Paramagnetic chemical exchange saturation transfer (PARACEST) agents offer a potential new paradigm in MR imaging. An advantage to this class of agents is the ability to switch each agent on or off through selective RF irradiation applied at the frequency of either its bound water resonance or an exchanging NH group. In their """"""""off"""""""" state, i.e. when not specifically irradiated, PARACEST agents will not interfere with conventional MR imaging sequences, with or without gadolinium. In principle, PARACEST agents can be tailored to each application because their effects depend on their water exchange rates, and these rates can be modified using rational chemical principles. This feature also makes them an attractive platform for the development of responsive agents. The goal of this BRP is to realize the full potential of these compounds as contrast agents in vivo, by systematically addressing a number of basic, theoretical and practical questions. These include establishing the relationships among the magnitude of the effect measured in an imaging experiment and the water exchange lifetime, the magnitude of the chemical shift difference between the bound and bulk water, the strength of the saturating RF field, SAR, concentration, and local environment in vivo. This partnership is made up of two academic institutions and an industrial collaborator. The three main overlapping and interactive areas of focus are: lanthanide chemistry, which will be carried out at UT Dallas (UTD);Pulse sequence implementation, theory, simulations and in vitro validation which will be carried out primarily at the General Electric Global Research Center (GEGRC) and in vivo validation carried out primarily at the BIDMC. Dean Sherry (Project Leader, UTD) is an internationally recognized expert in the synthesis and characterization of lanthanide chelates and has expertise in basic NMR exchange theory. Thomas Dixon and Ileana Hancu (Project Leaders, GEGRC) are both experts in NMR and MR imaging. Robert Lenkinski (PI, BIDMC) is an NMR spectroscopist with expertise both in lanthanide agents and MR imaging. David Alsop (Lead Investigator, BIDMC) has a long track record in optimizing Arterial Spin Labeling perfusion studies, where the detection of small signal intensity changes in the presence of RF irradiation is necessary. Over the past several years, this team has been collaborating on the theoretical and practical aspects of the PARACEST effect. The successful completion of this project will result in three agents (intravascular, pH, and Redox responsive) and MR acquisition strategies for use in human studies.

Public Health Relevance

Paramagnetic chemical exchange saturation transfer (PARACEST) agents offer a potential new paradigm in MR imaging. The goal of this BRP is to realize the full potential of these compounds as contrast agents in vivo, by systematically addressing a number of basic, theoretical and practical questions. The successful completion of this project will result in three agents (intravascular, pH, and Redox responsive) and MR acquisition strategies for use in human studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
7R01EB004582-06
Application #
8250400
Study Section
Special Emphasis Panel (ZRG1-SBIB-U (51))
Program Officer
Liu, Christina
Project Start
2005-01-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$880,058
Indirect Cost
$146,775
Name
University of Texas Sw Medical Center Dallas
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Liu, Zheng; Dimitrov, Ivan E; Lenkinski, Robert E et al. (2016) UCEPR: Ultrafast localized CEST-spectroscopy with PRESS in phantoms and in vivo. Magn Reson Med 75:1875-85
Wu, Yunkou; Zhang, Shanrong; Soesbe, Todd C et al. (2016) pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent. Magn Reson Med 75:2432-41
Kumas, Cemile; Fernando, W Shirangi; Zhao, Piyu et al. (2016) Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA-Tetraglycinate. Inorg Chem 55:9297-305
Wang, Xiaojing; Wu, Yunkou; Soesbe, Todd C et al. (2015) A pH-Responsive MRI Agent that Can Be Activated Beyond the Tissue Magnetization Transfer Window. Angew Chem Int Ed Engl 54:8662-4
Wu, Yunkou; Hao, Guiyang; Ramezani, Saleh et al. (2015) [(68) Ga]-HP-DO3A-nitroimidazole: a promising agent for PET detection of tumor hypoxia. Contrast Media Mol Imaging 10:465-72
De León-Rodríguez, Luis M; Martins, André F; Pinho, Marco C et al. (2015) Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging 42:545-65
Evbuomwan, Osasere M; Lee, Joohwan; Woods, Mark et al. (2014) The presence of fast-exchanging proton species in aqueous solutions of paraCEST agents can impact rate constants measured for slower exchanging species when fitting CEST spectra to the Bloch equations. Inorg Chem 53:10012-4
Lin, Chien-Yuan; Yadav, Nirbhay N; Ratnakar, James et al. (2014) In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI. Magn Reson Med 71:286-93
Soesbe, Todd C; Ratnakar, S James; Milne, Mark et al. (2014) Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI. Magn Reson Med 71:1179-85
Do, Quyen N; Ratnakar, James S; Kovács, Zoltán et al. (2014) Redox- and hypoxia-responsive MRI contrast agents. ChemMedChem 9:1116-29

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