A Vision of the FutureA Vision of the Future

Dr Alison MurrayDr Alison Murray

&&

Professor David WyperProfessor David Wyper

Our vision of the futureOur vision of the future

• Cutting edge imaging – equipment, techniques and people

• Attract inward investment

• Drugs and techniques to market faster

• Better outcomes for patients

• Molecular imaging in novel drug development in Alzheimer’s disease

• Multicentre stroke example

• Advanced imaging for early detection of brain disease

So what can we do now?So what can we do now?

RemberRemberTMTM in ADin AD

• Phase II clinical trial of novel drug in AD

• 138 patients with AD in 9 centres

• All imaging data transferred to Aberdeen for analysis

• Clinical outcomes - effect at 12 months

• Imaging biomarker (blood flow SPECT) -effect at 6 months

RemberRemberTMTM in ADin AD

TMRC acute stroke studyTMRC acute stroke study

• Aim – to identify brain that might be saved by “clot busting” drugs in patients following acute stroke

• 3 centres – Edinburgh, Glasgow, Aberdeen

• 2 modalities – CT and MRI within 6 hours of stroke

• Data on university and NHS networks so data transfer for analysis challenging

• CT perfusion data transferred from Edinburgh to Glasgow via the national PACS • Transferred from PACS to CT workstation and processed using Philip’s analysis software

TMRC acute stroke studyTMRC acute stroke study

Ageing brain cohortsAgeing brain cohorts

• Functional MRI– Memory and information

processing speed

• Early detection of brain failure – signal complexity

• Subtle differences on imaging that predate clinical onset of disease

Waiter GD et al. Neuroimage 2008; 41: 581-595 Roijals-Miras J, WIP

Sustainer Decliner

Hot topics in MRIHot topics in MRI

• Higher field strength – more detail

• Fast field cycling MRI – more information about different tissues

• Clever contrast agents – improved specificity

• Non-proton imaging – Xe, 13C

• Interventional MRI

• Hybrid imaging – PET MRI

Thanks to Scott Reid GE Healthcare, Patrick Revell Siemens, Annette Schmidt Philips

WhiteWhite matter tractsmatter tracts

Courtesy of NIHHigh resolution 7T brain imagingHigh resolution 7T brain imaging

PCR: posterior region of coronal radiata,SLF: superior longitudinal fasciculus

Diffusion tensor principle eigen vector (different subject) – high resolution white matter imaging

Images courtesy of NIH and Scott Reid at GE Healthcare

Fast fieldFast field--cycling MRIcycling MRI

• In “normal” MRI, the magnetic field B0 is fixed (and very stable)– e.g. 1.0 Tesla, 1.5 Tesla, 3.0 Tesla…

• In FFC-MRI the magnet is switched to different magnetic fields, during image acquisition

• This “unlocks” information about how tissues respond at different magnetic fields, leading to improved contrast between normal and diseased tissue– The new information relates particularly to protein

content, important in many diseases

Courtesy of Professor David Lurie, University of Aberdeen

Clever contrast agentsClever contrast agents

• Micro-engineered particles of gold-coated nickel discs with non-magnetic spacers• Magnetic field created between discs in opposition to external field• Coloured spectral signature produced – can probe various physiological properties• Analogous to quantum dots in optical spectrum

Zabow et al Nature 2008;453:1058-1063

First simultaneous MRI/PETFirst simultaneous MRI/PET

MRI

PET

MRI/PET

Schlemmer H-PW et al. Radiology 2008;248:1028-1035 Images courtesy of Dieter Heiss

The challengesThe challenges

• At present we are very few!

• A new way of working – communication

• Maximising grant income and research output – gaining recognition with funders, publishers and industry

• Maintaining clinical relevance – otherwise pointless

• Integration with the NHS

The NHS The NHS -- a research a research

imaging databaseimaging database

• NHS images acquired throughout Scotland will soon be networked by national PACS• Harmonise protocols across centres for common diseases• Enable images acquired for routine patient management to form useful research database

The NHS The NHS -- a research a research

imaging databaseimaging database

• NHS images acquired throughout Scotland will soon be networked by national PACS• Harmonise protocols across centres for common diseases• Enable images acquired for routine patient management to form useful research database

The NHS The NHS -- a research a research

imaging databaseimaging database

• NHS images acquired throughout Scotland will soon be networked by national PACS• Harmonise protocols across centres for common diseases• Enable images acquired for routine patient management to form useful research database

MOLECULAR IMAGING PETSPECT

1. Improvements in Physics

2. Improvements in Radio-chemistry

3. Cost effective drug discovery

4. Studying drug effects

A vision of the future: Molecular Imaging

A

B

The gain in Signal to Noise

30 cm patient with 600ps resolution - 1.8

40 cm patient with 600ps resolution - 2.1

40 cm patient with 30ps resolution - 9.4

Gain from 1.5Tesla to 3Tesla MRI ~ 1.7

A

B

The co-incidence window

•8-14 nano-seconds for conventional

PET

•600 pico-seconds currently available

for ToF PET

•30 pico-seconds needed to eliminate

back projection

Physics 1: Time of flight

Target molecules

Muscarinic receptors

Nicotinic receptors

Glutamate receptors

Serotonin transporters

Amino acid transport

Tk gene expression

Application

Dementia

Dementia

Stroke and schizophrenia

Clinical Depression

Cancer

Cancer

Chemistry 1: Novel tracers

Tracers produced to date by SINAPSE partners:

123I-Mk801 NMDA receptor

123I-CNS1261 NMDA receptor

123I-[R,S]QNB ACh muscarinic

123I-[R,R]QNB ACh muscarinic

123I-IBVM Vesicular ACh transporters

123I-betaCIT SERT & DAT

123I-IMT protein synthesis

123I-IUDR cell proliferation

123I-MIBG[nca] noradrenaline transporter

123I-FIAU TK gene expression

123I-5IA ACh nicotinic

Chemistry 1: Novel tracers

18F-FDG glucose metabolic rate

15O-Water blood flow

18F-Fluoride bone mineral turnover

13N-Ammonia myocardial perfusion

11C-Methionine protein synthesis

11C-Choline cell proliferation

11C-Raclopride D2 receptors

Neuropsychopharmacology. 2004 Jan;29(1):108-16.

Chemistry to develop precursor

Radio-labelling

In-vitro binding and displacement studies

Toxicology

Clinical application

GMP production

Chemistry 1: Stages in tracer development

In-vivo binding and displacement studies

The SINAPSE partners are already engaging with pharma on drug discovery

Fluoro-deoxy -glucose 11C-cocaine

The chemistry set

Chemistry 2: synthesis methods

11C

Microfluidics Speed

35 times faster than

conventional macrochemistry.

Synthesis times of 1 to 2

minutes

Multiple biomarker batches

produced from a single 18F batch

Efficiency

2.5 times greater yields and

lower reagent usage････

Chemistry 2: synthesis methods

Within SINAPSE we can explore these new technologies collectively

Drug Discovery

The problem

•15 years and $1Bn to get a drug to market

•Estimated savings of $30m from imaging

What molecular imaging can offer

•Drug delivery: Radio-labeling candidate drugs

•Patient selection: Cleaner smaller phase 3 trials

•Surrogate outcome assessment: To add precise biological component to clinical evaluation

•Occupancy measurement: To inform on dose levels

Degenerative parkinsonism

•Parkinson’s Disease (PD)

•Multiple System Atrophy

•Progressive Supranuclear Palsy

Pseudo parkinsonism

•Essential Tremor (ET)

•Drug-induced

•Dementia

Loss of dopamine producing

terminals in the putamenNo loss of dopamine producing

terminals in the putamen

Putamen

Caudate

Normal PD: H&Y1 PD: H&Y PD: H&Y3

Clinical applications

DaTSCAN

Patient selection Surrogate end points

Pre-synaptic terminal

Post-synaptic cell

Serotonin transporters

(SERT)

SynapseSerotonin reuptake

inhibitor (SSRI)

SPECT

Image of available

binding sites

Serotonin

Drug action

•The image on the left is a magnetic resonance scan showing

anatomy

•The other two images are SPECT scans showing tracer binding

to the target site for selective serotonin reuptake inhibitor

antidepressant drugs

Smaller drug effect

68% blocking of

serotonin reuptake

Large drug effect

- 96% blocking of

serotonin reuptake

Biol Psychiatry. 2006 Feb 15;59(4):301-8.

Drug action

A vision of the future

Nuclear Medicine

•SPECT

•PET

Nuclear Magnetic Resonance Imaging

•MRI

•DTI

•fMRI

•MRS

THE FUTURE IS UNCLEARNU

IMAGING