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Imaging Chemistry and Biology (pre-2019)

Novel 11C-methylation strategies and their application in CNS receptor imaging

Project ID: 2017_215

Student: Federico Luzi

1st supervisor: Tony Gee, King’s College London

The aim of the project is to develop novel and efficient carbon-11 labelling strategies for direct production of ‘in vial’ methylation agents for in situ labelling of PET molecular imaging agents. This new chemistry would obviate the need for expensive dedicated infrastructure and extended reaction processing times/reduced yields associated with current state-of-the art 11C-methylation approaches.

Key objectives:

  1. Develop direct CO2 in situ methylation methodology
  2. Apply and evaluate the novel labelling method on model substrates
  3. Demonstrate applicability to novel CNS radiotracers (e.g. RAGE)
  4. Evaluate the novel radiotracers in vitro and in vivo

Positron emission tomography (PET) imaging is a powerful tool for disease diagnosis, understanding in-vivo biomechanisms, and in drug discovery and development. PET Imaging probes are labelled with cyclotron-produced short-lived positron-emitting radionuclides (e.g. carbon-11 and fluorine-18, radioactive half-lives 20 min and 110 min, respectively) using a variety of labelling techniques. The vast majority of carbon-11 labelled PET imaging probes are synthesised by time consuming conversion of cyclotron produced carbon dioxide to methyl iodide and its subsequent alkylation reactions. This process, although extremely successful, relies on the use and maintenance of bespoke and expensive infrastructure and requires extended processing times with concomitant yield decreases, due to the short half-life of carbon-11. The project aims to develop a more time-efficient and cost effective method for 11C methylation generation as an attractive alternative to the current state of the art methods. This method, using readily available lab-ware, will be applied to proof of concept labelling of known model substrates (e.g. raclopride) and evaluated against the ‘standard’ current 11C labelling approaches. The novel radiochemistry will be applied to the development of CNS PET radiotracers for ‘RAGE’, an important emerging receptor target for the early detection of Alzheimer’s disease. This will involve a medicinal chemistry component to the studentship including some organic synthesis. The imaging properties of the radiolabelled compounds will be initially evaluated in vitro. Promising 11C-labelled compounds may be evaluated in vivo during the course of the project.

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