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 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.
Raghunand
Natarajan
N
Department of Radiology, University of Arizona, Tucson, 85724, USA. raghunan@email.arizona.edu
Jagadish
Bhumasamudram
B
Trouard
Theodore P
TP
Galons
Jean-Philippe
JP
Gillies
Robert J
RJ
Mash
Eugene A
EA
D000818:Animals; D001665:Binding Sites; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D019786:Gadolinium DTPA / Q000737:chemistry / Q000493:pharmacokinetics*; D007089:Image Enhancement / Q000379:methods; D007668:Kidney / Q000033:anatomy & histology* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism
D003287:Contrast Media; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; D019786:Gadolinium DTPA