title: Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin.
abstract: 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.
authors.affiliation: Department of Radiology, University of Arizona, Tucson, 85724, USA. raghunan@email.arizona.edu
authors.forename: Natarajan
authors.initials: N
authors.lastname: Raghunand
authors.forename: Bhumasamudram
authors.initials: B
authors.lastname: Jagadish
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Trouard
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Galons
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
mesh_terms: 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
chemical_list: D003287:Contrast Media; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; D019786:Gadolinium DTPA