PET Call: Development Of Quantitative CNS PET Imaging Probes For The Glutamate and GABA Systems

Lead Research Organisation: King's College London
Department Name: Neuroimaging

Abstract

Positron Emission Tomography: antimatter in the clinic:
Today, it is accepted that all subatomic particles have a "mirror" or antimatter counterpart with opposite charge and spin. Our understanding of particles and forces - the fundamental building blocks of the Universe - is built on these kinds of symmetries, which arise naturally out of the powerful framework of quantum mechanics. The positron is one such antimatter particle being the dark twin of the electron. Predicted by Dirac's equations, its existence was confirmed when discovered in cosmic rays using a cloud chamber, in 1932 by Carl Anderson at the California Institute of Technology.
Antimatter annihilation provides one of the main imaging techniques used in hospitals today. Positron emission tomography (PET) relies on short-lived positron-emitting isotopes (of carbon, oxygen, nitrogen and fluorine) which act as tracers when incorporated into selected pharmaceuticals introduced into the body. A pair of gamma-rays at 180 degree angle is emitted as the positrons emitted, once travelled a short distance (<1mm) annihilate as they come into contact with tissues and are detected by a surrounding position-sensitive detector array (largely developed as a spin-off from high-energy physics and astronomy research). The signals are used to construct a series of visual "slices" through the body that are then combined into a 3-D image.
Biological functions such as blood flow, tumour growth and the action of drugs in the body can be followed using PET scans. It has been very successful at imaging brain structure and activity. Although the images are not as detailed as those from CT or magnetic resonance imaging (MRI) scans, they can measure biomolecular changes in a quantitative way. Improvements in PET scans have allowed physiological changes to be followed such as those that occur in Alzheimer's disease. PET is also used to provide fast and accurate 3-D images of tumours to see response to treatment and allow radiotherapy planning.
Measuring the Brain:
PET is a booming field but also a very complex one; full use of the technology requires knowledge of physics, radiochemistry, pharmacology, biology and mathematics. Large steps have been made by UK universities to train people that can then be employed in research and industry in this area. This proposal wants to move this process one step further, providing integrative training to brilliant minds and enable them to work through the whole array of technologies involved in the development of a PET tracer. To achieve this we focus on a particular area of PET research that is the development of PET radiotracers that can measure the activity of the two most important neurotransmitters of the brain, Glutamate and GABA. The trainees will have the opportunity to train and operate in a unique international environment and interact with the best researchers in this area in academia and industry.

Technical Summary

Our interpretation of this specialist training call is that in the UK there is a primary unmet need for PET scientists who can design, develop, evaluate and interpret new PET probes for CNS imaging. The paradigmatic example is the lack of availability of PET radiotracers for the GABAergic and Glutamatergic systems that have been strongly implicated in many CNS disorders so that they are now primary targets for therapeutic strategies. Consequently, the primary deliverable of this proposal is to generate, through a novel integrative approach to training, talent that can think, communicate, innovate and make a tangible impact in this interdisciplinary field. The existence in the UK of cross-disciplinary post-doctoral programs has created a substantial pool of young talent with problem solving abilities in this area. We will select candidates with a core competency in a chemical or biological discipline and take them through 6 months of foundation training that will cover the basic aspects of radiochemistry/pharmacology/quantitative modelling/methodology that are relevant to the modern PET scientist. Core skills will then be expanded with 'on the job' training while performing longer projects in collaboration with our research partners (Karolinska, Toronto, Imanova, GE-Healthcare, Lilly).
The second aim of this proposal, is to synergize the talent elicited by this training program with the partners' research activities and bring into man and disease cohorts at least two new PET radioligands to be chosen from [18F]GE-179 (NMDA), [11C]ABP688 and [18F]FPEB (mGlur5), [11C]MMTP (mGlur1), [11C]CMGDE (mGlur2/3), [11C]Zolpidem (GABAA) and [11C]BU99008 (GABAB). These tracers are planned to be used in the investigation of CNS disorders such as psychosis, autism, addiction and epilepsy by the collaborating clinical partners. These parallel pre-clinical/clinical streams will give the opportunity to the trainees to develop independent projects of great value and impact.

Planned Impact

Beneficiaries:

This MRC call aims to create a pool of young talent with specialist knowledge in Positron Emission Tomography (PET) and its application to disorders of the central nervous system. As such the call is naturally designed to benefit:
- All those academic research centres that are active in PET brain research
- The National Health Service where PET is used as a diagnostic tool
- Research Councils and Government Agencies that are concerned with the Mental Health of the Nation
- The wider public (e.g. those who have Mental Health problems or support, either personally or though charity work someone who does).
- Industrial entities that are active in PET technology (e.g. manufacturers of PET related equipment, manufacturers of radiotracers)
- Industrial entities that use PET in their developmental pipeline (e.g. Pharma)

How this research will contribute to the nation's health, wealth or culture:

The two main outcomes of this proposal (trained personnel in CNS PET applications and novel technology to assay the GABA and Glutamate systems) will impact significantly the efficiency and speed of the developmental pipeline of drugs that aim at modifying disease progression during the earlier preclinical and clinical periods and, ultimately, enable these therapies to be directed at individuals in the preclinical phase of illness to prevent or slow the onset of clinical manifestations of disease. These outcomes will therefore expand the UK neuro-pharmacological toolbox and contribute to the UK leadership in such a competitive international sector of importance for our economy.

Time-horizon:
In the short-term the areas that will benefit more are those that are explicitly linked to this proposal (addiction, autism, schizophrenia, epilepsy). In the medium term it is to be expected that this would be extended to disorders where GABA and Glutamate are known to play a role (depression, Parkinson's disease). Longer term, a deeper understanding of GABA and Glutamate biology will widen our understanding of brain function. These newer frontiers in Neuroscience have great potential to fascinate experts and public alike, fostering greater interest in brain research and attracting new talent to the field.

Publications

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Albrecht DS (2018) Pseudoreference Regions for Glial Imaging with C-PBR28: Investigation in 2 Clinical Cohorts. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

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Anders DA (2017) Electrochemical [C]CO to [C]CO conversion for PET imaging. in Chemical communications (Cambridge, England)

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Bongarzone S (2017) From [C]CO to [C]amides: a rapid one-pot synthesis via the Mitsunobu reaction. in Chemical communications (Cambridge, England)

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Downey J (2018) In-loop flow [ C]CO fixation and radiosynthesis of N,N'-[ C]dibenzylurea. in Journal of labelled compounds & radiopharmaceuticals

 
Title Neuroscience and Graphic Design 
Description This is a digital image library to improve peer-to-peer scientific graphical communication 
Type Of Art Artefact (including digital) 
Year Produced 2017 
Impact Linked to this initiative we organised a set of workshop to improve the creation of scientific and conceptual figures. A description of the event is reported here: https://neuroscience-graphicdesign.com/workshops/ 
URL https://neuroscience-graphicdesign.com
 
Description In Vivo training award
Amount £5,000 (GBP)
Organisation British Association for Psychopharmacology 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2017
 
Description Computational simulation of ligands able to bind Metabotropic glutamate receptor 1. 
Organisation University of Bologna
Department Department of Pharmacy and Biotechnology (FaBiT)
Country Italy 
Sector Academic/University 
PI Contribution Design of a virtual library of small compounds (100 molecules) able to bind the mGluR1.
Collaborator Contribution Computational docking simulation of a virtual library of small compounds able to bind the mGluR1. Analysis and scoring of the molecules.
Impact Selection of three molecules that will be synthesized and tested in vitro.
Start Year 2015
 
Description GE collaboration on synthesis of NMDA receptor ligand GE179 
Organisation GE Healthcare Limited
Country United Kingdom 
Sector Private 
PI Contribution Development of an improved synthetic procedure for synthesising the NMDA receptor ligand GE179
Collaborator Contribution expertiese on the GE179 molecule. Contribution to equipment required for radiolabelling and analysis
Impact abstract for UK PET Chemistry and EANM in preparation
Start Year 2015
 
Description KCL Molecular Neuroimaging YouTube Channel 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We have created a YouTube channel where we have installed a series of introductory lectures as well as short pieces presenting to the interested public our research work
Year(s) Of Engagement Activity 2017,2018
URL https://www.youtube.com/channel/UCCu_TK13NmIU8LXIFj_XU7A