This title appears in the Scientific Report :
2019
Please use the identifier:
http://hdl.handle.net/2128/22655 in citations.
Preparation of novel PET probes for the visualization of tryptophan metabolism in vivo
Preparation of novel PET probes for the visualization of tryptophan metabolism in vivo
The two precursors 5 and 6 for the radiolabeled FTrps [18F]1 and [18F]2 were prepared successfully. 5-AcO-7-BPin-Boc-OtBu-Trp (5) was obtained after the initial setback of the unsuccessful deborylation of 11 using Pd(OAc)2. After the 2,7-diborylation, the 2-deborylation was achieved using the Bi(OAc...
Saved in:
Personal Name(s): | Kolks, Niklas (Corresponding author) |
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Contributing Institute: |
Nuklearchemie; INM-5 |
Imprint: |
2019
|
Physical Description: |
102 p. |
Dissertation Note: |
Masterarbeit, Universität zu Köln, 2019 |
Document Type: |
Master Thesis |
Research Program: |
Neuroimaging |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
The two precursors 5 and 6 for the radiolabeled FTrps [18F]1 and [18F]2 were prepared successfully. 5-AcO-7-BPin-Boc-OtBu-Trp (5) was obtained after the initial setback of the unsuccessful deborylation of 11 using Pd(OAc)2. After the 2,7-diborylation, the 2-deborylation was achieved using the Bi(OAc)3 method, which required some maintenance and optimization, however. The optimum conditions for this reaction were found to be 2 h at 80 °C, resulting in a yield of 51% for the 7-monoborylated product. The total yield for 5-AcO-7-BPin-Boc-OtBu-Trp (5) was 9% over 5 steps. The reason for the stability of 11 to Pd(OAc)2 is still unknown.The synthesis of (S,S)-BPB-Ni(II)-NInMe-6-BPin-Trp (6) starting from 6-BPin-indole (16) was achieved with a total yield of 12%. The Nin-methylation in the last step improved the synthesis outcome compared to that starting from the Nin-methylated analogue of 18. The likely explanation for this is the difference between the substitution of the nitrogen in the transition states during alkylation as illustrated in 3.2. (Scheme 11).Obtaining the reference compounds proved more difficult than initially expected. Because original proposals to synthesize 5-HO-7-FTrp (25) was unsuccessful, an investigation into producing 5-HO-7-FTrp (25) by fluorination of the BPin-precursor 5 was performed. The 19F-NMR showed that a fluorine atom was present in the obtained product after a screening and the synthesis was successful and can be used to synthesize the desired reference compound.The initial attempt to prepare rac-N-methyl-6-fluorotryptophan (30) by methylation of intermediate 28 was not successful, because both nitrogen atoms in the structure were methylated. The alternate pathway to furnish the N-methyl-6-fluorotryptophan (30) using alkylation of (S)- and (R) [6 FTrpNi(II)BPB] [(S)-36, (R)-36] with triethylaminium iodide 35, however, successfully lead to (S)- and (R)-N-methyl-6-FTrp × HCl [(S)-40, (R)-40]. Using alcohol enhanced Cu-mediated radiofluorination, 18F-incorporation rates of 35% and 90% were observed for Boc-7-[18F]F-(5-AcO)-L-Trp-OtBu ([18F]41) and (S,S)-BPB-Ni(II)-NInMe-6-[18F]F-Trp ([18F]42), respectively. After hydrolysis of [18F]41, the obtained product was isolated by HPLC in an RCY of 6% over 2 steps. The product is expected to be 5-HO-7[18F]fluoro-L-tryptophan ([18F]1) but is unverified due to the lack of a reference compound at this point. The product obtained after hydrolysis of [18F]42 in an RCY of 16% over 2 steps could not be verified yet, either, but is presumed to be the successfully synthesized N-methyl-6-[18F]fluoro-L-tryptophan ([18F]2).The picolinic acid based [GlyNi(II)PBP] (44) was synthesized successfully in a yield of 89%. Unfortunately, owing to its low solubility it could not be used for synthesis of racemic amino acids. (S)-[GlyNi(II)(2-Cl-B)PB] (46) was obtained from N-(2-chlorobenzyl)-L-proline-benzophenone (45) in a yield of 50%. For the synthesis of α-methyl amino acids, the rac-[AlaNi(II)BPA] (49) was produced in a total yield of 12% after 5 steps. Three Ni(II)-BPB based precursors for radiolabeled phenylalanines ([2-, [3- and [4-BPin-PheNi(II)BPB] (53 - 55)) were prepared in single step syntheses with (S)-[GlyNi(II)BPB] [(S)-15] and 2-(2-, 2-(3- and 2-(4-(bromomethyl)phenyl)-BPin (50 - 52) in good yields of 73 - 86%.Finally, a group of novel Cu-mediators for use in radiofluorination was formulated. The synthesis of these proved robust and easily applicable to a number of Cu-salts and nitrogen heteroarenes. Reactions proceeded rapidly and all products precipitated almost quantitively, save for the quinoline derivatives that had to be crystallized from a large volume of Et2O. Spectroscopic analysis and investigation of the Cu-complexes for radiofluorination are currently underway. |