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Smart Imaging Probes

A new radiolabelling paradigm for the preparation of 11C-labelled amino acids

Project ID: 2022_041

1st Supervisor: Prof Tony Gee, King’s College London
2nd Supervisor: Dr Philip Miller, Imperial College London
Clinical supervisor: Dr Paul Edison, Imperial College London

Aim of the PhD Project:

  • To enable the 11C-labelling of amino acids with high stereoselectivity, radiochemical yield and in short reaction times.  
  • To develop shelf-stable amino acid-palladium complex precursors that will react with 11CH3I and 11CO in order to rapidly generate 11C-amino acids. 
  • To measure the efficiency and expand the capability of this labelling process to a range of natural and unnatural amino acids, and peptides.

Project description/background:

Natural amino acids, the building blocks of peptides and proteins, are fundamental to almost all biological processes (e.g. protein synthesis, cell signalling, neurotransmission etc.).  The role of amino acids in specific transport systems, signalling and their uptake in many biological processes have led to the development of a range of amino acid imaging probes.[1]  Radiolabelled amino acids and peptides have a long and varied history of applications for nuclear imaging.  Labelled amino acids have been most widely used as ligands for a imaging a range of cancers (e.g. [11C]methionine for glioblastoma) and neurological conditions (e.g. [18F]DOPA for Parkinson’s).[1,2]  Despite their simple chemical structures, amino acids can be highly challenging to radiolabel.[1]  This is in part due to the low reactivities of labelling precursors, the need for stereoselectivity and issues with purification.  To date, the most common approach for the preparation of 11C amino acids has been via the Strecker reaction using [11C]HCN, however, the preparation and maintenance of [11C]HCN labelling units is fraught with challenges.  This project aims to develop a new labelling paradigm that will enable access to a range of natural and unnatural 11C-amino acids using the common 11C-labelling precursors 11CH3I and 11CO.   

Our group has recently developed a variety of novel amino acid functionalised Pd complexes that are capable of intramolecular C-H activation processes and the coupling of organohalides (figure 1).  These complexes are air and moisture stable, yet they are reactive enough to undergo fast and selective reactions with alkyl halides when heated.  This project will investigate the scope of these amino acid functionalised Pd complexes for 11CH3I and 11CO labelling reactions.  It is anticipated that such ‘preformed’ Pd complexes could provide convenient precursors for a simple one-pot labelling process to a range of 11C-labelled amino acids.   Our complexes are based on a picolinic acid group that is attached to the amino acid via an amide bond.  This group acts as a chelator, coordinating to the Pd centre forming a five-membered ring.  The Pd centre is then able to facilitate the selective C-H activation of the gamma-position of the amino acid for further functionalisation with appropriate electrophiles (e.g. alkyl halides and carbonyls).  Once reacted, the picolinic acid group, and other protecting groups, can be easily removed via acid deprotection.  To date, we have prepared and fully characterised >10 Pd dimers complexes and conducted preliminary stoichiometric reactions with alkyl halides.  One of our goals in this project therefore is to translate this work to a radiolabelling setting for the facile generation of 11C-amino acids.  Building on this, this project will explore the labelling of unnatural amino acids and small molecule peptides.   

The candidate for this position should have a strong background in synthetic organic or inorganic chemistry and desirably some experience working with short-lived radionuclides.

References 

  1. A. Pekošak, U. Filp, A. J. Poot, A. D. WindhorstMol. Imaging Biol. (2018) 20:510532
  2. A. Sun, X. Liu and G. Tang(2018) Front. Chem. 5:124 

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