Journal
INVESTIGATIVE RADIOLOGY
Volume 45, Issue 10, Pages 600-612Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/RLI.0b013e3181ee5a9e
Keywords
relaxivity; gadolinium; protein binding; water exchange; NMRD
Funding
- National Institutes of Health [R01EB009062, R21EB009738]
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Rationale and Objectives: The donor atoms that bind to gadolinium in contrast agents influence inner-sphere water exchange and electronic relaxation, both of which determine observed relaxivity. The effect of these molecular parameters on relaxivity is greatest when the contrast agent is protein bound. We sought to determine an optimal donor atom set to yield high relaxivity compounds. Methods: A total of 38 gadolinium-1,4,7,10-tetraazacyclo-dodecane-N, N',N '', N'''-tetraacetato derivatives were prepared and relaxivity was determined in the presence and absence of human serum albumin as a function of temperature and magnetic field. Each compound had a common albumin-binding group and differed only by substitution of different donor groups at one of the macrocycle nitrogens. Oxygen-17 isotope relaxometry at 7.05 T was performed to estimate water exchange rates. Results: Changing a single donor atom resulted in changes in water exchange rates ranging across 3 orders of magnitude. Donor groups increased water exchange rate in the order: phosphonate > phenolate > alpha-substituted acetate > acetate > hydroxamate > sulfonamide > amide > pyridyl > imidazole. Relaxivites at 0.47 and 1.4 T, 37 degrees C, ranged from 12.3 to 55.6 mM(-1)s(-1) and from 8.3 to 32.6 mM(-1)s(-1) respectively. Optimal relaxivities were observed when the donor group was an alpha-substituted acetate. Electronic relaxation was slowest for the acetate derivatives as well. Conclusions: Water exchange dynamics and relaxivity can be predictably tuned by choice of donor atoms.
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