Synthesis of Precursors for ^¹8F-Labeling of Folic Acid for PET Application

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 N^¹0 and the introduction of an N,N-dimethylaminomethylene group at N^², 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 N^²-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

References

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1

Current address: Radiopharmaceutical Chemistry, Institute for Nuclear Chemistry, Johannes Gutenberg-Universität Mainz, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.

35

Unpublished results.