Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin

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 relativities of the hexyl and propyl complexes at 37°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.