Albumin Binding, Relaxivity, and Water Exchange Kinetics of the Diastereoisomers of MS-325, a Gadolinium(III)-Based Magnetic Resonance Angiography Contrast Agent
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- 作者：Peter Caravan ; Giacomo Parigi ; Jaclyn M. Chasse ; Normand J. Cloutier ; Jeffrey J. Ellison ; Randall B. Lauffer ; Claudio Luchinat ; Sarah A. McDermid ; Marga Spiller ; Thomas J. McMurry
- 刊名：Inorganic Chemistry
- 出版年：2007
- 出版时间：August 6, 2007
- 年：2007
- 卷：46
- 期：16
- 页码：6632 - 6639
- 全文大小：124K
- 年卷期：v.46,no.16(August 6, 2007)
- ISSN：1520-510X
文摘
The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl]diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography(MRA). MS-325 consists of two slowly interconverting diastereoisomers, A and B (65:35 ratio), which can beisolated at pH > 8.5 (Tyekl
r, Z.; Dunham, S. U.; Midelfort, K.; Scott, D. M.; Sajiki, H.; Ong, K.; Lauffer, R. B.;Caravan, P.; McMurry, T. J. Inorg. Chem. 2007, 46, 6621-6631). MS-325 binds to human serum albumin (HSA)in plasma resulting in an extended plasma half-life, retention of the agent within the blood compartment, and anincreased relaxation rate of water protons in plasma. Under physiological conditions (37 
C, pH 7.4, phosphatebuffered saline (PBS), 4.5% HSA, 0.05 mM complex), there is no statistical difference in HSA affinity or relaxivitybetween the two isomers (A 88.6 ± 0.6% bound, r1 = 42.0 ± 1.0 mM-1 s-1 at 20 MHz; B 90.2 ± 0.6% bound,r1 = 38.3 ± 1.0 mM-1 s-1 at 20 MHz; errors represent 1 standard deviation). At lower temperatures, isomer A hasa higher relaxivity than isomer B. The water exchange rates in the absence of HSA at 298 K, kA298 = 5.9 ± 2.8× 106 s-1, kB298 = 3.2 ± 1.8 × 106 s-1, and heats of activation, 
H
A = 56 ± 8 kJ/mol, HB = 59 ± 11 kJ/mol,were determined by variable-temperature 17O NMR at 7.05 T. Proton nuclear magnetic relaxation dispersion (NMRD)profiles were recorded over the frequency range of 0.01-50 MHz at 5, 15, 25, and 35 C in a 4.5% HSA in PBSsolution for each isomer (0.1 mM). Differences in the relaxivity in HSA between the two isomers could be attributedto the differing water exchange rates.
r, Z.; Dunham, S. U.; Midelfort, K.; Scott, D. M.; Sajiki, H.; Ong, K.; Lauffer, R. B.;Caravan, P.; McMurry, T. J. Inorg. Chem. 2007, 46, 6621-6631). MS-325 binds to human serum albumin (HSA)in plasma resulting in an extended plasma half-life, retention of the agent within the blood compartment, and anincreased relaxation rate of water protons in plasma. Under physiological conditions (37 C, pH 7.4, phosphatebuffered saline (PBS), 4.5% HSA, 0.05 mM complex), there is no statistical difference in HSA affinity or relaxivitybetween the two isomers (A 88.6 ± 0.6% bound, r1 = 42.0 ± 1.0 mM-1 s-1 at 20 MHz; B 90.2 ± 0.6% bound,r1 = 38.3 ± 1.0 mM-1 s-1 at 20 MHz; errors represent 1 standard deviation). At lower temperatures, isomer A hasa higher relaxivity than isomer B. The water exchange rates in the absence of HSA at 298 K, kA298 = 5.9 ± 2.8× 106 s-1, kB298 = 3.2 ± 1.8 × 106 s-1, and heats of activation, HA = 56 ± 8 kJ/mol, HB = 59 ± 11 kJ/mol,were determined by variable-temperature 17O NMR at 7.05 T. Proton nuclear magnetic relaxation dispersion (NMRD)profiles were recorded over the frequency range of 0.01-50 MHz at 5, 15, 25, and 35 C in a 4.5% HSA in PBSsolution for each isomer (0.1 mM). Differences in the relaxivity in HSA between the two isomers could be attributedto the differing water exchange rates.