Albumin Binding, Relaxivity, and Water Exchange Kinetics of the Diastereoisomers of MS-325, a Gadolinium(III)-Based Magnetic Resonance Angiography Contrast Agent Peter Caravan,* ,² Giacomo Parigi, ¶ Jaclyn M. Chasse, ² Normand J. Cloutier, ² Jeffrey J. Ellison, ² Randall B. Lauffer, ² Claudio Luchinat, ¶ Sarah A. McDermid, ² Marga Spiller, ‡ and Thomas J. McMurry ² EPIX Pharmaceuticals, 67 Rogers Street, Cambridge, Massachusetts 02142, CERM and Department of Agricultural Biotechnology, UniVersity of Florence, Via L. Sacconi 6, I-50019 Sesto Fiorentino, Italy, and Department of Radiology, New York Medical College, Valhalla, New York 10595 Received April 10, 2007 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 be isolated at pH > 8.5 (Tyekla ´ 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 an increased relaxation rate of water protons in plasma. Under physiological conditions (37 °C, pH 7.4, phosphate buffered saline (PBS), 4.5% HSA, 0.05 mM complex), there is no statistical difference in HSA affinity or relaxivity between the two isomers (A 88.6 ± 0.6% bound, r 1 ) 42.0 ± 1.0 mM -1 s -1 at 20 MHz; B 90.2 ± 0.6% bound, r 1 ) 38.3 ± 1.0 mM -1 s -1 at 20 MHz; errors represent 1 standard deviation). At lower temperatures, isomer A has a higher relaxivity than isomer B. The water exchange rates in the absence of HSA at 298 K, k A 298 ) 5.9 ± 2.8 × 10 6 s -1 , k B 298 ) 3.2 ± 1.8 × 10 6 s -1 , and heats of activation, ∆H q A ) 56 ± 8 kJ/mol, ∆H q B ) 59 ± 11 kJ/mol, were determined by variable-temperature 17 O 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 PBS solution for each isomer (0.1 mM). Differences in the relaxivity in HSA between the two isomers could be attributed to the differing water exchange rates. Introduction The use of contrast agents in clinical magnetic resonance imaging (MRI) has become routine. The most widely used contrast agents are gadolinium(III) complexes. 1-3 The Gd- (III) complexes share the common feature of an octadentate ligand and one inner-sphere water molecule. In clinical MRI, water and fat are being imaged and contrast agents function by shortening the T 1 of water protons wherever the complex localizes. In a T 1 -weighted MR image, water molecules with the shortest T 1 will give the largest signal. Consequently, areas of the body containing contrast agent will appear as bright regions in an MR image. MS-325 is a commercial contrast agent (generic name gadofosveset, trade name Vasovist) approved in some countries to assess blockages in arteries. 4,5 MS-325 functions by reversibly binding to human serum albumin (HSA) in * To whom correspondence should be addressed. Current address: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129. E-mail: caravan@nmr.mgh.harvard.edu. Fax: 617-726-7422. ² EPIX Pharmaceuticals. ¶ University of Florence. ‡ New York Medical College. (1) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. ReV. 1999, 99, 2293-2352. (2) Caravan, P.; Lauffer, R. B., Contrast Agents: Basic Principles. In Clinical Magnetic Resonance Imaging, 3rd ed.; Edelman, R. R., Hesselink, J. R., Zlatkin, M. B., Crues, J. V., Eds.; Saunders: Philadelphia, 2005; Vol. 1, pp 357-375. (3) Merbach, A. E., Toth, E., Eds. The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging; Wiley: New York, 2001. Inorg. Chem. 2007, 46, 6632-6639 6632 Inorganic Chemistry, Vol. 46, No. 16, 2007 10.1021/ic700686k CCC: $37.00 © 2007 American Chemical Society Published on Web 07/11/2007