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Chelators for Radioimmunotherapy: I. NMR and Ab Initio Calculation Studies on 1,4,7,10-Tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-Tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr)

Keire, David A. and Jang, Yun Hee and Li, Lin and Dasgupta, Siddharth and Goddard, William A., III and Shively, John E. (2001) Chelators for Radioimmunotherapy: I. NMR and Ab Initio Calculation Studies on 1,4,7,10-Tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-Tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr). Inorganic Chemistry, 40 (17). pp. 4310-4318. ISSN 0020-1669. https://resolver.caltech.edu/CaltechAUTHORS:20170424-145553079

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Abstract

This work describes the modification of the chelating agent 1,4,7,10-tetraazacyclododecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid (DOTA) to improve the rate of metal loading for radioimmunotherapy applications. Previous ab initio calculations predicted that the compounds 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) have a ca. 2000-fold improvement in yttrium metal loading rates compared to those of DOTA (Jang, Y. H.; Blanco, M.; Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 6142−6151). In this study, we report the synthesis, purification, 1H-NMR chemical shift assignments, pKa values, metal loading rate measurements, and additional ab initio calculations of these two compounds. The yttrium loading rates of DO3A1Pr are approximately twice those of DOTA, at pH 4.6 and 37 °C. The NMR data indicates that the DO4Pr analogue forms a stable type I complex but does not form a type II complex. The new ab initio calculations performed on DO4Pr and DO3A1Pr indicate that the rate-determining step is the deprotonation of the first macrocycle amine proton, not the second proton as assumed in the previous calculations. The new calculations predict an improvement in the rate of metal loading that more closely matches the experimentally observed change in the rate.


Item Type:Article
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http://dx.doi.org/10.1021/ic0010297DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ic0010297PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/ic0010297PublisherSupporting Information
ORCID:
AuthorORCID
Dasgupta, Siddharth0000-0002-9161-7457
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2001 American Chemical Society. Received 13 September 2000. Published online 19 July 2001. Published in print 1 August 2001.
Issue or Number:17
Record Number:CaltechAUTHORS:20170424-145553079
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170424-145553079
Official Citation:Chelators for Radioimmunotherapy:  I. NMR and Ab Initio Calculation Studies on 1,4,7,10-Tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-Tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) David A. Keire, Yun Hee Jang, Lin Li, Siddarth Dasgupta, William A. Goddard III, and John E. Shively Inorganic Chemistry 2001 40 (17), 4310-4318 DOI: 10.1021/ic0010297
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76871
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:24 Apr 2017 22:26
Last Modified:03 Oct 2019 17:50

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