, M. Woods, P. Caravan, A.C.L. Opina, M. Spiller, J.C. Fettinger and A.D. Sherry, Chem. Eur. J. (2008), 7250-7258.
• "Towards the Rational Design of MRI Contrast Agents: Electron spin Relaxation is Largely Unaffected by the Coordination Geometry of Gadolinium(III) DOTA-type Complexes"
• A. Borel, J.F. Bean, R.B. Clarkson, L. Helm, L. Moriggi, A.D. Sherry, and M. Woods, Chem. Eur. J. (2008), 2658-2667.
• "Modulation of Water Exchange in Europium(III) DOTA-Tetraamide Complexes via Electronic Substituent Effects"
• S.J. Ratnakar, M. Woods, A.J.M. Lubag, Z. Kovács, and A.D. Sherry, J. Am. Chem. Soc. (2008) 130, 6-7.
• "Albumin-binding PARACEST agents"
• Md. M. Ali, M. Woods, E. Suh, Z. Kovacs, G. Tircsó, V. Kodibagkar and A.D. Sherry, J. Biol. Inorg. Chem., (2007), 12, 855-865.
• "Potentiometric and Relaxometric Properties of a Gadolinium-based MRI Contrast Agent for Sensing Tissue pH"
• F.K. Kálmán, M. Woods, P. Caravan, P. Jurek, M. Spiller, G. Tircsó, R. Király, E. Brücher, and A.D. Sherry, Inorg. Chem., (2007), 46, 5260-5270.
• "A Bridge to Isomer Selection in Lanthanide(III) DOTA-tetraamide complexes"
• J. Vipond, M. Woods, P. Zhao, J. Ren, G. Tircsó, Z. Kovacs, and A.D. Sherry, Inorg. Chem., (2007), 46, 2584-2595.
• "Spectral Properties of a Bifunctional PARACEST Europium Chelate: An Intermediate for Targeted Imaging Applications"
• C. Adair, M. Woods, P. Zhao, A. Pasha, P. Winter, G. Lanza, P. Athey, A.D. Sherry and G.E. Kiefer, Contrast Media and Molecular Imaging., (2007), 2 (1), 55-58.
• "Europium(III) Macrocyclic Complexes with Alcohol Pendant Groups as Chemical Exchange Saturation Transfer (CEST) Agents"
• M. Woods, D.E. Woessner, P. Zhao, A. Pasha, M-Y. Yang, C-H. Huang, O. Vasalitiy, J.R. Morrow, and A.D. Sherry, J. Am. Chem. Soc., (2006), 128, 10155 - 10162.
• "Towards the rational design of MRI contrast agents: a practical approach to the synthesis of gadolinium complexes that exhibit optimal water exchange"
• M. Woods, M. Botta, S. Avedano, J. Wang and A.D. Sherry, Dalton Trans, (2005), 3829 - 3837.
• "Structural and Chiroptical Properties of the Two Coordination Isomers of YbDOTA-Type Complexes"
• L. Di Bari, G. Pescitelli, A.D. Sherry, and M. Woods, Inorg. Chem. (2005), 44, 8391 - 8398.
• "Synthesis, Relaxometric and Photophysical Properties of a New pH-Responsive MRI Contrast Agent: The Effect of Other Ligating Groups on Dissociation of a p-Nitrophenolic Pendant Arm"
• M. Woods, G.E. Kiefer, S. Bott, A. Castillo-Muzquiz, C. Eshelbrenner, L. Michaudet, K. McMillan, S.D.K. Mudigunda, D. Ogrin, G. Tircsó, S. Zhang, P. Zhao, and A.D. Sherry, J. Am. Chem. Soc. (2004), 126, 9248 - 9256.
• "Studies into the Structure, Dynamics and Stability of Lanthanide(III) S-2-(p-nitrobenzyl)DOTA Complexes"
• M. Woods, Z. Kovacs, R. Király, E. Brücher, S. Zhang and A.D. Sherry, Inorg. Chem., (2004), 43, 2845-2851.
• "Towards the Rational Design of MRI Contrast Agents; Isolation of the Two Coordination Isomers of Lanthanide DOTA-type Complexes"
• M. Woods, Z. Kovacs, S. Zhang and A.D. Sherry, Angew. Chem. Int'l. Ed., (2003), 42, 5889-5892; Angew. Chem. (2003), 115, 6069-6072.
• "An Improved and Versatile Synthetic Route to 6,7:13,14-Dibenzo-1,8,4,11-dioxadiazacyclotetra-decane"
• M. Woods and A.D. Sherry, Inorg. Chim. Acta, (2003), 351, 395-398.
• "pH Sensitive Modulation of the Second Hydration Sphere in Lanthanide(III) Tetraamide-DOTA Complexes; A Novel Approach to Smart MR Contrast Media"
• M. Woods, S. Zhang, V.H. Ebron and A.D. Sherry, Chem. Eur. J., (2003), 9, 4634-4640.
• "Synthesis and Luminescence Studies of Aryl Substituted Tetraamide Complexes of Europium(III); A New Approach to pH Responsive Luminescent Europium Probes"
• M. Woods and A.D. Sherry, Inorg. Chem., (2003), 42, 4401-4408.