Pergamon zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA A&. Radim. I.wt. Vol. 45, No. 6, pp. 651-653, 1994 Copyright i 1994 Elsevier Science Ltd Printed in Greal Britain. All rights reserved 0969-8043194 $7.00 + 0.00 Enantioselective Synthesis of n.c.a. (S)-L-([a-“C]Methyl)-Tryptophan* ALAIN PLENEVAUX, CHRISTIAN LEMAIRE, GUY DELFIORE and DOMINIQUE COMAR Cyclotron Research Center, Liege University, 4000 Liege, Belgium zyxwvutsrqponmlkjihgfedcbaZ (Received 22 November 1993) N.c.a. (S)-L-([x-“Clmethyl)-tryptophan was prepared by treatment at -78-C of (2S,3aR,8aS)-I,2-bis(- methoxycarbonyl)-l,2,3.3a,8,8a-hexahydropyrrolo[2,3-b]-indole with lithium diisopropylamide and [“C]CH,I. After hydrolysis with HI and HPLC purification, the title compound was isolated with a radiochemical yield of 36% (EOB corrected) within 22 min; e.e. was shown >97% (n = 20); specific activity was ranging between 0.8 and 1.2 Ci (3045 GBq)/pmol EOB. Introduction The use of labeled r,-tryptophan in the study of the presynaptic serotoninergic neurotransmission process has not been very successful due to the important incorporation into proteins and to the very rapid formation of metabolites in the brain (Nagahiro et ul.. 1990). The a-methylated analogue of L-trypto- phan (r-MTryp) is converted in Go into z- methylserotonin, a false neurotransmitter which is not substrate for MAO and thus accumulates in the brain tissue (Diksic ef al., 1990). Furthermore, < 3% of !x-MTryp is incorporated into brain proteins (Dik- sic ef a/., 1990). These considerations indicate that r-MTryp must be considered as an interesting poten- tial radiopharmaceutical candidate. A different approach from the one reported by Chaly and Diksic (1988) and by Suehiro et al. (1992) is proposed for the synthesis of ~-(a- [“Clmethyl)-tryptophan. N,-Methoxycarbonyl-(S)- tryptophan methyl ester cychzed with 85% phosphoric acid gives (2S,3aR,8aS)-1,2-bis(methoxy- carbonyl) - I ,2,3,3a,8,8a - hexahydropyrrolo[2,3 - b]in - dole which on reaction with benzenesulfonyl chloride leads to (2S,3aR,8aS)-I,2-bis(methoxycarbonyl)- 8-(benzenesulfonyl)-1,2,3,3a,8,8a-hexahydropyrrolo- [2,3-b]-indole (1) (Bourne et al., 1991). Treatment of this protected L-(S)-tryptophan derivative (1) with lithium diisonropylamide at low temperature fol- lowed by reaction with methyl iodide results in alkylation, with retention of configuration, at C-2 of *Part of this work was presented at the Tenth Infernational Sy mposium on Radiopharmaceulical Chemistry 25- 28 October 1993, Kyoto, Japan, paper III-12 (oral presen- tation). the pyrroloindole system (Bourne et al., 1991). This procedure (illustrated in Scheme I), which was devel- oped for the rapid radiosynthesis of L-([z-“Cl- methyl)-tryptophan, is similar to that recently re- ported by Venkatachalam et al. (1993) for the label- ling of cc-MTryp with 14C and ‘H. Radiosynthesis Experimental [“C]CH,I (Comar et al., 1974) was trapped directly in a cold THF solution (- 78°C. 300 pL) of enolate generated in situ (10 min in advance), by treatment of 1 (4mg, 0.01 mmol) with LDA (freshly prepared 0.2 M solution in THF, 50 p L). The alkylation reac- tion was allowed to proceed for about 5 min at -78 C after which the THF was evaporated with a nitrogen stream. The reaction mixture was then hy- drolyzed with 57% HI (500 pL) at 200‘C for 5 min in a closed vial. After reaction, the vial was cooled off with running water and the residue partially neutral- ized with 6 N sodium hydroxide (350 p L) and directly injected onto the HPLC column [Partisil ODS 3 (500 x IOmm, Whatman) eluted with EtOH (5%)/0.05 M HOAc at pH 4 (95%) flow rate 9mL/min, retention time 9 min; U.V. detection at 254 nm and NaI (Tl) scintillation detector]. The final formulation consisted of isotonicity adjustment with NaCl followed by 0.22 pm membrane filtration. Enantiomeric purity The enantiomeric purity was measured with HPLC by ligand exchange chromatography on a Chiral Pro = Si 100 column (250 x 4.6 mm, 5 pm, Serva), flow rate: 1.5 mL/min; solvent: 50 mM KH,PO,, 651