The overall goals of this project are: 1) to develop highly efficient water proton NMR relaxation agents in the form of gadolinium(III) complexes that bind non-covalently to human serum albumin (HSA) and 2) to elucidate the structural features of the complexes that control HSA binding behavior and relaxation efficiency (relaxivity). This basic structure-binding and structure-relaxivity investigation will define a new class of selectively intravascular NMR imaging diagnostic agents for potential human use at much lower doses than current agents. In addition, the HSA-chelate interactions studied in this project will serve as a useful model system to understand the effect of in-vivo binding of agents on the relaxation properties of tissue. A variety of hydrophobic groups will be incorporated into known aminocarboxylate ligands to promote HSA binding. The complexes of Gd3+ or other lanthanide ions (terbium(III), europium(III), prasedymium(III), or ytterbium(III)), will be isolated for HSA binding studies. Equilibrium dialysis and fluorescence techniques will be utilized to characterize the binding behavior; the influence of the structure of the different complexes on the nature of the binding interactions and their affinities will be assessed. Proton NMR spectra and luminescence lifetime measurements will be obtained to assess the structure of the complexes, before and after binding to HSA. The water proton NMR relaxivities of the free and HSA-bound Gd3+ complexes will be measured at multiple magnetic field strength to fully characterize the enhancement effect stemming from HSA binding. Structure-relaxivity comparisons, including the influence of flexibility in the chelate or in its attachment to HSA, the number of metal-coordinated water molecules, and the effective symmetry of the metal center, will be obtained.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM037777-01
Application #
3293480
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1986-12-01
Project End
1989-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199