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Synthesis 2011(22): 3639-3648  
DOI: 10.1055/s-0030-1260247
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Viola Groehn*a, Rudolf Mosera, Tobias L. Rossb,, Thomas Betzelb, Cristina Müllerc, Roger Schiblib,c, Simon Ametameyb
a Merck & Cie, Im Laternenacker 5, 8200 Schaffhausen, Switzerland
Fax: +41(52)6307255; e-Mail: viola.groehn@merckgroup.com;
b Animal Imaging Center-PET, Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Institute of Pharmaceutical Science ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland
c Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland
Further Information

Publication History

Received 14 July 2011
Publication Date:
29 September 2011 (online)

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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

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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.