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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 N2-(N,N-dimethylaminomethylene)-2¢-nitrofolic acid di-tert-butyl ester (13) and N2-(N,N-dimethylaminomethylene)-N10- 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. [ABSTRACT FROM AUTHOR]