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Mechanistic Studies of a Calcium-Dependent MRI Contrast Agent

Li, Wen-hong and Parigi, Giacomo and Fragai, Marco and Luchinat, Claudio and Meade, Thomas J. (2002) Mechanistic Studies of a Calcium-Dependent MRI Contrast Agent. Inorganic Chemistry, 41 (15). pp. 4018-4024. ISSN 0020-1669. doi:10.1021/ic0200390.

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Intracellular Ca^(2+) plays an important role in signal transduction, and we are developing new MRI techniques to study its regulation in living animals. We have reported on an MRI contrast agent (DOPTA-Gd) where the relaxivity of the complex is controlled by the presence or absence of the divalent ion Ca^(2+). By structurally modulating inner-sphere access of water to a chelated Gd^(3+) ion, we observe a substantial and reversible change in T_1 upon the addition of Ca^(2+) and not other divalent ions. Luminescence lifetime and NMRD measurements of the complex have been acquired, and several parameters contribute to the Ca^(2+) dependent relaxivity change of DOPTA-Gd. The number of inner-sphere water molecules is more than doubled after the Ca^(2+) concentration is increased. This finding strongly supports the proposed conformational change of DOPTA-Gd when Ca^(2+) is bound. Relaxometric measurements confirm these results and provide an indication that second-sphere water molecules are probably responsible for paramagnetic relaxation enhancement in the absence of Ca^(2+). After Ca^(2+) is bound to DOPTA-Gd, the molecule undergoes a substantial conformational change that opens up the hydrophilic face of the tetraazacyclododecane macrocycle. This change dramatically increases the accessibility of chelated Gd^(3+) ion to bulk solvent. The design of this class of calcium-activated MR contrast agent was based primarily on the assumption that the number of coordinated inner-sphere water molecules would be the dominating factor in observed relaxivity measurements. This result has been confirmed; however, careful mechanistic studies reveal that additional factors are involved in this process.

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Additional Information:© 2002 American Chemical Society. Received 14 January 2002. Published online 28 June 2002. Published in print 1 July 2002. The work was supported by the Biological Imaging Center of the Beckman Institute, National Institutes of Health, the Human Brain Project, and CNR, Italy, Contracts 970113349 and 01.00832.PF28. W.-h.L. was supported by a fellowship from the American Heart Association, Western States Affiliates. We thank Drs. Gary M. Hathaway and Jie Zhou at the Caltech Protein Microanalytical Laboratory for performing mass spectroscopy analysis.
Funding AgencyGrant Number
Caltech Beckman InstituteUNSPECIFIED
Human Brain ProjectUNSPECIFIED
Consiglio Nazionale delle Ricerche (CNR)970113349
Consiglio Nazionale delle Ricerche (CNR)01.00832.PF28
American Heart Association, Western States AffiliatesUNSPECIFIED
Issue or Number:15
Record Number:CaltechAUTHORS:20170425-101447350
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Official Citation:Mechanistic Studies of a Calcium-Dependent MRI Contrast Agent Wen-hong Li, Giacomo Parigi, Marco Fragai, Claudio Luchinat, and Thomas J. Meade Inorganic Chemistry 2002 41 (15), 4018-4024 DOI: 10.1021/ic0200390
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76909
Deposited By: Ruth Sustaita
Deposited On:25 Apr 2017 19:21
Last Modified:15 Nov 2021 17:03

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