study of nucleophilic aromatic 18F-fluorination

230 Pages·2008·1.23 MB·English

Studies on the Nucleophilic Aromatic
18
F-Fluorination
- From Model Compounds to Aromatic Amino Acids -

Untersuchungen zur nucleophilen aromatischen
18
F-Fluorierung
- Von Modellverbindungen zu aromatischen Aminosäuren -

DISSERTATION

der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften

2008

vorgelegt von
Bin Shen
Tag der mündlichen Prüfung: 17. Dezember 2008
Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. H.-J. Machulla
2. Berichterstatter: Prof. Dr. K.-P. Zeller
Diese Arbeit entstand im Zeitraum vom Feb. 2005 bis Mai. 2008 in der Sektion
Radiopharmazie des Universitätsklinikums der Eberhard-Karls-Universität Tübingen
unter Anleitung von Herrn Prof. Dr. H.-J. Machulla.

Acknowledgements
At first, I would like to thank Prof. Dr. Hans-Jürgen Machulla for suggesting the
interesting subject of this thesis and for his constant guidance and support and in
every way for the excellent working conditions.
This work was finished by cooperation with Prof. Dr. Klaus-Peter Zeller. I would like
to thank for his steady and extensive support and his invaluable scientific assistance
and discussions.
Dr. Michael Übele I thank for many discussions and his helpful advice, in particular,
many thanks to Herren Dr. Roland Müller, Hans Bartholomä and Paul Schuler for
recording MS and NMR spectra.
For the almost daily production of [18F]fluoride ion, as well as excellent technical
supports, I sincerely thank Dr. Gerald Reischl, Anke Stahlschmidt, Matthias Kuntzsch,
Walter Ehrlichmann, Nadja Buckmüller, Denis Lamparter and Arzu Demir.
Adnan G. M. Al-Labadi, Uli Hagemann, Dirk Löffler, Dorothee Lutz, Noeen Malik and
Hans Jörg Rahm, I would like to thank them for many scientific as well as
non-scientific discussions and for the very pleasant atmosphere.
In general, I would like to thank all the people at Radiopharmacy PET Center, whose
vital support made the whole time so convenient and my work a great experience.

for Haiping Wang

I
Contents
1 INTRODUCTION........................................................................................1
1.1 BASIC ASPECTS OF POSITRON EMISSION TOMOGRAPHY (PET).....................................1
1.2 RADIONUCLIDES AND TRACERS FOR PET REGISTRATION............................................3
1.3 FLUORINE-18 AS A NUCLIDE FOR RADIOTRACERS........................................................4
1.3.1 Production pathway of fluorine-18....................................................................................6
1.3.2 Type of radiosyntheses and specific activity of the radioactive product...........................6
1.4 RADIOCHEMICAL SYNTHESES FOR INCORPORATING 18F INTO MOLECULES...................7
1.4.1 Electrophilic substitution...................................................................................................8
1.4.2 Nucleophilic substitution...................................................................................................9
1.4.2.1 Addition of a cation...............................................................................................................9
1.4.2.2 Water evaporation..................................................................................................................9
1.4.2.3 Addition of the precursor solution.......................................................................................10
1.4.3 Nucleophilic aromatic 18F-fluorination...........................................................................10
1.4.4 Indirect 18F-labeling method...........................................................................................11
1.5 AUTOMATIC TECHNOLOGY IN PET RADIOPHARMACEUTICALS..................................12
2 PROBLEM..................................................................................................14
3 RESULTS AND DISCUSSION.................................................................18
3.1 ORGANIC SYNTHESES OF PRECURSORS FOR MODELING 18F-LABELED
AROMATIC AMINO ACIDS...........................................................................................18
3.1.1 Model compounds as building blocks..............................................................................18
3.1.2 Model compounds with a methyl substituent...................................................................21
3.1.3 The other precursors for systematic study of S Ar reaction............................................26
N
3.1.3.1 Precursor with differentally-protected hydroxyl group........................................................26
3.1.3.2 Precursors with various numbers of methoxy substituents..................................................27
3.1.3.3 Precursors with two formyl substituents..............................................................................32
3.1.4 The precursors of [18F]fluoro-m-tyrosine containing protected
2-carboxy-2-aminoethyl substituents...............................................................................36
3.2 THE SYSTEMATIC STUDY ON THE NUCLEOPHILIC AROMATIC 18F-FLUORINATION.......39
3.2.1 The principle of nucleophilic aromatic substitution........................................................39
3.2.1.1 Substitution pattern effect on RCY in the case of nitrobenzene derivatives........................39
3.2.1.2 Formyl substituent as an EWG............................................................................................40
3.2.1.3 Effect by LG........................................................................................................................41
3.2.1.4 Solvent dependence.............................................................................................................42
II
3.2.1.5 Effects of [18F]nucleophile, concentration of precursor, temperature and reaction time.....48
3.2.1.6 Analytical assay of 18F-labeled product...............................................................................48
3.2.2 The effect of methoxy substituents on the S Ar reaction..................................................50
N
3.2.2.1 Selection of protective groups for the hydroxyl group........................................................50
3.2.2.2 Effect of methoxy groups....................................................................................................51
3.2.3 The effect of methyl substituent on S Ar reaction............................................................62
N
3.2.3.1 Dependence of RCY on LG.................................................................................................62
3.2.3.2 Influence of the methyl group..............................................................................................63
3.2.3.3 Attempts to improve the RCY of methyl-substituted precursors.........................................67
3.2.4 The effect of a second formyl substituent on the S Ar reaction.......................................70
N
3.2.4.1 Effect of a second formyl substituent on the maximum RCY.............................................70
3.2.4.2 Reaction Kinetics in 18F-labeling of dialdehydic compounds..............................................73
3.3 DECARBONYLATION OF THE 18F-LABELED BENZALDEHYDES.....................................76
3.3.1 Decarbonylation of model compounds with monoaldehydic substituent.........................76
3.3.1.1 Selection of catalyst.............................................................................................................77
3.3.1.2 Solvent dependence.............................................................................................................77
3.3.1.3 Influence of temperature......................................................................................................79
3.3.1.4 Effect of catalyst concentration...........................................................................................79
3.3.1.5 Decarbonylation of multiply-substituted model compounds under optimized condition....81
3.3.2 Decarbonylation of model compounds with dialdehydic functions.................................83
3.4 SYNTHESIS OF [18F]FLUORO-M-TYROSINE BY A NEW DEVELOPED STRATEGY............84
3.5 AUTOMATED SYNTHESIS OF N.C.A. [18F]FDOPA VIA NUCLEOPHILIC
AROMATIC SUBSTITUTION..........................................................................................88
3.5.1 Fluorination.....................................................................................................................92
3.5.2 Reductive iodination........................................................................................................93
3.5.3 Alkylation.........................................................................................................................94
3.5.4 Hydrolysis........................................................................................................................95
3.5.5 Overall synthesis..............................................................................................................96
4 SUMMARY.................................................................................................98
5 EXPERIMENTAL ...................................................................................102
5.1 GENERAL.................................................................................................................102
5.2 ORGANIC SYNTHESES OF PRECURSORS AND STANDARDS FOR SNAR WITH
[18F]FLUORIDE ION..................................................................................................104
5.2.1 Model compounds as building blocks for 18F-labeled aromatic amino acids...............104
5.2.1.1 4-Formylphenyl-trimethylammonium triflate (2-N+Me TfO-)..........................................104
3
5.2.1.2 5-Methoxy-2-nitrobenzaldehyde (3-NO )..........................................................................105
2
5.2.1.3 2-Chloro-5-methoxybenzaldehyde (3-Cl)..........................................................................106