A gadolinium chelate for detection of β-glucuronidase: A self-immolative approach

Joseph A. Duimstra, Frank J. Femia, Thomas J Meade*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

New classes of physiologically responsive magnetic resonance (MR) contrast agents are being developed that are activated by enzymes, secondary messengers, pH, and temperature. To this end, we have prepared a new class of enzyme-activated MR contrast agents using a self-immolative mechanism and investigated the properties of these agents using novel in vitro assays. We have synthesized in nine steps a Gd(III) agent 1 that is activated by the oncologically significant β-glucuronidase. 1 consists of Gd(III)DO3A (DO3A = 1,4,7-tricarboxymethylene-1,4,7,10-tetraazacyclododecane) bearing a pendant β-glucuronic acid moiety connected by a self-immolative linker to the macrocycle. LC-MS analysis reveals that 1 is enzymatically processed as predicted by bovine liver β-glucuronidase, generating 2-aminoethyl-GdDO3A, 2. Compound 2 was prepared independently in a four-step synthetic procedure. Complex 1 displays a decrease in relaxivity upon titration with bicarbonate anion. The relaxivity increases when 1 is converted to 2 in a buffer mimicking in vivo anion concentrations (Parker, D. In Crown Compounds: Towards Future Applications; Cooper, S. R., Ed.; VCH: New York, 1992; pp 51-67) by 17%, while the relaxivity decreases by 27% for the same experiment in human blood serum. Hydrolytic kinetics catalyzed by bovine liver β-glucuronidase at interstitial pH = 7.4 fit the Michaelis-Menten model with kcat/K m = 74.9 ± 10.9 M-1 s-1. Monitoring of bulk water proton T1 during incubation with enzyme shows an increase in T1 that mirrors results obtained through the relaxivity measurements of compounds 1 and 2.

Original languageEnglish (US)
Pages (from-to)12847-12855
Number of pages9
JournalJournal of the American Chemical Society
Volume127
Issue number37
DOIs
StatePublished - Sep 21 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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