MRI contrast agents that affect water proton relaxation lack sensitivity or specificity for molecular imaging of disease. Specific extracellular targets (e.g., ions, metabolites) can be imaged with MRI probes which have exchangeable protons. The chemical exchange saturation transfer (CEST) technique detects exchange between bulk water protons and -NHx or -OH protons in diamagnetic molecules or protons of an inner sphere of bound water that is shifted by the paramagnetic core of a lanthanide III (Ln3+) ion. Although paramagnetic CEST or PARACEST agents - especially derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA4-) - have great translational potential, quantitative molecular imaging is limited by contributions to the CEST effect from unmeasured influences of the agent's concentration and local environment (i.e., temperature and pH). We propose a new class of DOTA ligands containing Ln3+ that will allow measurement of these parameters while still retaining the CEST effect for an extracellular target. It is well known that paramagnetic complexes of 1,4,7,10-tetraazacyclododecane, primarily used as MRS shift agents, have several non- exchangeable protons that are easily detectable for agent concentration assessment and furthermore these signals are very sensitive to temperature and pH. Thus biosensor imaging of redundant deviation in shifts (BIRDS) of non-exchangeable protons (in

Public Health Relevance

Molecular imaging of extracellular targets with MRI is possible by detecting water-exchangeable protons in paramagnetic macrocyclics with chemical exchange saturation transfer (CEST). However CEST is limited by unknown influences of the agent's concentration and local environment (i.e., temperature and pH). Since MRS shift agents contain non-exchangeable protons for appraisal of these unmeasured parameters with biosensor imaging of redundant deviation in shifts (BIRDS), the new class of multivalent paramagnetic agents will contain both BIRDS and CEST properties for quantitative molecular imaging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB011968-03
Application #
8281539
Study Section
Special Emphasis Panel (ZRG1-SBIB-A (50))
Program Officer
Liu, Christina
Project Start
2010-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$319,892
Indirect Cost
$96,648
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520