Development of new precursors for asymmetric preparation of α-[11C]methyl amino acids for PET

Alexander Popkov

Research output: ThesisThesis fully internal (DIV)

2926 Downloads (Pure)


Positron emission tomography (PET) utilises positron emitting radiopharmaceuticals in the study of metabolic and physiological processes. After the injection of a carbon-11 or fluorine-18 labelled tracer, the space- and time-resolved image of positron annihilations is detected externally using rings of coincidence detectors placed around the subject (a PET scanner). New tomographs allow simultaneously recording of both CT or MRI and PET providing both anatomical information from CT (or MRI) and functionality from PET. PET investigations using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) become available in a large number of hospitals worldwide. FDG-PET is a useful technique for tumour detection, diagnosis of tumour recurrence.However, FDG has disadvantages. It is not only taken up by tumours, but also in the heart and the brain. This phenomenon hampers detection of tumours in these tissues. High physiological FDG uptake can be seen in muscle tissue, macrophages and other cells in inflammatory processes or activated after chemotherapy or radiation therapy causing false positive results. Decreased uptake can cause false negative results in patients with hyperglycaemia.More specific tracers are therefore being developed. The incorporation of labelled amino acids into brain tumours and into some other organ with high physiological consumption of glucose is the superior diagnostic method for its much higher selectivity compared to FDG. The first synthesis of an [11C]amino acid was published in 1973. Enantiomerically pure [11C]amino acids with exception of [11C]methionine are not yet available for routine PET diagnostics. Low availability hampers their evaluation as biological probes. Enantioselective synthesis of large aromatic α-[11C]methyl-α-amino acids by α-methylation of amino acids derivatives is an especially challenging goal due to relatively low steric volume of the methylation agent (methyliodide or methyltriflate). On the other hand, availability of both 11СH3I and 11СH3OSO3CF3 as starting materials makes the synthesis and disclosure of α-[11C]methylaminoacids diagnostic impact especially attractive for future routine application in PET diagnostics. Each large aromatic α-[11C]methyl amino acid has specific (potential) advantage based on its metabolic behaviour. In vivo, α-[11C]methyltryptophan is converted to the corresponding 5-hydroxyderivative followed by decarboxylation to α-[11C]methylserotonin. For this reason it is very useful for quantitative measurement of serotonin biosynthesis. Unlabelled α-MeTyr is routinely used for pre-surgery treatment of pacients with pheochromocytomas due to its high accumulation in this tumour followed by competitive suppression of uptake of tyrosine leading to lower biosynthesis of catecholamines. Thus α-[11C]MeTyr could be useful for diagnostics of pheochromocytomas, similar to application of fluorine-18 labelled α-MeTyr and the SPECT radiotracer 123I-IMT. This compound is not decarboxylated in vivo thus being a promising radiodiagnostic drug candidate for measurement of LAT expression in tumour cell membranes. Similarly to widely used FDOPA and ß-[11C]DOPA, α-[11C]MeDOPA may be applied for diagnostics of other neuroendocrine tumours and visualisation and possibly quantification of dopamine metabolism in the brain. Application of nickel(II) complexes BPB and α-amino acids for asymmetric synthesis of α-amino acids becomes a popular synthetic method due to cheap starting compounds, easy chromatographic detection of starting and alkylated complexes and re-usage of BPB without loss of enantiomeric purity of its stereogenic centre after several turnovers. The complexes provide easy generation of an intermediate carbanion due to high acidity of α-hydrogen of an amino acid fragment (pKa ≈ 19). The main aims of the work presented in this thesis are: 1. to increase stereochemical output of alkylation of the chiral nickel complexes derived from amino acids in order to avoid or at least simplify separation of diastereomeric products of alkylation; 2. to develop a new approach to create a quaternary asymmetric centre via alkylation of a chiral tertiary carbanion by 11CH3I or 11CH3OTf and evaluate the applicability of metallocomplex chiral synthons of α-amino acids for asymmetric synthesis of 11C-labeled α-methyl amino acids. Proximity of ortho-protons of the benzyl group to both the α-proton of the proline residue and substituents in α-position of the amino acid fragment in CDCl3 solution of the simplest studied complex led to formulation of the first hypothesis about structure of the improved synthon providing higher asymmetric induction. It should carry substituents in ortho-positions of the benzyl group. The donation of electron density from the π-system of the benzyl ring to nickel orbitals should influence the stereochemical result of alkylation of the complexes under thermodynamically controlled conditions. Replacement of the N-benzyl group by an polyalkyl-substituted benzyl group should also result in steric hindrance of 'ring-edge' bonding (between the η2-bonded aromatic ring and the metal atom), compared to 'ring-centre' bonding where the polyalkyl-substituted benzyl group is a η6-ligand. The polyalkyl-substituted benzyl group may also increase steric hindrance with respect to alkylation of the α-carbon of the glycine or the alanine fragment, thereby enhancing the diastereoselectivity of the reaction. X-Ray charge density studies of the Ni(II) complex of the Schiff base of BPB proved an interaction between Ni2+(dz2) orbital and benzyl π-electron density. Due to occupation of the dz2 orbital with two electrons no donation of electron density from the π-system of the benzyl ring to nickel orbitals is possible. Instead, polarisation of the π-system of the benzyl ring by a positive charge of the nickel atom leads to electrostatic attraction between the benzyl group and the nickel atom. Introduction of -C(CH3)3 substituents in meta-positions of the benzyl group or use the pentamethylbenzyl group in Ni(II) complexes of Schiff bases of (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide and glycine and alanine gave very efficient synthons of glycine and alanine capable of stereospecific preparation of α-monosubstituted glycines or highly stereoselective synthesis of α-methyl α-amino acids. A synthetic procedure suitable for the routine preparation of (S)-α-[11C]methylDOPA and (S)-α-[11C]methyltyrosine was developed, final radiochemical synthetic steps are now being optimised. Search for a suitable protective group for the indole nitrogen atom of similar tryptophan synthon for the preparation of enantiomers of α-[11C]methyltryptophan and, in the case of success, for preparation of enantiomers of α-[11C]methyl-5-hydroxytryptophan, is in progress. Preparation of the complexes was optimised with respect to minimisation of amount of nickel compounds in waste water.
Original languageEnglish
QualificationDoctor of Philosophy
  • Dierckx, Rudi, Supervisor
  • Elsinga, Philip, Supervisor
Award date3-Jan-0001
Place of PublicationGroningen
Publication statusPublished - 2008

Cite this