Substitutie reactie. + OH- + Br- Dept. of Nuclear Medicine & Molecular Imaging

Transcription

1 Substitutie reactie Br H + H- + Br- Dept. of uclear Medicine & Molecular Imaging 1

2 ucleofiele substitutie reacties - δ+ u + C - u L δ- - - C L u C + - L - u = F-, amines, phenolen, thiolen L = leaving group Dept. of uclear Medicine & Molecular Imaging 2

3 ucleofiele substituties R-L + R- + L in organische synthese H-/water Rhalides Camines thiolen Dept. of uclear Medicine & Molecular Imaging 3

4 Typische substitutiereacties in PET-chemie 11 CH 3 S CF 3 + H 11 CH F + S CH 3 18 F Dept. of uclear Medicine & Molecular Imaging 4

5 Radiofarmacon u L [ 18 F]FDG 18 F- Triflaat [ 18 F]FLT 18 F- osylaat [ 18 F]F-MIS 18 F- Tosylaat [ 11 C]Choline Amine Jodide [ 11 C]Raclopride Phenol Jodide [ 11 C]Methionine Thiol Jodide [ 11 C]Verapamil Amine Triflaat [ 11 C]Carvedilol Phenol Jodide Dept. of uclear Medicine & Molecular Imaging 5

6 ucleofielen H 2 amine H phenol SH thiol Dept. of uclear Medicine & Molecular Imaging 6

7 Afname nucleofiliciteit Afname basiciteit Afname nucleofiliciteit Afname basiciteit C 2 H 5 - H - C 6 H 5 - H 2 I - Br - Cl - F - Dept. of uclear Medicine & Molecular Imaging 7

8 Leaving groups R S CF 3 Triflate R S CH 3 Tosylate R S 2 osylate Dept. of uclear Medicine & Molecular Imaging 8

9 R-L + -> R- + L Rate = k [RL].[] 2 e orde kinetiek S 2 Rate = k [RL] 1 e orde kinetiek S 1 solvolyse Hoge concentratie [] gunstig voor S 2 Lage concentratie [] gunstig voor S 1 Hard/zacht nucleofiel Dept. of uclear Medicine & Molecular Imaging 9

10 Fluor-18 Bij 10 GBq is er 1,6 pmol fluor-18 Praktijk: Bij SA van 30 GBq/umol is er 0,33 μmol fluor Bij FDG wordt 42 μmol precursor gebruikt -> verhouding 1:127 Dept. of uclear Medicine & Molecular Imaging 10

11 Reactiecoordinaat en activeringsenergie S 2 S 1 Dept. of uclear Medicine & Molecular Imaging 11

12 S 2 neemt toe R-X = CH 3 X 1 o 2 o 3 o S 1 neemt toe Praktijk: CH 3 X, 1 o S 2 2 o mix 3 o S 1 Dept. of uclear Medicine & Molecular Imaging 12

13 Reactiviteit S1: bepalend is de stabiliteit van het carbokation allyl, benzyl>3 o >2 o >1 o tbubr iprbr EtBr MeBr S S 2 Dept. of uclear Medicine & Molecular Imaging 13

14 S 1 substitution nucleophilic unimolecular - racemisatie S 2 substitution nucleophilic bimolecular - inversie S 2 H- C 6 H 13 H Br C 6 H 13 H H Br H C 6 H 13 H CH 3 CH 3 CH 3 C 6 H 13 H H C 6 H 13 H inversie S 1 C 6 H 13 H Br CH 3 C 6 H 13 CH 3 CH 3 H H retentie H- CH 3 Dept. of uclear Medicine & Molecular Imaging 14

15 Carbocation - eliminatie CH 3 CH 3 CH 3 CH 3 CH 3 CH 2 Eliminatie 3 o > 2 o >1 o Dept. of uclear Medicine & Molecular Imaging 15

16 Substitutie vs eliminatie Toename eliminatie RX = 1 o 2 o 3 o Toename substitutie Dept. of uclear Medicine & Molecular Imaging 16

17 Invloed oplosmiddel (dielectrische constante) R-L -> [R + ---L - ] deze ladingsverdeling is stabieler in een polair oplosmiddel Effect polair oplosmiddel - + RL -> R- + L - (kleine vertraging) + RL -> R- + + L - (grote versnelling) - + RL + -> R- + L (grote vertraging) Dept. of uclear Medicine & Molecular Imaging 17

18 Aprotische polaire oplosmiddelen Vermijding solvatatie plosmiddel diel. const DMS 45 Acetonitril 38 DMF 37 HMPA 30 Aceton 23 THF 7 Dept. of uclear Medicine & Molecular Imaging 18

19 ucleofiele aromatische substitutie benzyn mechanisme -HCl H 2 Cl H H Dept. of uclear Medicine & Molecular Imaging 19

20 ucleofiele aromatische substitutie - additie-eliminatie S Ar Z Cl Z Cl Z Cl Z 2 plus resonantiestructuren Dept. of uclear Medicine & Molecular Imaging 20

21 Reactiviteit S Ar Electron zuigende groepen o,p van de leaving group 2 + Trimethylammonium 2 CF 3 Carbonyl Cyanide Halides S 3 - Effect leaving group: F > 2 > Ts > SPh > Cl, Br, I > R 3 + Effect nucleofiel correleert met base sterkte Dept. of uclear Medicine & Molecular Imaging 21

22 ucleofiele fluorideringen Electrofiel vs nucleofiel F- als nucleofiel en base Typische leaving groepen alifatisch vs aromatisch plosmiddelen Beschermgroepen Bespreking voorbeelden Eliminatie Dept. of uclear Medicine & Molecular Imaging 22

23 ucleofiel Electrofiel Fluoride Hoge Spec Act Alifatisch en aromatisch Fluor gas Lage Spec Act dubbele bindingen en aromaten Dept. of uclear Medicine & Molecular Imaging 23

24 Fluoride als nucleofiel en base Hoge concentratie: base eliminatie Lage concentratie: nucleofiel substitutie basiciteit wordt ook beinvloed door de hoeveelheid kaliumcarbonaat, bicarbonaat of oxalaat Dept. of uclear Medicine & Molecular Imaging 24

25 Type bereidingen van 18 F-tracers 1. Directe fluoridering 2. Directe fluoridering en ontscherming 3. Synthese 18 F-synthon gevolgd door koppeling aan precursor 4. Als 3. Gevolgd door ontscherming Dept. of uclear Medicine & Molecular Imaging 25

26 18 F-synthons 1. Fluoralkylhalides of sulfonylesters 2. Fluoraryl verbindingen 3. Fluor-aldehydes en ketones 4. Fluoracylhalides Dept. of uclear Medicine & Molecular Imaging 26

27 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) CH 2 Ac Ac Ac Tf 18 F - f l u o r i d e CH 2 Ac Ac Ac hydrolysis CH 2 H H H Ac Ac 18 F H 18 F Dept. of uclear Medicine & Molecular Imaging 27

28 DMBn DMBn DMTr Ms fluorination DMTr Ms=mesylate DMTr=dimethoxytrityl DMBn=dimethoxybenzyl 18 F deprotection H H 18 F FLT J.R. Grierson and A.F. Shields. Radiosynthesis of 3 -deoxy-3 -[F-18]fluorothymidine: [F-18]FLT for imaging of cellular proliferation in vivo (In press) Dept. of uclear Medicine & Molecular Imaging 28

29 Synthesis of [ 18 F]FE-SA 4503 and 5845 CH 3 R H 18 FCH 2 CH 2 Ts CH 3 R CH 2 CH 2 18 F R = H : FE-SA 4503 R = F : FE-SA 5845 Radiochemical yield: 4-7 % (EB) Synthesis time: 80 min Specific activity: > 100 TBq/mmol Dept. of uclear Medicine & Molecular Imaging 29

30 H 18 F H mono-substitution H H H 2 18 F H 18 H F H di-substitution H Dept. of uclear Medicine & Molecular Imaging 30

31 Most used labelling method is acylation of -terminus or Lys-amino group through [ 18 F]SFB -succinimidyl-4-[ 18 F]fluorobenzoate + Me 3 Et 18 F Et 18 F H 18 F Dept. of uclear Medicine & Molecular Imaging 31

32 Click chemistry: Huisgen 1,3-dipolar cycloaddition + Cu(I) Reactants are bio-orthogonal Dept. of uclear Medicine & Molecular Imaging 32

33 Comparison of synthesis of [ 18 F]peptides using SFB or through condensation reaction 18 F H 2 peptide 18 F peptide 18 F H H 2 H peptide 18 F H H peptide Poethko T, Schottelius M, Thumshirn G, Hersel U, Herz M, Henriksen G, Kessler H, Schwaiger M, Wester HJ [2004] J. ucl. Med. 45: Dept. of uclear Medicine & Molecular Imaging 33

34 Application of click chemistry in 18 F-labelling of peptides 3 peptide 3 peptide 18 F peptide 18 F Challenge: in vivo copper free click Dept. of uclear Medicine & Molecular Imaging 34

35 Copper Free Click Chemistry Alkyne Activation by Alternative Means: Electron Withdrawing power Strained Cyclic Systems Z. Li, T. Seo and J. Ju. Tetrahedron Lett., 2004, 45, J. Agard, J. A. Prescher and C. R. Bertozzi. J. Am. Chem. Soc., 2004, 126,

36 Strain-Promoted Copper-Free "Click" Chemistry for 18 F Radiolabeling of Bombesin. 18 F R 1 H H 18 F H R 3 15 min, r.t. DMF H R 1 H H R RCY= 19% Reaction time= 60min logp= SA= 62 GBq/µmol RCY= 37% Reaction time= 60min logp= 0.26 SA= 53 GBq/µmol Lachlan S. Campbell-Verduyn *, Leila Mirfeizi *, Anne K. Schoonen, Rudi A. Dierckx, Philip H. Elsinga, Ben L. Feringa. Angew. Chem. 2011,50,1 5

37 F-18-TA-Affibody Z HER2 ew approach, based on a chelator Current methods require azeotropic drying and are time-consuming. Metal-fluoride bond is an extremely strong chemical bond. Chelation of metal-fluoride in a TA-chelator Two-step one-pot reaction: 1. Prepare (Al 18 F) Add to TA-conjugated peptide McBride et al, J ucl Med 2009;50: Radboud University ijmegen Medical Center, The etherlands

38 Radiolabeling procedure TA-Z HER2 [ 18 F]aF AlCl 3 H H H ZHER2 Al 18 F 2+ sodium acetate, ph % MeC 15 min, 90 C - Al 18 F 2+ - H ZHER2 Radboud University ijmegen Medical Center, The etherlands

39 Conclusion Yield up to 95%. Specific activity 10,000-25,000 GBq/mmol Fast method: 45 min (o need for azeotropic drying). Radboud University ijmegen Medical Center, The etherlands

40 eliminaties fluoride Ts fluoride CH 2 Ts Dept. of uclear Medicine & Molecular Imaging 40