Journal
MAGNETIC RESONANCE IN MEDICINE
Volume 55, Issue 6, Pages 1272-1280Publisher
JOHN WILEY & SONS INC
DOI: 10.1002/mrm.20904
Keywords
gadolinium; redox; blood-pool; albumin; thiol
Funding
- NCI NIH HHS [P30 CA023074, U54-CA090821, U54 CA090821, P30-CA23074] Funding Source: Medline
- NIDDK NIH HHS [R21 DK063124, R21-DK63124] Funding Source: Medline
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DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM-1 and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0,1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.
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