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 ¹8 F.
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
References <A NAME="RT69811SS-1">1 </A>
Current address: Radiopharmaceutical
Chemistry, Institute for Nuclear Chemistry, Johannes Gutenberg-Universität Mainz,
Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.
2a </A>
Weitmann SD.
Lark RH.
Coney LR.
Fort DW.
Frasca V.
Zurawski VR.
Cancer Res.
1991,
52:
3396
2b </A>
Parker N.
Turk MJ.
Westrick E.
Lewis JD.
Low PS.
Leamon CP.
Anal Biochem.
2005,
338:
284
<A NAME="RT69811SS-3">3 </A>
Sega EI.
Low PS.
Cancer Metastasis Rev.
2008,
27:
655
<A NAME="RT69811SS-4">4 </A>
Leamon CP.
Reddy JA.
Adv. Drug Delivery
Rev.
2004,
56:
1127
<A NAME="RT69811SS-5">5 </A>
Li S.
Deshmukh HM.
Huang L.
Pharm.
Res.
1998,
15:
1540
<A NAME="RT69811SS-6">6 </A>
Cho BK.
Roy EJ.
Patrick TA.
Kranz DM.
Bioconjugate Chem.
1997,
8:
338
<A NAME="RT69811SS-7">7 </A>
Leamon CP.
Pastan I.
Low PS.
J.
Biol. Chem.
1993,
268:
24847
8a </A>
Low PS.
Henne WA.
Doornweerd DD.
Acc. Chem. Res.
2008,
41:
120
8b </A>
Hilgenbrink AR.
Low PS.
J.
Pharm. Sci.
2005,
94:
2135
8c </A>
Gabizon A.
Shmeeda H.
Horowitz AT.
Zalipsky S.
Adv. Drug. Delivery Rev.
2004,
56:
1177
9a </A>
Mathias CJ.
Lewis MR.
Reichert DE.
Laforest R.
Sharp TL.
Lewis JS.
Nucl. Med. Biol.
2003,
30:
725
9b </A>
Mathias CJ.
Wang S.
Lee RJ.
Waters DJ.
Low PS.
Green MA.
J.
Nucl. Med.
1996,
37:
1003
10a </A>
Müller C.
Forrer F.
Schibli R.
Krenning EP.
de Jong M.
J. Nucl. Med.
2008,
49:
310
10b </A>
Müller C.
Dumas C.
Hoffmann U.
Schubiger PA.
Schibli R.
J. Organomet. Chem.
2004,
689:
4712
10c </A>
Mindt TL.
Müller C.
Melis M.
de Jong M.
Schibli R.
Bioconjugate Chem.
2008,
19:
1689
10d </A>
Mindt TL.
Müller C.
Stuker F.
Salazar J.-F.
Hohn A.
Bioconjugate Chem.
2009,
20:
1940
10e </A>
Sparr C.
Michel U.
Marti RE.
Müller C.
Schibli R.
Moser R.
Groehn V.
Synthesis
2009,
787
10f </A>
Guo W.
Hinkle G.
Lee R.
J.
Nucl. Med.
1999,
40:
1563
10g </A>
Reddy JA.
Xu LC.
Parker N.
Vetzel M.
Leamon CP.
J. Nucl. Med.
2004,
45:
857
10h </A>
Mathias CJ.
Hubers D.
Low PS.
Green MA.
Bioconjugate
Chem.
2000,
11:
253
11a </A>
Siegel BA.
Dehdashti F.
Mutch DG.
Podoloff DA.
Wendt R.
Sutton GP.
J. Nucl. Med.
2003,
44:
700
11b </A>
Mathias CJ.
Green MA.
Nucl.
Med. Biol.
1998,
25:
585
11c </A>
Wang S.
Luo J.
Lantrip DA.
Waters DJ.
Mathias CJ.
Green MA.
Fuchs PL.
Low PS.
Bioconjugate
Chem.
1997,
8:
673
12a </A>
Bettio A.
Honer M.
Müller C.
Brühlmeier M.
Müller U.
Schibli R.
Groehn V.
Schubiger AP.
Ametamey SM.
J. Nucl. Med.
2006,
47:
1153
12b </A>
Ross TL.
Honer M.
Lam PYH.
Mindt TL.
Groehn V.
Schibli R.
Schubiger AP.
Ametamey SM.
Bioconjugate Chem.
2008,
19:
2462
12c </A>
Ametamey SM,
Moser R,
Ross TL, and
Groehn V. inventors; Patent WO2008/125617 A2.
; Chem. Abstr. 2008 ,
1282601
12d </A>
Low PS,
Varghese B, and
Vlahov IR. inventors; Patent WO2006/071754 A2.
; Chem. Abstr. 2006 ,
656863
13a </A>
Haka SM.
Klibourn MR.
Watkins LG.
Toorongian SA.
J. Labelled Compd. Radiopharm.
1989,
27:
823
13b </A>
Iwata R.
Pascali C.
Bogni A.
Horvath G.
Kovacs Z.
Yanai K.
Ido T.
Appl.
Radiat. Isot.
2000,
52:
87
13c </A>
Angelini G.
Speranza M.
Wolf AP.
Shiue C.-Y.
J. Fluorine Chem.
1985,
27:
177
<A NAME="RT69811SS-14">14 </A>
Cosulich DB.
Seeger DR.
Fahrenbach MJ.
Collins KH.
Roth B.
Hultquist ME.
Smith JM.
J. Org. Chem.
1953,
75:
4675
<A NAME="RT69811SS-15">15 </A>
Backer HJ.
Houtman AC.
Recl. Trav. Chim.
Pays-Bas
1951,
70:
738
<A NAME="RT69811SS-16">16 </A>
Ross TL.
Honer M.
Müller C.
Groehn V.
Schibli R.
Ametamey SM.
J. Nucl. Med.
2010,
51:
1756
17a </A>
Taylor EC.
Portnoy RC.
Hochstetler DC.
Kobayashi T.
J. Org. Chem.
1975,
40:
2347
17b </A>
Taylor EC.
Perlmann KL.
Kim Y.-H.
Sword IP.
Jacobi PA.
J. Am. Chem. Soc.
1973,
95:
6413
18a </A>
Taylor EC.
Henrie RN.
Portnoy RC.
J.
Org. Chem.
1978,
43:
736
18b </A>
Taylor EC.
Kobayashi T.
J.
Org. Chem.
1973,
38:
2817
<A NAME="RT69811SS-19">19 </A>
Mautner HG.
Kim Y.-H.
J. Org. Chem.
1975,
40:
3447
<A NAME="RT69811SS-20">20 </A>
Bader H.
Rosowsky A.
J. Org. Chem.
1991,
56:
3386
<A NAME="RT69811SS-21">21 </A>
Baugh CM.
Shaw E.
J. Org. Chem.
1964,
29:
3610
22a </A>
Thijssen HHW.
Anal.
Biochem.
1973,
54:
609
22b </A>
Taylor EC.
Henrie RN.
Portnoy RC.
J. Org. Chem.
1978,
43:
736
23a </A>
Freisleben A.
Schieberle P.
Rychlik M.
J. Agric. Food Chem.
2002,
50:
4760
23b </A>
Roberts EC.
Shearly YF.
J.
Med. Chem.
1972,
15:
1310
23c </A>
Roberts EC.
Shearly YF.
J.
Med. Chem.
1973,
16:
697
23d </A>
Sletzinger M.
Reinhold D.
Grier J.
Beachem M.
Tishler M.
J.
Am. Chem. Soc.
1955,
77:
6365
23e </A>
Roberts EC.
Shearly YF.
J.
Med. Chem.
1974,
17:
219
23f </A>
Martinelli JE.
Chaykovsky M.
J. Med.
Chem.
1979,
22:
874
23g </A>
Dueker SR.
Jones AD.
Smith GM.
Clifford AJ.
J.
Labelled Compd. Radiopharm.
1995,
36:
981
23h </A>
Maunder P.
Finglas PM.
Mallet AI.
Mellon FA.
Razzaque MA.
Ridge B.
Vehteristo L.
Witthöft C.
J.
Chem. Soc., Perkin Trans. 1
1999,
1311
23i </A>
Khalifa E.
Sengupta PK.
Bieri JH.
Viscontini M.
Helv.
Chim. Acta
1976,
59:
242
23j </A>
Sengupta PK.
Bieri JH.
Viscontini M.
Helv. Chim. Acta
1975,
58:
1374
23k </A>
Bieri JH.
Viscontini M.
Helv. Chim.
Acta
1973,
56:
2905
<A NAME="RT69811SS-24">24 </A>
Traub H.
Pfleiderer W.
Pteridines
1999,
10:
79
25a </A>
Piper JR.
McCaleb SG.
Montgomery JA.
J.
Heterocycl. Chem.
1986,
24:
279
25b </A>
Montgomery JA.
Rose JD.
Temple C.
Piper J. In Chemistry and Biology of Pteridines, Proceedings
of the 5th International Symposium
Pfleiderer W.
de Gruyter;
Berlin:
1975.
p.485
<A NAME="RT69811SS-26">26 </A>
Curtius T.
Bollenbach HFr.
J. Prakt.
Chem.
1907,
74:
281
<A NAME="RT69811SS-27">27 </A>
Seeger DR.
Cosulich DB.
Smith JM.
Hultquist MH.
J.
Am. Chem. Soc.
1949,
71:
1253
<A NAME="RT69811SS-28">28 </A>
Taylor EC.
Cain CK.
J. Am. Chem. Soc.
1949,
71:
2538
<A NAME="RT69811SS-29">29 </A>
Bodanszky A.
Bodanszky M.
Chandramouli N.
Kwei JZ.
Martinez J.
Tolle JC.
J. Org. Chem.
1980,
45:
72
30a </A>
Takagishi G.
Katsoulos G.
Schlosser M.
Synlett
1992,
360
30b </A>
Gangjee A.
Jain HD.
McGuire J.
Kisliuk RL.
J. Med. Chem.
2004,
47:
6730
<A NAME="RT69811SS-31">31 </A>
Kanai F.
Kaneko T.
Morishima H.
Isshiki K.
Takita T.
Takeuchi T.
Umezawa H.
J.
Antibiot.
1985,
38:
39
<A NAME="RT69811SS-32">32 </A>
Martinez J.
Laur J.
Synthesis
1982,
979
<A NAME="RT69811SS-33">33 </A>
Waki M.
Meienhofer J.
J. Org. Chem.
1977,
42:
2019
<A NAME="RT69811SS-34">34 </A>
Groehn V.
Moser R.
Pugin B.
Adv.
Synth. Catal.
2005,
347:
1855
<A NAME="RT69811SS-35">35 </A>
Unpublished results.
36a </A>
Glaser M.
Arstad E.
Bioconjugate
Chem.
2007,
18:
989
36b </A>
Waterhouse RN.
Collier TL.
Nucl.
Med. Biol.
1997,
24:
127
36c </A>
Gründer G.
Siessmeier T.
Piel M.
Vernaleken I.
Buchholz H.-G.
Zhou Y.
Hiemke C.
Wong DF.
Rösch F.
Bartenstein P.
J. Nucl.
Med.
2003,
44:
109
