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DOI: 10.1055/s-0030-1260247
Synthesis of Precursors for ¹8F-Labeling of Folic Acid for PET Application
Publication History
Received
14 July 2011
Publication Date:
29 September 2011 (online)
Abstract
Radiolabeled folate derivatives have the potential to target folate receptor-positive tumor cells for noninvasive diagnosis via positron emission tomography (PET) and single photon emission computed tomography (SPECT). We report the regiospecific synthesis of N ²-(N,N-dimethylaminomethylene)-2′-nitrofolic acid di-tert-butyl ester (13) and N ²-(N,N-dimethylaminomethylene)-N ¹0-formyl-2′-nitrofolic acid dimethyl ester (25), which are precursors for the radiolabeling of folic acid with the PET isotope ¹8F. A modular synthetic strategy was applied: Fmoc- and Boc-protected 4-amino-2-nitrobenzoic acid were linked via amide bonds to di-tert-butyl l-glutamate and dimethyl l-glutamate, respectively, to form building blocks 10 and 19. After Fmoc and Boc removal, both compounds were coupled to 6-(bromomethyl)pterin hydrobromide to give crude 2′-nitrofolic acid di-tert-butyl ester and 2′-nitrofolic acid dimethyl ester. After formylation of 2′-nitrofolic acid dimethyl ester at N¹0 and the introduction of an N,N-dimethylaminomethylene group at N², precursor 25 was obtained in an overall yield of 3%. The analogous 2′-fluoroderivative 28 was obtained in 7% overall yield from 4-amino-2-fluorobenzoic acid. Precursor 13 was obtained from 2′-nitrofolic acid di-tert-butyl ester in 6% yield after N²-protection. The synthesis of the reference materials 2′-nitro- and 2′-fluorofolic acid was achieved by the reaction of N-(4-amino-2-nitrobenzoyl)- and N-(4-amino-2-fluorobenzoyl)-l-glutamic acid with 6-(bromomethyl)pterin hydrobromide, giving 7% and 14% overall yield, respectively.
Key words
nucleophilic substitution - halides - amino acids - protecting groups
