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001027698 0247_ $$2ISSN$$a1872-9614
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001027698 1001_ $$0P:(DE-Juel1)178654$$aKolks, Niklas$$b0$$eCorresponding author$$ufzj
001027698 1112_ $$a24th International Symposium on Radiopharmaceutical Sciences$$cNantes$$d2022-05-29 - 2022-06-03$$gISRS2022$$wFrance
001027698 245__ $$aPreparation of 5-[18F],7-difluoro- and 5,7-[18F]difluorotryptophans
001027698 260__ $$c2022
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001027698 520__ $$aObjective: Tryptophan (Trp) is an essential proteinogenic aminoacid with an indole side chain that can serve as a precursor for differ-ent signaling molecules. The two main branches of Trp metabolism -serotonin/melatonin biosynthesis and the kynurenine pathway - aredifferentially altered in a variety of neurological, psychiatric andoncological diseases. Positron emission tomography (PET) withradiolabeled Trp analogs like 7-[ 18 F]Fluorotryptophan (7-[ 18 F]FTrp),which has been recently introduced and underwent first in-humanstudies, represents a promising approach for in vivo imaging of Trpmetabolism [1]. However, imaging probes capable of selectivelyvisualizing different Trp metabolic pathways are still lacking. Theobjective of this work was the preparation of 5-[ 18 F],7-difluoro- and5,7-[ 18 F]-difluorotryptophans ([ 18 F]1 and [ 18 F]2, respectively). 5-FTrpis known to be a good substrate of tryptophan hydroxylase (TPH), akey enzyme of serotonin/melatonin biosynthesis, which transforms5-FTrp into 5-HOTrp. Similarly, [ 18 F]1 should lose the 18 F-label dueto 5-hydroxylation by TPH and thus enable selective visualization of the kynurenine pathway. In contrast, [ 18 F]2 should target both mainbranches of Trp metabolism.Methods: The Ni-BPB-(S,S)-5-BPin-7-F- and -7-BPin-5-F-Trpprecursors (3, 4) were synthesized from 5-Br-7-F- and 7-Br-5-F-indoles, which were in turn prepared from 4-Br-2-F- and 2-Br-4-F-anilines. Miyaura borylation of these heterocylces furnished5-BPin-7-F- and 7-BPin-5-F-indoles, which were transformedinto N,N,N-(5-Bpin-7-F-indolyl)- and N,N,N-(7-Bpin-5-F-indolyl)-methyltrimethylammonium iodides using a Mannich type reactionfollowed by quaternization with MeI. Finally, alkylation of (S)-Ni-BPB-Gly with the quaternary methylammonium salt afforded the desiredradiolabeling precursors 3 and 4. The latter were 18 F-fluorinatedusing a modified protocol for alcohol-enhanced Cu-mediated radi-ofluorination [2, 3]. Accordingly, [ 18 F]F – was eluted from an anionexchange resin using Et 4 NOTf in MeOH, MeOH was evaporated, and asolution of the respective precursor and copper mediator in nBuOH/DMI (1:2) was added. After stirring of the reaction mixture at 110°Cfor 10 min under air, the radiolabeled intermediates Ni-BPB-(S,S)-5-[ 18 F],7-F 2 Trp ([ 18 F]5) or Ni-BPB-(S,S)-5,7-[ 18 F]-F 2 Trp ([ 18 F]6) were iso-lated by C 18 SPE and decomposed with 2 m HCl at 110°C for 10 min.Finally, HPLC purification and formulation yielded [ 18 F]1 and [ 18 F]2 asready-to-use solutions.Results: The precursors 3 and 4 were synthesized in 13% and 7%yield over 8 steps, respectively. [ 18 F]5 and [ 18 F]6 were prepared inyields of 77% (non-isolated, determined by HPLC). [ 18 F]1 and [ 18 F]2were produced within 68 min in isolated activity yields over twosteps of 35% and 33%, respectively, and in high radiochemical andchemical purities.Conclusion: 5-[ 18 F],7-difluoro- and 5,7-[ 18 F]-difluorotryptophanswere efficiently prepared using alcohol-enhanced Cu-mediatedradiofluorination and can now be subjected to biological evaluationas potential PET-probes for delineation of the main Trp metabolicpathways.Acknowledgements: This work was supported by the GermanResearch Foundation (DFG grants ZL 65/1-1 and ZL 65/3-1).References:[1] B. D. Zlatopolskiy et al.; J. Med. Chem., 2018, 61, 189.[2] A. Craig et al. Chem. Commun., 2020, 56, 9505-9508.[3] J. Zischler et al., Chem. Eur. J. 2017, 23, 3251.
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001027698 7001_ $$0P:(DE-Juel1)185610$$aZlatopolskiy, Boris$$b1$$ufzj
001027698 7001_ $$0P:(DE-Juel1)166419$$aNeumaier, Bernd$$b2$$ufzj
001027698 773__ $$0PERI:(DE-600)1498538-X$$a10.1016/S0969-8051(22)00110-X$$gVol. 108-109, p. S35 -$$x0969-8051$$y2022
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