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Synthesis 2008(2): 215-220  
DOI: 10.1055/s-2007-1000857
PAPER
© Georg Thieme Verlag Stuttgart · New York

The Design and Synthesis of Highly Branched and Spherically Symmetric Fluorinated Macrocyclic Chelators

Zhong-Xing Jiangb, Y. Bruce Yu*a,b
a Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
Fax: +1(410)7065017; e-Mail: byu@rx.umaryland.edu;
b Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA
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Publikationsverlauf

Received 10 July 2007
Publikationsdatum:
18. Dezember 2007 (online)

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Abstract

Two novel, highly fluorinated macrocyclic chelators with highly branched and spherically symmetric fluorocarbon moieties have been designed and efficiently synthesized. This is achieved by conjugating a spherically symmetric fluorocarbon moiety to the macrocyclic chelator DOTA, with or without a flexible oligo-oxyethylene linker between these two parts. As a result of the spherical symmetry, all 27 fluorine atoms in each fluorinated chelator give a sharp singlet 19F NMR signal. The hydrophilicity and the 19F relaxation behavior of fluorinated chelators can be modulated by the insertion of a flexible linker between the fluorocarbon moiety and the macrocyclic linker. These chelators serve as prototypes for 1H-19F dual nuclei magnetic resonance imaging agents.

Key words

fluorinated macrocyclic chelator - fluorinated amphile - 19F NMR - spherical symmetry - DOTA

9

Since F-DOTA 1 and F-DOTA 2 each contains three carboxylic groups, the protonation status of which is pH-dependent, the 1-octanol/H2O partition measurements were conducted with physiological saline buffer (PBS, 50 mM phosphate, 100 mM NaCl, 1 mM EDTA, pH 7.0) as the aqueous phase. Specifically, F-DOTA 1 or F-DOTA 2 (5 mg) was dissolved in mixture of PBS buffer (0.5 mL) and 1-octanol (0.5 mL). The sample was put into an Eppendorf® microcentrifuge tube (1.5 mL), which was then taped to a type 16700 mixer from Thermolyne to be shaken vigorously for 20 min. After phase separation, the aqueous phase and 1-octanol phases were taken out for 19F NMR, respectively, with a sealed capillary of 1% hexafluorobenzene in MeOH-d 4 as the internal standard. P oct was calculated based on the ratio of 19F NMR signal areas in the 1-octanol and H2O.

10

T1 and T2 of of the trifluoromethyl group of perfluorooctyl bromide were measured under the same condition as for F-DOTA 1 and F-DOTA 2 by 19F NMR spectroscopy (376 MHz) in MeOH-d 4 at a concentration of 0.025 M.